Co-reporter:Yanzhou Chang, Lizhen He, Zhibin Li, Lilan Zeng, Zhenhuan Song, Penghui Li, Leung Chan, Yuanyuan You, Xue-Feng Yu, Paul K. Chu, and Tianfeng Chen
ACS Nano May 23, 2017 Volume 11(Issue 5) pp:4848-4848
Publication Date(Web):May 1, 2017
DOI:10.1021/acsnano.7b01346
Radiotherapy is an important regime for treating malignant tumors. There is interest in the development of radiosensitizers to increase the local treatment efficacy under a relatively low and safe radiation dose. In this study, we designed Au@Se-R/A nanocomposites (Au@Se-R/A NCs) as nano-radiosensitizer to realize synergistic radiochemotherapy based on the radiotherapy sensitization property of Au nanorods (NRs) and antitumor activity of Se NPs. In vitro studies show that the combined treatment of A375 melanoma cells in culture with NCs and X-ray induces cell apoptosis through alteration in expression of p53 and DNA-damaging genes and triggers intracellular ROS overproduction, leading to greatly enhanced anticancer efficacy. Further studies using clinically used radiotherapy equipment demonstrate that the combined treatment of NCs and X-ray significantly inhibits the tumor growth in vivo and shows negligible acute toxicity to the major organs. Taken together, this study provides a strategy for clinical translation application of nanomedicne in cancer radiochemotherapy.Keywords: cancer therapy; nanocomposites; radiochemotherapy; radiosentization; targeting;
Co-reporter:Chang Liu, Yuanting Fu, Chang-e Li, Tianfeng Chen, and Xiaoling Li
Journal of Agricultural and Food Chemistry June 7, 2017 Volume 65(Issue 22) pp:4405-4405
Publication Date(Web):May 16, 2017
DOI:10.1021/acs.jafc.7b00896
Accumulation of palmitic acid (PA) in human bodies could cause damage to pancreatic β cells and lead to chronic diseases by generation of reactive oxygen species (ROS). Therefore, it is of great significance to search for nutrition-available agents with antioxidant activity to protect pancreatic islet cells against PA-induced damage. Phycocyanin (PC) and selenium (Se) have been reported to have excellent antioxidant activity. In this study, PC-functionalized selenium nanoparticles (PC-SeNPs) were synthesized to investigate the in vitro protective effects on INS-1E rat insulinoma β cells against PA-induced cell death. A potent protective effect was achieved by regulation of particle size and PC content. Among three PC-SeNPs (165, 235, and 371 nm), PC-SeNPs-235 nm showed the highest cellular uptake and the best protective activities. For cell cycle analysis, PC-SeNPs showed a better protective effect on PA-induced INS-1E cell apoptosis than PC or SeNPs, and PC-SeNPs-235 nm exhibited the best effect. Further mechanistic studies demonstrated that PA induced overproduction of intracellular ROS, mitochondria fragmentation, activation of caspase-3, -8, and -9, and cleavage of PARP. However, pretreatment of the cells with PC-SeNPs effectively blocked these intracellular events, which suggests that PC-SeNPs could protect INS-1E cells against PA-induced cell apoptosis via attenuating oxidative stress and downstream signaling pathways. This finding provides a great promising nutritional approach for protection against diseases related to islet damage.Keywords: antioxidant activities; oxidative stress; palmitic acid (PA); PC-functionalized selenium nanoparticles (PC-SeNPs);
Co-reporter:Lina Xie;Zuandi Luo;Zhennan Zhao
Journal of Medicinal Chemistry January 12, 2017 Volume 60(Issue 1) pp:202-214
Publication Date(Web):December 7, 2016
DOI:10.1021/acs.jmedchem.6b00917
Thioredoxin reductase (TrxR) is a selenoenzyme that could regulate intracellular oxidative balance and found to be overexpressed in many human tumor cells. Due to its important role in cancer progression, TrxR is becoming an attractive target in chemotherapeutic drug design. In this study, a new class of Fe(II) complexes with phenanthroline derivatives as ligands were synthesized and characterized. The mechanism of cell death induced by complex 3 revealed that the growth of cancer cells was suppressed by apoptosis and specifically inhibited the activities of TrxR. Furthermore, complex 3 exhibited brilliant antiangiogenic activity against HUVEC cells and inhibited cell migration and invasion. In addition, results of hematological analysis and H&E staining demonstrated that complex 3 has negligible toxicity on function of the major organs of mice. Taken together, this study provides a strategy for drug design to exploit Fe-based phenanthroline derivative as a chemotherapeutic agent in cancer treatment.
Co-reporter:Yahui Yang, Qiang Xie, Zhennan Zhao, Lizhen He, Leung Chan, Yingxiang Liu, Yongle Chen, Mingjun Bai, Tao Pan, Yanni Qu, Long Ling, and Tianfeng Chen
ACS Applied Materials & Interfaces August 9, 2017 Volume 9(Issue 31) pp:25857-25857
Publication Date(Web):July 18, 2017
DOI:10.1021/acsami.7b07167
Although radiotherapy has been extensively applied in cancer treatment, external beam radiation therapy is still unable to avoid damage to adjacent normal tissues in the process of delivering a sufficient radiation dose to the tumor sites of patients. To overcome this limitation, chemoradiotherapy, as a combination of chemotherapy and radiotherapy of a radioactive seed, has been proposed to decrease the damage to tumor-surrounding tissues and enhance the radiosensitivity of solid tumors. In this study, we designed and synthesized folic acid-conjugated selenium nanoparticles (FA@SeNPs) as a cancer-targeting agent that could be synergistically enhanced by radioactive 125I seeds to realize anticancer efficacy and inhibited colony formation ability. Interestingly, when compared with X-ray irradiation, 125I seeds demonstrate a larger synergistic effect with the FA@SeNPs, drastically increasing reactive oxygen species overproduction to trigger apoptosis and influencing the cell cycle distribution in human breast cancer cells, inducing DNA damage and activating the mitogen-activated protein kinase and p53 signaling pathways. Moreover, this combination treatment demonstrates better in vivo antitumor activity and lower systemic toxicity. Therefore, this study demonstrates a new strategy for using functionalized SeNPs as a radiation sensitizer for 125I seeds for cancer therapy.Keywords: 125I seeded irradiation; apoptosis; chemoradiotherapy; radiation sensitizer; selenium nanoparticle;
Co-reporter:Ping Wu;Siyuan Liu;Jianyu Su;Jianping Chen;Lin Li;Runguang Zhang
Food & Function (2010-Present) 2017 vol. 8(Issue 10) pp:3707-3722
Publication Date(Web):2017/10/18
DOI:10.1039/C7FO00778G
Cancer cells are well known to require a constant supply of protein, lipid, RNA, and DNA via altered metabolism for accelerated cell proliferation. Targeting metabolic pathways is, therefore, a promising therapeutic strategy for cancers. Isoquercitrin (ISO) is widely distributed in dietary and medicinal plants and displays selective cytotoxicity to cancer cells, primarily by inducing apoptosis and cell cycle arrest. The aims of this study were to find out whether ISO could stabilize in a bladder-like acidic environment and inhibit bladder cancer cell proliferation by affecting their metabolism, and to investigate its molecular mechanism. In this study, the exposure of T24 bladder cancer cells to ISO (20–80 μM) decreased cell viability by causing ROS overproduction. This ROS change regulated the AMPK signaling pathway, and caused Caspase-dependent apoptosis as well as metabolism dysfunction. Metabolic alterations elevated metabolic pathway variation, which in turn destabilized lipid synthesis and altered anaerobic glycolysis. This linkage was proved by immunoblotting assay, and metabolomics as identified by UHPLC-QTOF-MS. Our findings provide comprehensive evidence that ISO influenced T24 bladder cancer cell metabolism, and that this process was mainly involved in activating the AMPK pathway. This study could lead to an understanding of how ISO suppresses bladder cancer cell growth, and whether the affected cancer metabolism is a common mechanism by which nutritional compounds suppress cancers.
Co-reporter:Shulin Deng;Delong Zeng;Yi Luo;Jianfu Zhao;Xiaoling Li;Zhennan Zhao
RSC Advances (2011-Present) 2017 vol. 7(Issue 27) pp:16721-16729
Publication Date(Web):2017/03/14
DOI:10.1039/C6RA28801D
Serum albumin is an important carrier in the transport of endogenous and exogenous substances across cell membranes. Small molecule drugs could bind to serum albumin to various extents after intravenous injection, which may affect the bioavailability, metabolism, pharmacological and toxicological potency. Organic selenium (Se) compounds exhibit favorable biocompatibility and low toxicity that attracts increased attention from researchers. Herein, a series of selenadiazole derivatives (4a–e) have been synthesized and their cytotoxicity towards various kinds of cells were evaluated. The results suggested that isopropyl benzo[c][1,2,5]selenadiazole-5-carboxylate (4d) exhibited a broad inhibition spectrum on the proliferation of tested cancer cells, with a relatively higher anticancer activity than other derivatives. We found that the differences in their anticancer activities were attributed to the various binding abilities of the Se compounds toward BSA. The bimolecular quenching constant (Kq), apparent quenching constant (KSV), effective binding constant (KA) and binding site number (n) were obtained through fluorescence quenching calculations, which indicated that all compounds could efficiently bind to BSA molecules and the fluorescence quenching mechanism was mainly a static quenching procedure. Moreover, serum albumin was found to interact with selenadiazole derivatives (4a–e), thus promoting the cellular uptake and anticancer activity of the Se compounds. Taken together, this study demonstrated that the synthetic selenadiazole derivatives exhibited high anticancer activity and cellular uptake through delivery by human serum.
Co-reporter:Wei Huang;Yanyu Huang;Yuanyuan You;Tianqi Nie
Advanced Functional Materials 2017 Volume 27(Issue 33) pp:
Publication Date(Web):2017/09/01
DOI:10.1002/adfm.201701388
Tellurium (Te) is an important semiconductor material with low band-gap energy, which has attracted considerable attention in recent years, due to its special chemical and physical properties and wide potential in electrochemistry, optoelectronics, and biological fields. This study demonstrates a facile and high-yield synthesis strategy of Te nanorods (PTW-TeNRs) decorated by polysaccharide–protein complex, which can achieve simultaneous chemo-photothermal combination therapy against cancers. PTW-TeNRs alone possess high stability under physiological conditions, potent anticancer activities through induction of reactive oxygen species overproduction, and high selectivity among tumor and normal cells. More importantly, they exhibit strong near-infrared (NIR) absorbance and good photothermal conversion ability from NIR light to heat energy. Furthermore, in combination with NIR laser irradiation, PTW-TeNRs exhibit excellent chemo-photothermal efficiency and low toxicity as evidenced by highly efficient tumor ablation ability, but show no obvious histological damage to the major organs. Taken together, this study provides a valid tactic for facile synthesis of multifunctional tellurium nanorods for efficient and combinational cancer therapy.
Co-reporter:Yuanyuan You;Lizhen He;Bin Ma
Advanced Functional Materials 2017 Volume 27(Issue 42) pp:
Publication Date(Web):2017/11/01
DOI:10.1002/adfm.201703313
AbstractNanorod-based drug delivery systems have attracted great interest because of their enhanced cell internalization capacity and improved drug loading property. Herein, novel mesoporous silica nanorods (MSNRs) with different lengths are synthesized and used as nanocarriers to achieve higher drug loading and anticancer activity. As expected, MSNRs-based drug delivery systems can effectively enhance the loading capacity of drugs and penetrate into tumor cells more rapidly than spherical nanoparticles due to their greater surface area and trans-membrane transporting rates. Interestingly, these tailored MSNRs also enhance the cellular uptake of doxorubicin (DOX) in cancer cells, thus significantly enhancing its anticancer efficacy for hundreds of times by inducing of cell apoptosis. Internalized MSNRs-DOX triggers intracellular reactive oxygen species (ROS) overproduction, which subsequently activates p53 and mitogen-activated protein kinases (MAPKs) pathways to promote cell apoptosis. MSNRs-DOX nanosystem also shows prolonged blood circulation time in vivo. In addition, MSNRs-DOX significantly inhibits in vivo tumor growth in nude mice model and effectively reduced its in vivo toxicity. Therefore, this study provides an effective and safe strategy for designing chemotherapeutic agents for precise cancer therapy.
Co-reporter:Zhiqin Deng, Pan Gao, Lianling Yu, Bin Ma, Yuanyuan You, Leung Chan, Chaoming Mei, Tianfeng Chen
Biomaterials 2017 Volume 129(Volume 129) pp:
Publication Date(Web):1 June 2017
DOI:10.1016/j.biomaterials.2017.03.017
Elucidation of the communication between metal complexes and cell membrane may provide useful information for rational design of metal-based anticancer drugs. Herein we synthesized a novel class of ruthenium (Ru) complexes containing phtpy derivatives (phtpy = phenylterpyridine), analyzed their structure-activity relationship and revealed their action mechanisms. The result showed that, the increase in the planarity of hydrophobic Ru complexes significantly enhanced their lipophilicity and cellular uptake. Meanwhile, the introduction of nitro group effectively improved their anticancer efficacy. Further mechanism studies revealed that, complex (2c), firstly accumulated on cell membrane and interacted with death receptors to activate extrinsic apoptosis signaling pathway. The complex was then transported into cell cytoplasm through transferrin receptor-mediated endocytosis. Most of the intracellular 2c accumulated in cell plasma, decreasing the level of cellular ROS, inducing the activation of caspase-9 and thus intensifying the apoptosis. At the same time, the residual 2c can translocate into cell nucleus to interact with DNA, induce DNA damage, activate p53 pathway and enhance apoptosis. Comparing with cisplatin, 2c possesses prolonged circulation time in blood, comparable antitumor ability and importantly, much lower toxicity in vivo. Taken together, this study uncovers the role of membrane receptors in the anticancer actions of Ru complexes, and provides fundamental information for rational design of membrane receptor targeting anticancer drugs.A class of novel ruthenium complexes has been rationally designed and found be able to inter-act with cell membrane receptors to induce cancer cell apoptosis.Download high-res image (328KB)Download full-size image
Co-reporter:Xueyang Fang;Xianlin Wu;Chang'e Li;Binwei Zhou;Xiaoyin Chen;Fang Yang
RSC Advances (2011-Present) 2017 vol. 7(Issue 14) pp:8178-8185
Publication Date(Web):2017/01/23
DOI:10.1039/C6RA28229F
As a traditional Chinese medicine, baicalin exhibits high antitumor activity towards hepatitis B virus (HBV)-infected liver cancer, but low toxicity towards normal tissues. However, the properties of baicalin, including its low hydrophilicity and poor biocompatibility, have limited its clinical application. Herein, in this study, we have designed and synthesized multifunctional selenium nanoparticles (SeNPs) with baicalin (B) and folic acid (FA) surface-modifications for the targeted treatment of HBV infected liver cancer. B–SeNPs–FA showed appropriate particle size distribution, high stability, and higher cellular uptake by tumor cells than normal cells. The nanoparticles primarily targeted lysosomes in HepG2215 cells through utilization of the main pathways of caveolae-mediated endocytosis and energy-dependent endocytosis. B–SeNPs–FA induced HepG2215 cell apoptosis by down-regulating the generation of reactive oxygen species (ROS) and the expression of the HBxAg protein. In addition, B–SeNPs–FA exhibited an excellent ability to inhibit cancer cell migration and invasion. Taken together, these results suggest that baicalin-loaded selenium nanoparticles with a folic acid targeting moiety could be a promising strategy for the design and synthesis of cancer-targeted nanomaterials to treat HBV-infected liver cancer.
Co-reporter:Yanxin Du;Hong Li;Bolai Chen;Haoqiang Lai;Xiaoling Li
RSC Advances (2011-Present) 2017 vol. 7(Issue 47) pp:29656-29664
Publication Date(Web):2017/06/05
DOI:10.1039/C7RA01306J
Long-term use of glucocorticoids (GC), especially dexamethasone (Dex), could result in osteoporosis through induction of oxidative stress-mediated apoptosis of osteoblasts and increased differentiation of osteoclasts, finally leading to bone loss. Therefore, searching for new agents that could block Dex-induced cytotoxicity would be a good way to treat osteoporosis. In this study, we show that, synthetic benzo[1,2,5]selenadiazole derivatives (SeDs) could be used as effective inhibitors of Dex-induced osteoblasts apoptosis. This protective effect was correlated with their lipophilicity, cellular uptake and antioxidant activities. Furthermore, mechanistic studies reveal that, treatment of osteoblast cells with Dex resulted in overproduction of intracellular reactive oxygen species (ROS), DNA fragmentation, activation of caspase-3/-9, mitochondria fragmentation, phosphorylation of p53, and activation of MAPKs and AKT pathways. However, pre-treatment of the cells with the synthetic SeDs effectively blocked these intracellular events, which suggest that SeDs could protect osteoblast cells against Dex-induced cell apoptosis via attenuating oxidative stress and downstream signalling pathways. Therefore, this study demonstrates a new therapeutic application of SeDs to antagonize GC-induced osteoporosis.
Co-reporter:Hongzhi He;Saijun Liu;Huashou Li
RSC Advances (2011-Present) 2017 vol. 7(Issue 68) pp:43266-43272
Publication Date(Web):2017/09/04
DOI:10.1039/C7RA08250A
Selenium-containing phycocyanin (Se–PC) was purified from Se-enriched cultures of a nitrogen-fixing cyanobacterium (Nostoc sp.) using fast protein liquid chromatography. Ammonium sulfate precipitation, DEAE-Sepharose ion-exchange chromatography, and Sephacry S-300 size exclusion chromatography were employed in the process of protein purification. The purity ratio and the separation factor of the purified Se–PC were found to be 5.97 and 14.73, respectively. The Se content in the Se–PC was 550 μg g−1 protein as determined by ICP-AES analysis. Interestingly, we also found that, Se–PC could effectively suppress the paraquat (PQ)-induced cell death and morphological changes, reverse PQ-induced DNA fragmentation and nuclear condensation, and block PQ-induced cell apoptosis through inhibition of superoxide overproduction in human kidney HK-2 cells. The results indicate that Se–PC is a promising selenium species for the protection of renal cells from paraquat-induced damage.
Co-reporter:Jianfu Zhao;Delong Zeng;Yuedan Liu;Yi Luo;Shengbin Ji;Xiaoling Li
Metallomics (2009-Present) 2017 vol. 9(Issue 5) pp:535-545
Publication Date(Web):2017/05/24
DOI:10.1039/C7MT00001D
Hyperglycemia is an important factor for chemoresistance of breast cancer patients with diabetes. In the present study, a novel selenadiazole derivative has been evaluated and found to be able to antagonize the doxorubicin (DOX) resistance of MCF-7 cells under simulated diabetes conditions. Hyperglycemia promotes the proliferation, invasion and migration of MCF-7 cells through activation of ERK and AKT pathways, which could be inhibited by the synthetic selenadiazole derivative. The antitumor effects of the selenadiazole derivative were attributed to its ability to activate AMPK pathways. Furthermore, the high lipophilicity (log P = 1.9) of the synthetic selenadiazole derivative facilitated its uptake by cancer cells and subsequently potentiated the cellular uptake of DOX, leading to a strong enhancment of the antiproliferative activity of DOX on MCF-7 cells by induction of apoptosis. The apoptosis was initiated by the ROS overproduction induced by the cooperation of the selenadiazole derivative and DOX. The excessive ROS then caused damage to DNA, which upregulated the expression of proapoptosis Bcl-2 family proteins and led to fragmentation of mitochondria, which finally caused apoptosis of the cancer cells. Taken together, this study provides a rational strategy for using selenadiazole derivatives to overcome hyperglycemia-induced drug resistance in breast cancer by activation of AMPK-mediated pathways.
Co-reporter:Xueyang Fang;Wenting Jiang;Yanyu Huang;Fang Yang
Journal of Materials Chemistry B 2017 vol. 5(Issue 5) pp:944-952
Publication Date(Web):2017/02/01
DOI:10.1039/C6TB02361D
Multidrug resistance is one of the main causes leading to failure of chemotherapy. Therefore, the rational design of targeting drug systems to reverse multidrug resistance is becoming an important strategy for cancer therapy. Herein, we present a novel copolymer-based nanoparticle that was size changeable and could realize the goal of precise drug controlled release under acidic conditions, and could overcome the multidrug resistance in breast cancer cells. This PCP/uPA nanosystem was formed through the crosslinking between chitosan (CS) and poly(N-isopropylacrylamide) (PNIPAM), followed by surface decoration with polyethylene glycol (mPEG) and a breast cancer targeting peptide uPA, which was then used to encapsulate metal complexes (RuPOP and Fe(PiP)3) to solve their bottleneck of low solubility and stability under physiological conditions. These multifunctional nanosystems (PCP-Ru/uPA and PCP-Fe/uPA) exhibited remarkable anticancer activity and could overcome the poor stability and low solubility of RuPOP and Fe(PiP)3. Noticeably, PCP-Ru/uPA reversed the multidrug resistance of drug-resistant MCF-7 (MCF-7R) human breast cancer cells by enhancing the cellular uptake of RuPOP by MCF-7R cells and inhibiting the expression of ABC family proteins. Furthermore, when PCP-Ru/uPA was at pH 5.3 with lysozyme, the release amount of RuPOP is the largest compared with pH at 5.3 or 7.4, and the release rate of RuPOP reached 75% at 48 h. In other words, the nanosystem with a pH-responsive effect swelled in an acidic environment and released free RuPOP in the lysosome of cancer cells efficiently, which triggered ROS up-regulation and induced apoptosis in MCF-7R cells. Taken together, this study presents a novel size changeable nanosystem for precise drug controlled release and efficient overcoming of cancer multidrug resistance.
Co-reporter:Lizhen He;Lilan Zeng;Xiaoxuan Mai;Changzheng Shi;Liangping Luo
Journal of Materials Chemistry B 2017 vol. 5(Issue 16) pp:3024-3034
Publication Date(Web):2017/04/19
DOI:10.1039/C6TB03365B
Glioblastoma is considered as the most lethal cancer, due to the inability of chemotherapeutic agents to reach the glioma core as well as the infiltration zone of the invasive glioma cells. Nanotechnology based delivery systems bring new hope to cancer targeted therapy and diagnosis owing to their enhancement of selective cellular uptake and cytotoxicity to cancer cells through various smart designs. We prepared a novel selenium-based composite nanosystem (QDs/Se@Ru(A)) surface functionalized with the AS1411 aptamer and loaded with quantum dots to realize selectivity against glioblastoma and enhance theranostic effects. This cancer targeted nanosystem significantly enhanced the cellular uptake in glioma cells through nucleolin mediated endocytosis, and increased selectivity between cancer and normal cells. The QDs/Se@Ru(A) nanosystem can also be used for spontaneous fluorescence of biological probes to explore their localization in cancer cells, because of the green fluorescent quantum dots loaded into the selenium nanoparticles. QDs/Se@Ru(A) promotes excess reactive oxygen species (ROS) production in glioma cells to induce DNA damage, thus activating diverse downstream signaling pathways, and inhibiting proliferation of U87 cells through the G2/M phase cycle. Thus, this study provides an effective strategy to design a theranostic agent to simultaneously realize cell imaging and therapy for glioblastoma treatment.
Co-reporter:Yanyu Huang;Lizhen He;Zhenhuan Song;Leung Chan;Jintao He;Wei Huang;Binwei Zhou
Journal of Materials Chemistry B 2017 vol. 5(Issue 18) pp:3300-3314
Publication Date(Web):2017/05/10
DOI:10.1039/C7TB00287D
Resistance to chemotherapy remains the primary obstacle for the successful treatment of cancers. Nanotechnology-based studies have developed many smart nanomedicines and efficient strategies to overcome multidrug resistance (MDR), which have brought new horizons to cancer therapy. Among them, protein-based nanomedicine represents an appealing drug delivery platform to realize safe and superior therapeutic effects due to its paramount biocompatibility with minimized toxicity. Herein we describe the rational design and construction of a novel protein-based nanocarrier using the naturally-occurring protein phycocyanin (PC) as the base material, to achieve safe and tumor-specific drug delivery. This cancer-targeting nanosystem (FA-PCNP@DOX) with bio-responsive properties exhibits positive targeting accumulation in resistant cancer cells and overcomes drug efflux by enhancing cellular uptake and retention time. Specifically, FA-PCNP@DOX inhibits the function of pumping proteins of the ABC family and triggers ROS-mediated apoptotic signaling pathways, thereby attaining highly efficient anticancer efficacy and overcoming drug resistance. Pharmaceutical studies demonstrate that FA-PCNP@DOX overwhelms DOX by sustained release in the blood, which verifies its prolonged circulation in vivo. Moreover, FA-PCNP@DOX efficiently accumulates in tumors and strengthens the tumor inhibitory effect of DOX by enhanced tumoral penetration. Importantly, FA-PCNP@DOX effectively reduces the hepatic, pulmonary, renal and cardiac toxicity caused by DOX. Therefore, as a new nanocarrier, this novel nanosystem could be further exploited as a safe and versatile nanoplatform for next-generation cancer therapy.
Co-reporter:Lizhen He;Yanyu Huang;Yanzhou Chang;Yuanyuan You;Hao Hu;Kam W. Leong
Journal of Materials Chemistry B 2017 vol. 5(Issue 41) pp:8228-8237
Publication Date(Web):2017/10/25
DOI:10.1039/C7TB02163A
The rational design of highly selective and cancer-targeted nanodrug delivery systems with attractive anticancer activities is urgently needed for future exploration and translational application of nanomedicine. As angiogenesis and tumor growth could be mutually enhanced, dual therapeutic nanomedicine with simultaneous antiangiogenesis and anticancer activities is practical for cancer therapy. Therefore, herein we have rationally designed functionalized mesoporous silica nanoparticles (MSNs) to realize the dual therapy of tumor growth and angiogenesis based on the biochemical similarity of membranes of cancer cells and angiogenic cells. This nanosystem demonstrates high selectivity in vivo against cancer cells with high integrin expression levels in two-tumor bearing models, and could simultaneously inhibit cancer cell growth and disrupt tumor neovasculature, thus achieving satisfactory in vivo anticancer efficacy. Interestingly, the nanosystem triggers ROS overproduction in both cancer and human umbilical vein endothelial cells, which activates various downstream signaling pathways to regulate cell cycle arrest and apoptosis. Moreover, the nanosystem also effectively reduces the toxic side effects of loaded drugs to normal tissues and prolongs blood circulation in vivo. Therefore, this study provides a simple approach for facile manufacture of a potent nanodrug delivery system that could achieve dual therapy of tumor growth and angiogenesis.
Co-reporter:Leung Chan, Yanyu Huang and Tianfeng Chen
Journal of Materials Chemistry A 2016 vol. 4(Issue 26) pp:4517-4525
Publication Date(Web):24 May 2016
DOI:10.1039/C6TB00514D
Cancer targeting delivery and controlled release of metal complexes may offer a new approach to improve their anticancer efficacy with eliminated systemic toxicities. Herein, a biotin-conjugated tri-block polymer delivery system was designed and used as a carrier of potent ruthenium polypyridyl (RuPOP) complexes to achieve superior biocompatibility, higher water solubility and cancer-targeting ability. Biotin was used as a targeting molecule to enhance the cellular uptake and retention of RuPOP in diverse carcinoma cells. Furthermore, the nanosystem (Bio-PLGA@Ru) was efficiently internalized by cancer cells by the lipid raft-mediated endocytosis pathway, triggered ROS overproduction and activated p53-mediated apoptosis in cancer cells. Moreover, the nanosystem effectively accumulated in tumor tissue and alleviated the damage of the metal complex to the organs. Taken together, this study demonstrates a smart strategy for the fabrication of a biocompatible and cancer-targeted PLGA-based copolymer nanosystem to achieve superior tumor cell localization and anticancer ability with eliminated systemic toxicities.
Co-reporter:Tianqi Nie, Hualian Wu, Ka-Hing Wong and Tianfeng Chen
Journal of Materials Chemistry A 2016 vol. 4(Issue 13) pp:2351-2358
Publication Date(Web):23 Feb 2016
DOI:10.1039/C5TB02710A
Selenium nanoparticles (SeNPs) have attracted increasing attention due to their potential application as an effective drug delivery system. However, the conventional synthetic methods are mostly confined to solution-based synthesis that are time consuming and with low efficiency. Herein, we demonstrate the facile synthesis of highly uniform SeNPs using glucose as the reductant and surface decorator (Glu–SeNPs) that could induce cancer cell apoptosis. Glucose was used as the reducing agent to reduce sodium selenite (Na2SeO3) at high temperature (115 °C), which also acted as the surface decorator of SeNPs to prevent aggregation in an aqueous solution, thus enhancing its stability under physiological conditions. The functionalized nanoparticles demonstrated high hemocompatibility and showed selective cytotoxicity towards various human cancer cells, but not normal cells, through induction of apoptosis by initiating both intrinsic and extrinsic pathways. Furthermore, studies on the action mechanisms revealed that internalized Glu–SeNPs significantly and rapidly triggered intracellular ROS overproduction and mitochondria dysfunction to regulate the cell fate. Taken together, this study provides a new and effective method for facile synthesis of SeNPs possessing potent anticancer efficacy.
Co-reporter:Mingxian Liu, Yanzhou Chang, Jing Yang, Yuanyuan You, Rui He, Tianfeng Chen and Changren Zhou
Journal of Materials Chemistry A 2016 vol. 4(Issue 13) pp:2253-2263
Publication Date(Web):01 Mar 2016
DOI:10.1039/C5TB02725J
Halloysite nanotubes (HNTs) have a unique tubular structure in nanoscale, and have shown potential as novel carriers for various drugs. Coating the nanotubes with a hydrophilic polymer shell can significantly decrease the toxicity and provide colloidal stability during blood circulation. Here, we synthesized chitosan grafted HNTs (HNTs-g-CS) and investigated their potential as a nano-formulation for the anticancer drug curcumin. The structure and properties of HNTs-g-CS were characterized using water contact angle, zeta-potential, Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), and transmission electron microscopy (TEM) techniques. HNTs-g-CS exhibit a maximum 90.8% entrapment efficiency and 3.4% loading capacity of curcumin, which are higher than those of raw HNTs. HNTs-g-CS also show no obvious hemolytic phenomenon and good stability in serum. The cumulative release ratio of curcumin from HNTs-g-CS/curcumin at cell lysate after 48 hours is 84.2%. The curcumin loaded HNTs-g-CS show specific toxicity to various cancer cell lines, including HepG2, MCF-7, SV-HUC-1, EJ, Caski and HeLa, and demonstrate an inhibition concentration of IC50 at 5.3–192 μM as assessed by cytotoxicity studies. The anticancer activity of this nanoformulation is extremely high in EJ cells compared with the other cancer cell lines. The cell uptake of HNTs-g-CS is confirmed by fluorescence microscopy. Flow cytometric analysis of curcumin loaded HNTs-g-CS shows that curcumin loaded HNTs-g-CS increase apoptosis on EJ cells. The content of ROS created by HNTs-g-CS/curcumin is more than that of free curcumin. All these results suggest that HNTs-g-CS are potential nanovehicles for anticancer drug delivery in cancer therapy.
Co-reporter:Jianbin Mo, Lizhen He, Bin Ma, and Tianfeng Chen
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 11) pp:6811
Publication Date(Web):February 25, 2016
DOI:10.1021/acsami.5b11730
The blood–brain barrier (BBB) is the main bottleneck to prevent some macromolecular substance entering the cerebral circulation, resulting the failure of chemotherapy in the treatment of glioma. Cancer nanotechnology displays potent applications in glioma therapy owing to their penetration across BBB and accumulation into the tumor core. In this study, we have tailored the particle size of mesoporous silica nanoparticles (MSNs) through controlling the hydrolysis rate and polycondensation degree of reactants, and optimized the nanosystem that could effectively penetrate BBB and target the tumor tissue to achieve enhanced antiglioma efficacy. The nanoparticle was conjugated with cRGD peptide to enhance its cancer targeting effect, and then used to load antineoplastic doxorubicin. Therefore, the functionalized nanosystem (DOX@MSNs) selectively recognizes and binds to the U87 cells with higher expression level of ανβ3 integrin, sequentially enhancing the cellular uptake and inhibition to giloma cells, especially the particle size at 40 nm. This particle could rapidly enter cancer cells and was difficult to excrete outside the cells, thus leading to high drug accumulation. Furthermore, DOX@MSNs exhibited much higher selectivity and anticancer activity than free DOX and induced the glioma cells apoptosis through triggering ROS overproduction. Interestingly, DOX@MSNs at about 40 nm exhibited stronger permeability across the BBB, and could disrupt the VM-capability of glioma cells by regulating the expression of E-cadherin, FAK, and MMP-2, thus achieving satisfactory antiglioblastoma efficacy and avoiding the unwanted toxic side effects to normal brain tissue. Taken together, these results suggest that tailoring the particle size of MSNs nanosystem could be an effective strategy to antagonize glioblastoma and overcome BBB.Keywords: apoptosis; BBB; glioblastoma; mesoporous silica nanosystem; particle size
Co-reporter:Xiaoyan Fu, Yahui Yang, Xiaoling Li, Haoqiang Lai, Yanyu Huang, Lizhen He, Wenjie Zheng, Tianfeng Chen
Nanomedicine: Nanotechnology, Biology and Medicine 2016 Volume 12(Issue 6) pp:1627-1639
Publication Date(Web):August 2016
DOI:10.1016/j.nano.2016.01.012
Angiogenesis is essential for tumorigenesis, progression and metastasis. Herein we described the synthesis of RGD peptide-decorated and doxorubicin-loaded selenium nanoparticles (RGD-NPs) targeting tumor vasculature to enhance the cellular uptake and antiangiogenic activities in vitro and in vivo. After internalization by receptor-mediated endocytosis, this nanosystem disassembled under acidic condition with the presence of lysozymes and cell lysate, leading to bioresponsive triggered drug release. Mechanistic investigation revealed that RGD-NPs inhibited angiogenesis through induction of apoptosis and cell cycle arrest in human umbilical vein endothelial cells (HUVECs) via suppression of VEGF-VEGFR2-ERK/AKT signaling axis by triggering ROS-mediated DNA damage. Additionally, RGD-NPs can inhibit MCF-7 tumor growth and angiogenesis in nude mice via down-regulation of VEGF-VEGFR2, effectively reduce the toxicity and prolong the blood circulation in vivo. Our results suggest that the strategy to use RGD-peptide functionalized SeNPs as carriers of anticancer drugs is an efficient way to achieve cancer-targeted antiangiogenesis synergism.Herein we described the synthesis of RGD peptide-decorated and doxorubicin-loaded selenium nanoparticles (RGD-NPs) that could target tumor vasculature to enhance the cellular uptake and antiangiogenic activities in vitro and in vivo. The nanosystem could also inhibit angiogenesis through induction of apoptosis and cell cycle arrest in HUVECs via suppression of VEGF-VEGFR2-ERK/AKT signaling axis by triggering ROS-mediated DNA damage, and suppress MCF-7 tumor growth and angiogenesis in nude mice model.
Co-reporter:Bo Yu, Ting Liu, Yanxin Du, Zuandi Luo, Wenjie Zheng, Tianfeng Chen
Colloids and Surfaces B: Biointerfaces 2016 Volume 139() pp:180-189
Publication Date(Web):1 March 2016
DOI:10.1016/j.colsurfb.2015.11.063
•X-ray responsive PEG-SeNPs were facilely fabricated through PEG-templated synthesis method.•The X-ray responsive property was attributed to its amorphous status.•PEG-SeNPs sensitizes cancer cells to X-ray via induction of ROS-mediated apoptosis.Resistance of cancer to radiotherapy and/or chemotherapy is one of the important reasons of clinical treatment failure and recurrence. Chemoradiation is an optional method to over-coming of radioresistance and chemoresistance. Selenium nanoparticles (SeNPs) with special chemical and physical properties, has been identified as a novel nanocarrier and therapy agent with broad-spectrum anticancer activities due to generate ROS in cells. Herein, X-ray responsive selenium nanoparticles were facilely fabricated by using PEG as surface decorator and template. This nanosystem (PEG-SeNPs) demonstrated X-ray responsive property that was attributed to its amorphous characteristic. Interestingly, the nanosystem demonstrated significant radiosensitization effects with X-ray. Specifically, co-treatment of cancer cells with PEG-SeNPs and X-ray significantly and synergistically enhanced the cells growth inhibition through induction of cell apoptosis, as evidenced by DNA fragmentation and activation of caspase-3. In the cell model, we found that internalized nanoparticles could degrade upon X-ray exposure, which further confirm the X-ray responsive property of the nanoparticles. Moreover, the nanosystem could significantly induced intracellular ROS generation in a time-dependent manner, which peaked at about 40 min and gradually decreased thereafter. As a results, ROS overproduction led to mitochondria fragmentation and the cell apoptosis. Taken together, this study provides a novel strategy for rational design and facile synthesis of chemo-radio therapeutic radiosensitization nanomaterials.X-ray-responsive nanomaterials: an X-ray responsive selenium nanoparticles (PEG-SeNPs) were facilely fabricated through PEG-templated synthesis method and identified as synergistic cancer chemoradiation agent for cancers through enhancement of ROS generation, which may provide a novel strategy for design of chemo-radiotherapeutic nanomaterials.
Co-reporter:Yifan Wang, Wenying Li, Yahui Yang, Qinsong Zeng, Ka-Hing Wong, Xiaoling Li and Tianfeng Chen
Journal of Materials Chemistry A 2015 vol. 3(Issue 48) pp:9374-9382
Publication Date(Web):05 Nov 2015
DOI:10.1039/C5TB01929J
The development of novel therapeutics for patients with bladder cancer is an important area of research, particularly considering the rather limited treatment options currently available. In this study, we designed and synthesized a conjugate of cancer-targeting selenadiazole derivative BSeC (benzo[1,2,5]selenadiazole-5-carboxylic acid) and the RGD (arginine–glycine–aspartate) peptide, which was used as a targeting molecule, using a PEI polymer as a linker. The results showed that BSeC–PEI–RGD formed core–shell spherical nanoparticles with improved stability in physiological and low pH solutions. The cancer-targeting design significantly enhanced cellular uptake of BSeC–PEI–RGD and decreased its cytotoxicity to normal cells. The nanoparticles could inhibit the migration and invasion of EJ and T24 bladder cancer cell and reduce cancer cell proliferation through the induction of reactive oxygen species (ROS)-dependent apoptosis and mitochondrial dysfunction. Further mechanistic studies using western blotting showed that BSeC–PEI–RGD triggered bladder cancer cell apoptosis by activating p38, JNK and p53 and by inactivating AKT and ERK. In summary, this study demonstrates the rational design of a polymer-based cancer-targeting nanosystem as a carrier of the selenadiazole derivative to treat bladder cancer.
Co-reporter:Lizhen He, Shengbin Ji, Haoqiang Lai and Tianfeng Chen
Journal of Materials Chemistry A 2015 vol. 3(Issue 42) pp:8383-8393
Publication Date(Web):14 Sep 2015
DOI:10.1039/C5TB01501D
The lack of early and timely diagnosis of tumors and the monitoring of their response to therapeutics have limited the successful cancer treatments. Theranostic agents are expected to realize the dual-purpose of simultaneous diagnosis and therapy for treatments of cancers. In the present study, we have examined the effects of the chemical structure of selenadiazole derivatives (SeDs) on their anticancer efficacy and radio-sensitization against clinically used X-rays. The results showed that the introduction of a nitro group (–NO2) into SeD-3 significantly enhanced the anticancer activity of SeDs. The higher lipophilicity endowed SeD-3 with higher cellular internalization ability, resulting in higher cellular uptake and anticancer efficacy. Specifically, the capacity of autofluorescence allowed the use of SeD-3 as a promising theranostic agent to directly monitor the cellular uptake, localization and biodistribution in vitro and in vivo. Interestingly, SeD-3 also significantly enhanced the sensitivity of HeLa cervical cells to X-ray-induced apoptosis by targeting the inhibition of TrxR and promoting intracellular ROS overproduction, which activated the downstream ROS-mediated signaling pathways to regulate cell apoptosis. Furthermore, SeD-3 exhibited satisfactory in vivo antitumor efficacy through the inhibition of tumor proliferation and induction of tumor cell apoptosis, and showed no toxicity to the main organs. Moreover, from the results of hematological analysis, we found that not only inhibiting the tumor growth, treatment of SeD-3 also alleviated the damage of liver, kidney and heart function of nude mice induced by HeLa xenografts. Taken together, this study demonstrates that SeDs could be further developed as an effective and safe theranostic agent for simultaneous cancer chemo-/radiotherapy.
Co-reporter:Hao Hu, Yuanyuan You, Lizhen He and Tianfeng Chen
Journal of Materials Chemistry A 2015 vol. 3(Issue 30) pp:6338-6346
Publication Date(Web):22 Jun 2015
DOI:10.1039/C5TB00612K
Angiogenesis is essential for tumorous progression and metastasis. The RGD (Arg–Gly–Asp acid) peptide has been demonstrated to be a remarkable targeting reagent and can be distinguished by the integrin receptor overexpressed in various human tumor cells. Mesoporous silica nanoparticles (MSNs) are one of the most promising carriers applied for delivery of drugs or genes. It is well known that NAMI-A is an excellent drug for antimigration of tumor cells. Targeting the tumor vasculature with RGD-modified nanomaterials is expected to be a promising strategy for cancer therapy. Herein we have investigated the antiangiogenic activity of NAMI-A-loaded and RGD peptide surface decorated mesoporous silica nanoparticles in vitro and in vivo. The results revealed that NAMI-A@MSN-RGD remarkably enhanced the cellular uptake and antiangiogenic efficacy in contrast to bare NAMI-A in vitro. The nanosystem of NAMI-A@MSN-RGD also exhibited inspiring antiangiogenic action in vivo. Furthermore, the RGD-functionalized nanodrug inhibited angiogenesis by means of apoptosis by triggering ROS-mediated DNA damage in human umbilical vein endothelial cells (HUVECs). Our results suggested that the use of RGD-peptide modified MSNs as a vehicle of anticancer drugs is an efficient way to construct cancer-targeted nanosystems with antiangiogenic activity.
Co-reporter:Lilan Zeng, Jingjing Chen, Shengbin Ji, Leung Chan, Wenjie Zheng and Tianfeng Chen
Journal of Materials Chemistry A 2015 vol. 3(Issue 21) pp:4345-4354
Publication Date(Web):16 Apr 2015
DOI:10.1039/C4TB02010C
Multidrug resistance has been identified as a major cause of failure of cancer treatment. Due to their relative non-toxicity, selenium nanoparticles (SeNPs) have been reported as excellent cancer therapeutic nanodrugs. In this study, we designed and prepared a novel nanosystem with borneol surface-functionalized and liver targeting to overcome the multidrug resistance. Borneol (Bor)-modified SeNPs can significantly improve the stability of SeNPs and their anticancer activity. Fe(PiP)3 (PiP = 2-phenylimidazo [4,5-f][1,10] phenanthroline) is a novel anticancer agent with low solubility and stability. In this study, we have constructed a functionalized SeNPs (GAL/Bor@SeNPs) by the surface decoration of galactosamine (GAL), which is a liver targeting ligand that significantly enhanced the cellular uptake of Fe(PiP)3-loaded nanosystem via dynamin-mediated lipid raft endocytosis and clathrin-mediated endocytosis in liver cancer cells overexpressing asialoglycoprotein receptor, thus achieving amplified anticancer efficacy. This multifunctional nanosystem exhibited excellent hemocompatibility and anticancer activity comparing with Fe(PiP)3 or SeNPs alone. Remarkably, GAL/Bor@SeNPs antagonized the multidrug resistance in R-HepG2 cells by inhibiting the expression of ABC family proteins, resulting in enhanced drug accumulation and retention. Internalized nanoparticles released free iron complexes into the cytoplasm, which triggered ROS down-regulation and induced apoptosis through activating AKT and MAPKs pathways. Moreover, this nanosystem effectively prolonged the circulation time of encapsulated drugs. Taken together, this study suggests that GAL and Bor functionalization could be an effective strategy to design cancer-targeted nanomaterials to antagonize multidrug resistance in cancers.
Co-reporter:Bo Yu, Hong Li, Jinhui Zhang, Wenjie Zheng and Tianfeng Chen
Journal of Materials Chemistry A 2015 vol. 3(Issue 12) pp:2497-2504
Publication Date(Web):03 Feb 2015
DOI:10.1039/C4TB02146K
The rational design and fabrication of nanodelivery systems to encapsulate drugs has been proven to be a promising and effective strategy for cancer therapy. Selenocystine (SeC), a naturally occurring selenoamino acid, has received more and more attention due to its novel pharmacological properties in the treatments of cancers. In this study, we fabricated a cancer-targeted nanodrug delivery system by encapsulating SeC into chitosan (CS) nanoparticles with folate surface decoration (FA–SeC–CSNPs) and evaluated its antiproliferative activities. The nanosystem entered the cells through endocytosis and released SeC in lysosomes under an acidic environment. Compared with SeC–CSNPs and SeC, FA–SeC–CSNPs significantly inhibited the growth of HeLa human cervical cancer cells that overexpressed folate receptors through the induction of apoptosis with the involvement of PARP cleavage and caspase activation. Moreover, FA–SeC–CSNPs also significantly suppressed the migration and invasion of HeLa cells in a dose-dependent manner. Furthermore, the intracellular nanosystem triggered the overproduction of reactive oxygen species (ROS) as early as 25 min after treatment, which activated various downstream signaling pathways such as p53, AKT and MAPKs to induce the cell death. Taken together, this study demonstrates a strategy for rational design of a cancer-targeted nanosystem loaded with selenocompounds to achieve selective cellular uptake and enhanced anticancer efficacy.
Co-reporter:Ni Wang, Yanxian Feng, Lilan Zeng, Zhennan Zhao, and Tianfeng Chen
ACS Applied Materials & Interfaces 2015 Volume 7(Issue 27) pp:14933
Publication Date(Web):June 24, 2015
DOI:10.1021/acsami.5b03739
Multidrug resistance and radioresistance are major obstacles for successful cancer therapy. Due to the unique characteristics of high surface area, improved cellular uptake, and the possibility to be easily bound with therapeutics, carbon nanotubes (CNTs) have attracted increasing attention as potential nanodrug delivery systems. In this study, a CNT-based radiosensitive nanodrug delivery system was rationally designed to antagonize the multidrug resistance in hepatocellular carcinoma. The nanosystem was loaded with a potent anticancer ruthenium polypyridyl complex (RuPOP) via π–π interaction and formation of a hydrogen bond. The functionalized nanosystem (RuPOP@MWCNTs) enhanced the cellular uptake of RuPOP in liver cancer cells, especially drug-resistant R-HepG2 cells, through endocytosis. Consistently, the selective cellular uptake endowed the nanosystem amplified anticancer efficacy against R-HepG2 cells but not in normal cells. Interestingly, RuPOP@MWCNTs significantly enhanced the anticancer efficacy of clinically used X-ray against R-HepG2 cells through induction of apoptosis and G0/G1 cell cycle arrest, with the involvement of ROS overproduction, which activated several downstream signaling pathways, including DNA damage-mediated p53 phosphorylation, activation of p38, and inactivation of AKT and ERK. Moreover, the nanosystem also effectively reduces the toxic side effects of loaded drugs and prolongs the blood circulation in vivo. Taken together, the results demonstrate the rational design of functionalized carbon nanotubes and their application as effective nanomedicine to overcome cancer multidrug resistance.Keywords: anticancer; carbon nanotube; drug delivery system; drug resistance; radioresistance;
Co-reporter:Zhiqin Deng, Lianling Yu, Wenqiang Cao, Wenjie Zheng and Tianfeng Chen
Chemical Communications 2015 vol. 51(Issue 13) pp:2637-2640
Publication Date(Web):02 Jan 2015
DOI:10.1039/C4CC07926D
A novel selenium-containing ruthenium complex Ru(phtpy)(phenSe)Cl(ClO4) (phtpy = 4-phenyl-2,2′:6′,2′′-terpyridine, phenSe = 2-selenicimidazole[4,5-f]1,10-phenanthroline) has been synthesized and found be able to enhance radiation-induced DNA damage through superoxide overproduction, which leads to G2/M arrest and apoptosis in cancer cells by activating ROS-mediated pathways.
Co-reporter:Liye Yang;Wenying Li;Yanyu Huang;Yangliang Zhou
Macromolecular Rapid Communications 2015 Volume 36( Issue 17) pp:1559-1565
Publication Date(Web):
DOI:10.1002/marc.201500243
Co-reporter:Haoqiang Lai, Zhennan Zhao, Linlin Li, Wenjie Zheng and Tianfeng Chen
Metallomics 2015 vol. 7(Issue 3) pp:439-447
Publication Date(Web):23 Jan 2015
DOI:10.1039/C4MT00312H
Antiangiogenic therapy is considered to be a promising strategy for the treatment of cancers. VEGF and its receptors are important angiogenic factors involved in tumor growth. In the present study, the new ruthenium(II) complexes containing 2,6-bis(benzimidazolyl)pyridine have been identified as potent antiangiogenic agents in vitro and in vivo, through activation of distinct antiangiogenic signaling pathways. Specifically, [Ru(bbp)(p-mpip)Cl]ClO4 (complex 2, bbp = 2,6-bis(benzimidazolyl)pyridine; p-mpip = 2-(4-methylphenyl)imidazo[4,5-f]-1,10-phenanthroline) exhibited the highest antiangiogenic activity, as evidenced by significant suppression of neovessel formation in chick chorioallantoic membranes and blockage of the angiogenesis in a matrigel plugs assay, which are significantly higher than those of the most accepted anti-metastasis ruthenium-based drug NAMI-A. Generally, these kinds of complexes induced the G0/G1cell cycle by inhibiting the formation of a Cyclin D1/CDK4 complex and CDK2 activation, through up regulation of the expression levels of p15INK4B, p21Cip1 and p27Kip1. Moreover, the complexes also triggered intracellular DNA damage, and thus activated the phosphorylation of ATM, ATR, CHK1, Histone and p53. The suppression of Akt and ERK1/2 pathways reinforced the cell cycle perturbation effects of the complexes. Interestingly, complex 2 displayed strong inhibition on the activation of VEGF and VEGFR-2 phosphorylation, which blocked the transmission of the mitogenic signal through Akt and ERK1/2 pathways, and thus enhanced cell cycle arrest. In contrast, we found that the most accepted anti-metastasis ruthenium based drug NAMI-A exerted lower antiangiogenic activity via activation of the DNA damage-mediated pathway, but showed no effects on VEGF and VEGFR-2 phosphorylation. Taken together, this study clearly demonstrates the distinct antiangiogenic mechanisms of metal complexes, and these kinds of complexes can be further developed as anti-vascularized drugs and as alternative agents of NAMI-A for the treatment of cancers.
Co-reporter:Jianping Chen, Lin Li, Jianyu Su, Bing Li, Tianfeng Chen, Fengqing Ling, Xia Zhang
Journal of Functional Foods 2015 Volume 17() pp:103-114
Publication Date(Web):August 2015
DOI:10.1016/j.jff.2015.05.013
•NB enhanced the antiproliferative activity of DCur.•DCur entered into the HepG2 cells by the pathway of TfR.•ROS was one cause of NB/DCur-induced cell cycle arrest in the G2/M phase.This study was to investigate whether natural borneol (NB) could enhance the anti-cancer effect of demethoxycurcumin (DCur) on HepG2 cell line by MTT assay, flow cytometry, and western blotting assay. Our results demonstrated that NB/DCur resulted in a significant decrease in cell viability due to pretreatment of NB enhancing the cellular uptake of DCur. Flow cytometric assay showed that NB/DCur-induced HepG2 cells growth inhibition was mainly caused by induction of G2/M arrest, as evidenced by accumulation of the G2/M cell population. Immunoblotting assay demonstrated that NB/DCur down-regulated expression levels of cdc2 and cyclin B1, which contributed to G2/M arrest. Moreover, NB/DCur elevated the level of intracellular reactive oxygen species (ROS), indicating that NB/DCur-induced G2/M arrest was achieved by triggered ROS-mediated DNA damage involving MAPK and Akt signaling pathways. Taken together, our results suggested that the combination of NB and DCur induced G2/M phase arrest in HepG2 through ROS overproduction. This study demonstrated that NB had the potential to be further developed into a chemosensitizer of DCur in the treatment of human cancers.
Co-reporter:Meiyun Zhou, Shengbin Ji, Zhaojun Wu, Yiqun Li, Wenjie Zheng, Hua Zhou, Tianfeng Chen
European Journal of Medicinal Chemistry 2015 Volume 96() pp:92-97
Publication Date(Web):26 May 2015
DOI:10.1016/j.ejmech.2015.03.069
•A series of selenazolopyridine derivatives have been synthesized and characterized.•PSeD demonstrates novel anticancer activity.•PSeD could induce cancer cells apoptosis by scavenging intracellular ROS.A series of selenazolopyridine derivatives have been synthesized and characterized by X-ray diffraction, high resolution NMR and Mass spectrum. The in vitro anticancer activities of the synthetic compounds were screened against a panel of human cancer cell lines, human breast carcinoma MCF-7 cells, human liver carcinoma HepG2 cells and L02 normal cell line by MTT assay. By analyzing the structure–activity relationship among the synthetic compounds, it was found that 2-(phenylamino) selenazolo [5,4-b] pyridine, (PSeD, 7) had higher growth inhibitory effect on MCF-7 cells. The intracellular mechanism of cell death was evaluated by flow cytometric analysis and ROS assay, which revealed that PSeD could induce MCF-7 cells apoptosis by scavenging intracellular ROS. Taken together, we regard PSeD as an antioxidant which could inhibit cancer cell growth through induction of apoptosis.Herein we demonstrate the synthesis of selenazolopyridine derivatives and identify them as novel anticancer agents to induce cancer cells apoptosis through scavenging intracellular ROS.
Co-reporter:Lijuan Ma, Yuanting Fu, Lianling Yu, Xiaoling Li, Wenjie Zheng and Tianfeng Chen
RSC Advances 2015 vol. 5(Issue 23) pp:17405-17412
Publication Date(Web):20 Jan 2015
DOI:10.1039/C4RA15152F
Human islet amyloid polypeptide (hIAPP) aggregation is essential in the loss of insulin-producing pancreatic beta cells in type 2 diabetes mellitus (T2DM). Recent studies have identified hIAPP fibril as a therapeutic target of T2DM. Metal complexes could covalently bind to the intracellular peptides to regulate their biological functions. In the present study, ruthenium (Ru) complexes NAMI-A (1) [Ru(bpy)3](ClO4)2 (2) (bpy = 2,2′-dipyridyl), [Ru(pip)3](ClO4)2 (3) (pip = 2-phenylimidazo[4,5-f]-[1,10]phenanthroline) and [Ru(phtpy)(phen)Cl]ClO4 (4) (phtpy = 2,6-bis(2-pyridyl)-4-phenylpyridine, phen = 1,10-phenanthroline) were selected to investigate their influence on hIAPP fibrillation in vitro. The results of thioflavin T (ThT) fluorescence assay showed that Ru complexes effectively inhibited the formation of hIAPP fibril. AFM images and TEM images further validated that the hIAPP fibrillation was disaggregated by the Ru complexes and then formed nanoscale particles, which tends to be a time-dependent process. Moreover, Ru complexes demonstrated a protective effect towards hIAPP-caused cell damage by restraining ROS generation and blocking cell apoptosis. In addition, it has been found that Ru complexes can also disaggregate hIAPP fibrils effectively inside the cells, and that the effects were proportional to the lipophilicity of the Ru complexes. Taken together, this study provides a strategy for designing Ru complexes for treating T2DM by targeting hIAPP.
Co-reporter:Jianping Chen, Lin Li, Jianyu Su, Bing Li, Xia Zhang, and Tianfeng Chen
Journal of Agricultural and Food Chemistry 2015 Volume 63(Issue 28) pp:6440-6449
Publication Date(Web):June 6, 2015
DOI:10.1021/acs.jafc.5b01773
Curcumin (Cur), an active ingredient from the rhizome of the plant Curcuma longa, has wide anticancer activities. However, due to its poor solubility and hence poor absorption, Cur has limited clinical applications. It is therefore important to develop an effective method to improve its absorption. Natural borneol (NB), a terpene and bicyclic organic compound, has been extensively used as a food additive, and our previous studies show that it can improve the uptake of Cur in cancer cells. However, the anticancer mechanism of NB/Cur remains unclear. In this study, the effects of NB/Cur on HepG2 cells were investigated by proteomic analysis. The results showed that 32 differentially expressed proteins identified by matrix assisted laser desorption ionization time-of-flight mass spectrometry were significantly changed after NB/Cur treated HepG2 cells for 24 h. Moreover, 17 proteins increased and 12 proteins decreased significantly. Biological progress categorization demonstrated that the identified proteins were mainly associated with cell cycle and apoptosis (28.1%). Subcellular location categorization exhibited that the identified proteins were mainly located in nucleus (28.1%) and mitochondrion (21.9%). Among of all proteins, we selected three differential proteins (hnRNPC1/C2, NPM, and PSMA5), which were associated with the p53 pathway. Down-regulation of hnRNPC1/C2 and NPM contributed to the enhancement of phosphorylated p53. Activated p53 and down-regulation of PSMA5 resulted in an increase in p21 protein. Further studies showed that NB/Cur induced reactive oxygen species (ROS) generation, indicating that ROS might be upstream of the G2/M arrest signaling pathway. In summary, the results exhibited the whole proteomic response of HepG2 cells to NB/Cur, which might lead to a better understanding of its underlying anticancer mechanisms.
Co-reporter:Jianping Chen, Lin Li, Jianyu Su and Tianfeng Chen
Food & Function 2015 vol. 6(Issue 3) pp:740-748
Publication Date(Web):24 Dec 2014
DOI:10.1039/C4FO00807C
Bisdemethoxycurcumin (BDCur) has been found widely in foods such as cheese, butter, etc., and in curry (powder) as a spice. It has been reported to possess anticancer activity. However, its poor absorption limited its application. Natural borneol (NB) has been used as a promoter of drug absorption and widely used in candies, beverages, baked goods, chewing gum and other foods. Thus, we investigated whether NB could potentiate the cellular uptake of BDCur, and elucidated the molecular mechanisms of their combined inhibitory effects on HepG2 cells. Our results demonstrate that NB significantly enhanced the cellular uptake of BDCur. Induction of cell cycle arrest in HepG2 cells by NB and BDCur in combination was evidenced by accumulation of the G2/M cell population. Further investigation on the molecular mechanism showed that NB and BDCur in combination resulted in a significant decrease in the expression level of Cdc2 and cyclin B. Moreover, studies also found that ROS acted as an upstream mediator in NB/BDCur-induced HepG2 cell growth inhibition and led to DNA damage with up-regulation of the expression level of phosphorylated ATM and p53. Our findings suggest that the strategy of using NB and BDCur in combination may have promising potential applications in cancer chemoprevention.
Co-reporter:Zhiqin Deng;Lianling Yu;Dr. Wenqiang Cao; Wenjie Zheng ; Tianfeng Chen
ChemMedChem 2015 Volume 10( Issue 6) pp:991-998
Publication Date(Web):
DOI:10.1002/cmdc.201500127
Abstract
The rational design of metal-based complexes is an effective strategy for the discovery of potent sensitizers for use in cancer radiotherapy. In this study, we synthesized three ruthenium complexes containing bis-benzimidazole derivatives: Ru(bbp)Cl3 (1), [Ru(bbp)2]Cl2 (2 a) (in which bbp=2,6-bis(benzimidazol-1-yl)pyridine), and [Ru(bnbp)2]Cl2 (2 b) (where bnbp=2,6-bis-(6-nitrobenzimidazol-2-yl)pyridine). We evaluated their radiosensitization capacities in vitro and mechanisms of action. Complex 2 b was found to be particularly effective in sensitizing human melanoma A375 cells toward radiation, with a sensitivity enhancement ratio of 2.4. Along with this potency, complex 2 b exhibited a high degree of selectivity between human cancer and normal cells. Mechanistic studies revealed that 2 b promotes radiation-induced accumulation of intracellular reactive oxygen species (ROS) by reacting with cellular glutathione (GSH) and then causing DNA stand breaks. The subsequent DNA damage induces phosphorylation of p53 (p-p53) and upregulates the expression levels of p21, which inhibits the expression of cyclin-B, leading to G2M arrest. Moreover, p-p53 activates caspases-3 and -8, triggers cleavage of poly(ADP-ribose) polymerase (PARP), finally resulting in apoptosis. Taken together, the results of this study provide a strategy for the design of ruthenium-based radiosensitizers for use in cancer therapy.
Co-reporter:Zhiqin Deng;Lianling Yu;Dr. Wenqiang Cao; Wenjie Zheng ; Tianfeng Chen
ChemMedChem 2015 Volume 10( Issue 6) pp:
Publication Date(Web):
DOI:10.1002/cmdc.201590016
Co-reporter:Ting Liu, Lilan Zeng, Wenting Jiang, Yuanting Fu, Wenjie Zheng, Tianfeng Chen
Nanomedicine: Nanotechnology, Biology and Medicine 2015 Volume 11(Issue 4) pp:947-958
Publication Date(Web):May 2015
DOI:10.1016/j.nano.2015.01.009
Multidrug resistance is one of the greatest challenges in cancer therapy. Herein we described the synthesis of folate (FA)-conjugated selenium nanoparticles (SeNPs) as cancer-targeted nano-drug delivery system for ruthenium polypyridyl (RuPOP) exhibits strong fluorescence, which allows the direct imaging of the cellular trafficking of the nanosystem. This nanosystem could effectively antagonize against multidrug resistance in liver cancer. FA surface conjugation significantly enhanced the cellular uptake of SeNPs by FA receptor-mediated endocytosis through nystain-dependent lipid raft-mediated and clathrin-mediated pathways. The nanomaterials overcame the multidrug resistance in R-HepG2 cells through inhibition of ABC family proteins expression. Internalized nanoparticles triggered ROS overproduction and induced apoptosis by activating p53 and MAPKs pathways. Moreover, FA-SeNPs exhibited low in vivo acute toxicity, which verified the safety and application potential of FA-SeNPs as nanodrugs. This study provides an effective strategy for the design of cancer-targeted nanodrugs against multidrug resistant cancers.From the Clinical EditorIn the combat against hepatocellular carcinoma, multidrug resistance remains one of the obstacles to be overcome. The authors designed and synthesized folate (FA)-conjugated selenium nanoparticles (SeNPs) with enhanced cancer-targeting capability. This system carried ruthenium polypyridyl (RuPOP), an efficient metal-based anti-cancer drug with strong fluorescence. It was shown that this combination was effective in antagonizing against multidrug resistance in vitro.Herein we present the rational design of a cancer-targeted selenium nanoparticles (SeNPs) drug delivery system as carrier of ruthenium polypyridyl complexes to overcome multidrug resistance and achieve enhanced theranostic effects, which allows the direct fluorescence monitoring of the selective cellular uptake and colocalization of the nanoparticles in drug resistant cancer cells.
Co-reporter:Lizhen He, Haoqiang Lai, Tianfeng Chen
Biomaterials 2015 51() pp: 30-42
Publication Date(Web):
DOI:10.1016/j.biomaterials.2015.01.063
Co-reporter:Lizhen He;Yanyu Huang;Huili Zhu;Guanhua Pang;Wenjie Zheng;Yum-Shing Wong
Advanced Functional Materials 2014 Volume 24( Issue 19) pp:2754-2763
Publication Date(Web):
DOI:10.1002/adfm.201303533
Mesoporous silica nanoparticles (MSNs) have been well-demonstrated as excellent carriers for anticancer drug delivery. Presented here is a cancer-targeted MSNs drug delivery system that allows the direct fluorescence monitoring of the cellular uptake and localization of theranostic agents in cancer cells. Specifically, the anticancer action mechanisms of RGD peptide-functionalized MSNs carrying ruthenium polypyridyl complexes (RuPOP@MSNs) are elucidated in detail. RGD peptide surface decoration significantly enhances the cellular uptake of the nanoparticles through receptor-mediated endocytosis, and increases the selectivity between cancer and normal cells. RuPOP@MSNs exhibits unprecedented enhanced cytotoxicity toward cancer cells overexpressing integrin receptor, which is significantly higher than that of free RuPOP, through induction of apoptosis. The important contribution of extrinsic pathway to cell apoptosis is confirmed by increase in expression levels of death receptors, activation of caspase-8 and truncation of Bid. The internalized nanoparticles release free RuPOP into the cytoplasm, where they modulate the phosphorylation of p53, AKT, and MAPKs pathways to promote cell apoptosis. Moreover, the strong autofluorescence of RuPOP permits the direct monitoring of drug delivery, and extends the power of theranostics to subcellular level. Taken together, this study provides an effective strategy for the design and development of cancer-targeted theranostic agents.
Co-reporter:Bo Yu, Xiaoling Li, Wenjie Zheng, Yanxian Feng, Yum-Shing Wong and Tianfeng Chen
Journal of Materials Chemistry A 2014 vol. 2(Issue 33) pp:5409-5418
Publication Date(Web):10 Jun 2014
DOI:10.1039/C4TB00399C
Selenium nanoparticles (SeNPs) have been widely used in various biomedical applications, including cancer therapy, diagnosis and drug delivery. Herein, we fabricated a novel type of structure-transformable capsules by decoration of SeNPs with folate-chitosan to form smart-shell nanocapsules (FAC@CurP–SeNPs). The shrink particles could target cancer cells over expressing folate receptor and enter the cells via folate receptor-mediated endocytosis. FAC@CurP–SeNPs were expanded to snowflake particles under acidifying stimulus (pH 5.3), which led to enhanced drug-release over prolonged periods. Treatment with FAC@CurP–SeNPs significantly inhibited the growth of MCF-7 human breast carcinoma cells through induction of apoptosis, which was evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. The contribution of extrinsic and intrinsic apoptotic pathways to the cell apoptosis was confirmed by activation of caspase-9 and caspase-8. Internalized FAC@CurP–SeNPs triggers intracellular ROS overproduction, thus activates p53, MAPKs pathways and inhibits NFκB and to promote cell apoptosis. Our results suggest that FAC@CurP–SeNPs may be a candidate for further evaluation as a agent for human cancers, and the strategy to use transformable nanocapsules could be a highly efficient way to enhance controlled drug release and anticancer efficacy.
Co-reporter:Yanyu Huang, Yi Luo, Wenjie Zheng, and Tianfeng Chen
ACS Applied Materials & Interfaces 2014 Volume 6(Issue 21) pp:19217
Publication Date(Web):October 14, 2014
DOI:10.1021/am505246w
Radiotherapy displays curative potential for cervical cancer management, but radioresistance occurs during long-term therapy. To overcome this limitation, tumor-targeted nanotechnology has been proposed to enhance the radiosensitivity of solid tumors. Herein, we used biocompatible bovine serum albumin nanoparticles (BSANPs) as carriers of organic selenocompound (PSeD) with folate (FA) as the targeting ligand to fabricate a cancer-targeted nanosystem. The combination of PSeD and BSANPs endowed the nanosystem with higher light absorption and reactive oxygen species (ROS) generation owing to their properties of surface plasmon resonance (SPR) effect, heavy metal effect, high refractive index and nanoparticulate interfacial effect. The combined treatment drastically increased the ROS overproduction, VEGF/VEGFR2 inactivation and inhibition of XRCC-1-mediated repair of DNA damage, thus triggering G2/M phase arrest and apoptosis. Taken together, our findings demonstrate the utility of FA-BSANPs as a promising radiosensitizer to improve cancer radiotherapy.Keywords: bovine serum albumin nanoparticles; cancer-targeted nanosystem; folate; radiosensitization; radiotherapy
Co-reporter:Yibo Zhang, Shanyuan Zheng, Jun-Sheng Zheng, Ka-Hing Wong, Zhi Huang, Sai-Ming Ngai, Wenjie Zheng, Yum-Shing Wong, and Tianfeng Chen
Molecular Pharmaceutics 2014 Volume 11(Issue 4) pp:1282-1293
Publication Date(Web):February 21, 2014
DOI:10.1021/mp400749f
Cisplatin-based therapy is one of the most important chemotherapy treatments for cancers. However, its efficacy is greatly limited by drug resistance and undesirable side effects. Therefore, it is of great importance to develop chemosensitizing agents to cisplatin. In the present study, we demonstrated the strategy to use methylseleninic acid (MeSe) as a synergistic agent of cisplatin and elucidated their action mechanisms. The combination of MeSe and cisplatin exhibited synergistic anticancer efficacy and achieved greater selectivity between cancer cell and normal cell. By inducing intracellular oxidative stress, MeSe potentiated cisplatin-induced DNA damage and led to enhanced p53 phosphorylation, followed by increased activation of both mitochondrial and death receptor pathway. Down-regulation of phosphorylated AKT and ERK also played important roles in the synergistic effects of MeSe and cisplatin. Our results suggested that the strategy to apply MeSe as a synergistic agent to cisplatin could be a highly efficient way to achieve anticancer synergism by targeting the intracellular redox system. MeSe might be a candidate for clinical application as a chemosensitizer to cisplatin-based therapy for cancer treatments, especially for hepatocellular carcinoma.Keywords: apoptosis; cisplatin; methylseleninic acid; ROS; synergetic effects;
Co-reporter:Yuan-Wei Liang, Junsheng Zheng, Xiaoling Li, Wenjie Zheng, Tianfeng Chen
European Journal of Medicinal Chemistry 2014 Volume 84() pp:335-342
Publication Date(Web):12 September 2014
DOI:10.1016/j.ejmech.2014.07.032
•Selenadiazoles are identified as radiosensitizers for the first time.•Selenadiazoles act as effective TrxR inhibitor.•Selenadiazoles sensitize cancer cells to X-ray via ROS-mediated signaling.Thioredoxin system is an attractive target to overcome radioresistance in cancer therapy. The redox enzyme thioredoxin reductase (TrxR) plays a vital role in restoring cellular thiol redox balance disrupted by radiation-induced reactive oxygens species (ROS) generation and oxidative damage. In this study, a series of 1,2,5-selenadiazoles have been synthesized and identified as highly effective inhibitors of TrxR to disrupt the intracellular redox balance, and thus significantly enhanced the sensitivity of cancer cells to X-ray. Upon irradiation, 1,2,5-selenadiazoles displayed a marked synergistic inhibitory effect on radioresistant A375 melanoma cell through enhancement of ROS overproduction, and subsequent induction of ROS-promoted apoptotic pathways, which triggered then mitochondrial dysfunction and caspase activation, finally resulted in augment of radiotherapeutic efficacy. Interestingly, we also found the interaction sites between 1,2,5-selenadiazole and the model peptide of TrxR, which can be confirmed by MALDI-ToF-MS. These results clearly demonstrate TrxR as a potential target for therapy of radioresistant cancers, and selenadiazole derivatives may be attractive radiosensitizing agent by targeting TrxR.
Co-reporter:Qiang Xie, Shenggui Liu, Xiaoling Li, Qiong Wu, Zuandi Luo, Xiaoyan Fu, Wenqiang Cao, Guoqiang Lan, Dan Li, Wenjie Zheng and Tianfeng Chen
Dalton Transactions 2014 vol. 43(Issue 19) pp:6973-6976
Publication Date(Web):03 Mar 2014
DOI:10.1039/C4DT00198B
Herein we demonstrated that dinuclear zinc complexes could overcome drug resistance in R-HepG2 drug resistance hepatocellular carcinoma cells through induction of mitochondria-mediated apoptosis or by triggering mitochondria fragmentation, depletion of the membrane potential and intracellular ATP levels.
Co-reporter:Zhennan Zhao, Zuandi Luo, Qiong Wu, Wenjie Zheng, Yanxian Feng and Tianfeng Chen
Dalton Transactions 2014 vol. 43(Issue 45) pp:17017-17028
Publication Date(Web):17 Jul 2014
DOI:10.1039/C4DT01392A
Ruthenium (Ru) polypyridyl complexes have emerged as leading players among the potential metal-based candidates for cancer treatment. However, the roles of cellular translocation in their action mechanisms remain elusive. Herein we present the synthesis and characterization of a series of ruthenium (Ru) complexes containing phenanthroline derivatives with varying lipophilicities, and examine their mechanism of anticancer action. Results showed that increasing the lipophilicity of complexes can enhance the rates of cellular uptake. The in vitro anticancer efficacy of these complexes depended on the levels of ROS overproduction, rather than on cellular Ru uptake levels. The introduction of a phenolic group on the ligand effectively enhanced their intracellular ROS generation and anticancer activities. In particular, complex 4, with an ortho-phenolic group on the ligand, exhibited better selectivity between cancer and normal cells in comparison with cisplatin. Notably, complex 4 entered the cancer cells partially through transferrin receptor-mediated endocytosis, and then it translocated from lysosomes to the mitochondria, where it activated mitochondrial dysfunction by regulation of Bcl-2 family proteins, thus leading to intracellular ROS overproduction. Excess ROS amplified apoptotic signals by activating many downstream pathways such as p53 and MAPK pathways to promote cell apoptosis. Overall, this study provides a drug design strategy for discovery of Ru-based apoptosis inducers, and elucidates the intracellular translocation of these complexes.
Co-reporter:Yanxian Feng, Jianyu Su, Zhennan Zhao, Wenjie Zheng, Hualian Wu, Yibo Zhang and Tianfeng Chen
Dalton Transactions 2014 vol. 43(Issue 4) pp:1854-1861
Publication Date(Web):01 Nov 2013
DOI:10.1039/C3DT52468J
The use of selenium for anticancer therapy has been heavily explored during the last decade. Amino acids (AAs) play central roles both as building blocks of proteins and intermediates in metabolism. In the present study, AAs-modified selenium nanoparticles (SeNPs@AAs) have been successfully synthesized in a simple redox system. Typical neutral (valine), acidic (aspartic acid) and basic (lysine) amino acids were used to decorate SeNPs, and the stable and homodisperse nanoparticles were characterized by zeta potential and transmission electron microscope. The result of X-ray photoelectron spectra (XPS) showed that the interaction of –NH3+ groups of the amino acids with negative-charged SeNPs could be a driving force for dispersion of the nanoparticles. The screening of in vitro anticancer activities demonstrated that SeNPs@AAs exhibited differential growth inhibitory effects on various human cancer cell lines. Among them, SeNPs decorated by Lys displayed higher anticancer efficacy than those of valine and aspartic acid. The studies on the in vitro cellular uptake mechanisms revealed that SeNPs@AAs were internalized by cancer cells through endocytosis. Flow cytometric analysis and the determination of caspase activity indicated that treatment of the MCF-7 breast adenocarcinoma cells with SeNPs@AAs led to a dose-dependent increase in apoptosis. Moreover, it was found that SeNPs@AAs-induced ROS overproduction could be the upstream signal of caspase activation and mitochondrial dysfunction in cancer cells. Taken together, our results suggest that these amino acid biocompatible nanoparticles might have potential application as chemopreventive and chemotherapeutic agents for human cancers.
Co-reporter:Zuandi Luo, Lianling Yu, Fang Yang, Zhennan Zhao, Bo Yu, Haoqiang Lai, Ka-Hing Wong, Sai-Ming Ngai, Wenjie Zheng and Tianfeng Chen
Metallomics 2014 vol. 6(Issue 8) pp:1480-1490
Publication Date(Web):27 Mar 2014
DOI:10.1039/C4MT00044G
TrxR is an NADPH-dependent selenoenzyme upregulated in a number of cancers. It plays a pivotal role in cancer progression and represents an increasingly attractive target for anticancer drugs. The limitations of cisplatin in cancer treatment have motivated the extensive investigation to other metal complexes, especially ruthenium (Ru) complexes. In this study, we present the in vitro biological evaluation of four Ru(II) polypridyl complexes with diimine ligands, namely, [Ru(bpy)3]2+ (1), [Ru(phen)3]2+ (2), [Ru(ip)3]2+ (3), [Ru(pip)3]2+ (4) (bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, ip = imidazole[4,5-f][1,10]phenanthroline, pip = 2-phenylimidazo[4,5-f][1,10]phenanthroline), and demonstrate that they exhibit antiproliferative activities against A375 human melanoma cells through inhibition of TrxR. As the planarity of the structure increases, their TrxR-inhibitory effects and in vitro anticancer activities were enhanced. Among them, complex 4 exhibited higher antiproliferative activity than cisplatin, and the TrxR-inhibitory potency of 4 was more effective than auranofin, a positive TrxR inhibitor. Complex 4 suppressed the cancer cell growth through induction of apoptosis as evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Moreover, complex 4 was able to localize in mitochondria and therein induced ROS-dependent apoptosis by inhibition of TrxR activity. Activation of MAPKs, AKT, DNA damage-mediated p53 phosphorylation and inhibition of VEGFR signaling were also triggered in cells exposed to complex 4. On the basis of this evidence, we suggest that Ru polypyridyl complexes could be developed as TrxR-targeted agents that demonstrate application potentials for treatment of cancers.
Co-reporter:Qiang Xie, Lizhen He, Haoqiang Lai, Wenjie Zheng and Tianfeng Chen
RSC Advances 2014 vol. 4(Issue 64) pp:34210-34216
Publication Date(Web):24 Jul 2014
DOI:10.1039/C4RA07031C
Radiotherapy has been the primary treatment for cancer along with chemotherapy and surgical therapy for decades. However, radiotherapy still fails to efficiently deracinate the hypoxic tumors because of their insensitivity to X-rays. In the present study, we report that selenocysteine (SeC), an analog of cystine (Cys) through selenium substitution of sulfur, could act as an effective radiosensitizer to enhance the anticancer efficacy of radiotherapy through induction of cancer cell apoptosis. By comparing the ROS generation activity of SeC and Cys, we found that selenium substitution significantly enhances the X-ray-induced ROS overproduction in human cervical cancer HeLa cells. Excess ROS could attack various components of DNA and activated downstream signaling pathways in HeLa cells. Specifically, SeC enhanced the radiation-induced phosphorylation of p53 and p38MAPK pathways, and down-regulation of phosphorylated AKT and ERK, and finally resulted in increased radiation sensitivity and inhibited tumor reproduction. Taken together, this study suggests that selenium substitution could be a novel strategy for design of cancer radiosensitizers.
Co-reporter:Jun-Yi Xue;Guang-Xiong Zhou;Si Gao;Mei-Yuk Choi;Yum-Shing Wong
Journal of Cellular Biochemistry 2014 Volume 115( Issue 3) pp:464-475
Publication Date(Web):
DOI:10.1002/jcb.24680
Abstract
Annonaceous acetogenins (ACGs) are a group of fatty acid-derivatives with potent anticancer effects. In the present study, we found desacetyluvaricin (Dau) exhibited notable in vitro antiproliferative effect on SW480 human colorectal carcinoma cells with IC50 value of 14 nM. The studies on the underlying mechanisms revealed that Dau inhibited the cancer cell growth through induction of S phase cell cycle arrest from 11.3% (control) to 33.2% (160 nM Dau), which was evidenced by the decreased protein expression of cyclin A Overproduction of superoxide, intracellular DNA damage, and inhibition of MEK/ERK signaling pathway, were also found involved in cells exposed to Dau. Moreover, pre-treatment of the cells with ascorbic acid significantly prevented the Dau-induced overproduction of superoxide, DNA damage and cell cycle arrest. Taken together, our results suggest that Dau induces S phase arrest in cancer cells by firstly superoxide overproduction and subsequently the involvement of various signaling pathways. J. Cell. Biochem. 115: 464–475, 2014. © 2013 Wiley Periodicals, Inc.
Co-reporter:Lijuan Ma, Xiaoling Li, Yi Wang, Wenjie Zheng, Tianfeng Chen
Journal of Inorganic Biochemistry 2014 140() pp: 143-152
Publication Date(Web):
DOI:10.1016/j.jinorgbio.2014.07.002
Co-reporter:Yanxin Du;Xiaoyan Fu;Hong Li;Bolai Chen;Yuhai Guo;Guoyi Su;Hu Zhang;Feipeng Ning;Yongpeng Lin;Wenjie Mei
ChemMedChem 2014 Volume 9( Issue 4) pp:714-718
Publication Date(Web):
DOI:10.1002/cmdc.201300379
Abstract
A series of ruthenium(II) polypyridyl complexes were synthesized and evaluated for their in vitro anticancer activities. The results showed that ruthenium polypyridyl complexes, especially [Ru(bpy)2(p-tFPIP)]2+ (2 a; bpy=bipyridine, tFPIP=2-(2-trifluoromethane phenyl)imidazole[4,5-f][1,10]phenanthroline), exhibited novel anticancer activity against human cancer cell lines, but with less toxicity to a human normal cell line. The results of flow cytometry and caspase activities analysis indicated that the 2 a-induced growth inhibition against MG-63 osteosarcoma cells was mainly caused by mitochondria-mediated apoptosis. DNA fragmentation and nuclear condensation as detected by TUNEL–DAPI co-staining further confirmed 2 a-induced apoptotic cell death. Further, fluorescence imaging revealed that ruthenium(II) polypyridyl complexes could target mitochondria to induce mitochondrial fragmentation, accompanied by depletion of mitochondrial membrane potential. Taken together, these findings suggest a potential application of theses ruthenium(II) complexes in the treatment of cancers.
Co-reporter:Xiaoling Li, Lijuan Ma, Wenjie Zheng, Tianfeng Chen
Biomaterials 2014 35(30) pp: 8596-8604
Publication Date(Web):
DOI:10.1016/j.biomaterials.2014.06.056
Co-reporter:Lizhen He;Dr. Tianfeng Chen;Yuanyuan You;Hao Hu;Dr. Wenjie Zheng;Dr. Wai-Lun Kwong;Taotao Zou;Dr. Chi-Ming Che
Angewandte Chemie 2014 Volume 126( Issue 46) pp:12740-12744
Publication Date(Web):
DOI:10.1002/ange.201407143
Abstract
Construction of delivery systems for anticancer gold complexes to decrease their toxicity while maintaining efficacy is a key strategy to optimize and develop anticancer gold medicines. Herein, we describe cancer-targeted mesoporous silica nanoparticles (MSN) for delivery of a gold(III) porphyrin complex (Au-1 a@MSN(R)) to enhance its anticancer efficacy and selectivity between cancer and normal cells. Encapsulation of Au-1 a within mesoporous silica nanoparticles amplifies its inhibitory effects on thioredoxin reductase (TrxR), resulting in a loss of redox balance and overproduction of reactive oxygen species (ROS). Elevated cellular oxidative stress activates diversified downstream ROS-mediated signaling pathways, leading to enhanced apoptosis-inducing efficacy.
Co-reporter:Lizhen He;Dr. Tianfeng Chen;Yuanyuan You;Hao Hu;Dr. Wenjie Zheng;Dr. Wai-Lun Kwong;Taotao Zou;Dr. Chi-Ming Che
Angewandte Chemie International Edition 2014 Volume 53( Issue 46) pp:12532-12536
Publication Date(Web):
DOI:10.1002/anie.201407143
Abstract
Construction of delivery systems for anticancer gold complexes to decrease their toxicity while maintaining efficacy is a key strategy to optimize and develop anticancer gold medicines. Herein, we describe cancer-targeted mesoporous silica nanoparticles (MSN) for delivery of a gold(III) porphyrin complex (Au-1 a@MSN(R)) to enhance its anticancer efficacy and selectivity between cancer and normal cells. Encapsulation of Au-1 a within mesoporous silica nanoparticles amplifies its inhibitory effects on thioredoxin reductase (TrxR), resulting in a loss of redox balance and overproduction of reactive oxygen species (ROS). Elevated cellular oxidative stress activates diversified downstream ROS-mediated signaling pathways, leading to enhanced apoptosis-inducing efficacy.
Co-reporter:Yinghua Li, Xiaoling Li, Wenjie Zheng, Cundong Fan, Yibo Zhang and Tianfeng Chen
Journal of Materials Chemistry A 2013 vol. 1(Issue 46) pp:6365-6372
Publication Date(Web):01 Oct 2013
DOI:10.1039/C3TB21168A
The most frequent adverse effect of cisplatin-based chemotherapy is nephrotoxicity. Oxidative stress has been implicated as an important mechanism in the pathogenesis of cisplatin-induced nephrotoxicity. In the present study, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox) surface-functionalized selenium nanoparticles (Se@Trolox) with enhanced antioxidant activity have been prepared by self-assembly of trolox on the surface of the nanoparticles, and their nephroprotective effects have been investigated. Functionalization by trolox significantly enhanced cell uptake and in vitro antioxidant activities of the nanoparticles. In addition, pretreatment with Se@Trolox dose-dependently blocked cisplatin-induced cell growth inhibition against HK-2 cells. Mechanistic investigation suggested that Se@Trolox markedly prevented cisplatin-induced apoptosis in HK-2 cells, as evidenced by inhibition of chromatin condensation, DNA fragmentation, PARP cleavage and activation of caspase-3. Furthermore, Se@Trolox effectively blocked the cisplatin-induced reactive oxygen species (ROS) accumulation, activation of AKT and MAPK signaling and DNA damage-mediated p53 phosphorylation in HK-2 cells. Taken together, our findings suggest that Se@Trolox is a promising Se species with potential application in prevention of cisplatin-induced renal injury.
Co-reporter:Shenggui Liu, Wenqiang Cao, Lianling Yu, Wenjie Zheng, Linlin Li, Cundong Fan and Tianfeng Chen
Dalton Transactions 2013 vol. 42(Issue 16) pp:5932-5940
Publication Date(Web):08 Feb 2013
DOI:10.1039/C3DT33077J
In the present study, two zinc(II) complexes containing bis-benzimidazole derivatives, Zn(bpbp)Cl2 (1) and [Zn(bpbp)2](ClO4)2·CH3CH2OH·H2O (2) (bpbp = 2,6-bis(1-phenyl-1H-benzo[d]imidazol-2-yl)pyridine), have been designed, synthesized and evaluated for their in vitro anticancer activities. The underlying molecular mechanisms through which they caused the cancer cell death were also elucidated. The complexes were identified as potent antiproliferative agents against a panel of five human cancer cell lines by comparing with cisplatin. Complex 2 demonstrated dose-dependent growth inhibition on MCF-7 human breast carcinoma cells with IC50 at 2.9 μM. Despite this potency, the complexes possessed great selectivity between human cancer cells and normal cells. Induction of apoptosis in MCF-7 cells by complex 2 was evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Further investigation on intracellular mechanisms revealed that complex 2 was able to induce p53-dependent apoptosis in cancer cells by triggering DNA damage. On the basis of this evidence, we suggest that Zn(II) complexes containing bis-benzimidazole derivatives may be candidates for further evaluation as chemotherapeutic agents for human cancers.
Co-reporter:Ling Zhao, Jianping Chen, Jianyu Su, Lin Li, Songqing Hu, Bing Li, Xia Zhang, Zhenbo Xu, and Tianfeng Chen
Journal of Agricultural and Food Chemistry 2013 Volume 61(Issue 44) pp:10604-10611
Publication Date(Web):October 9, 2013
DOI:10.1021/jf403098y
5-HMF is widely presented in foods and produced through the degradation of hexoses and Maillard reaction during heat treatment of foods containing reducing sugars and amino acids in an acid environment. However, controversial conclusions on the biological effects of 5-HMF have been drawn in previous studies. Therefore, the main aim of this study was to investigate the antioxidant and antiproliferative activities of 5-HMF. The 2,2′-azinobis-3-ethylbenzothiazolin-6-sulfonic acid (ABTS) assay, the 1,1-diphenyl-2-picryhydrazyl (DPPH) assay, and the hemolysis assay induced by 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH) were performed to evaluate the antioxidant capacity of 5-HMF. The results showed that 5-HMF exhibited novel antioxidant activity by scavenging the ABTS and DPPH free radicals and inhibited the AAPH-induced hemolysis in a dose-dependent manner. In the hemolysis assay, the reduction of ROS and MDA contents and the increase in enzyme activities of SOD, CAT, and GPx were found in erythrocytes pretreated with 5-HMF, which demonstrated that 5-HMF could prevent the peroxidation from the source to protect the erythrocytes. The morphological changes of erythrocytes was also verified by observation using atomic force microscopy. The inhibitory effect of 5-HMF on human cancer cell proliferation was investigated by MTT assay, flow cytometric analysis, and the TUNEL and DAPI costaining assay. The results showed that 5-HMF displayed higher antiproliferative activity on human melanoma A375 cells than other cell lines. Further investigation on the action mechanisms revealed that 5-HMF could induce A375 cell apoptosis and G0/G1 cell cycle arrest. The A375 cell apoptosis that 5-HMF induced was characterized by a TUNEL and DAPI costaining assay. These findings suggest that 5-HMF could be developed as a novel natural antioxidant with potential applications in cancer chemoprevention.
Co-reporter:Yanyu Huang, Lizhen He, Wen Liu, Cundong Fan, Wenjie Zheng, Yum-Shing Wong, Tianfeng Chen
Biomaterials 2013 34(29) pp: 7106-7116
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.04.067
Co-reporter:Hualian Wu, Xiaoling Li, Wen Liu, Tianfeng Chen, Yinghua Li, Wenjie Zheng, Cornelia Wing-Yin Man, Man-Kin Wong and Ka-Hing Wong
Journal of Materials Chemistry A 2012 vol. 22(Issue 19) pp:9602-9610
Publication Date(Web):04 Apr 2012
DOI:10.1039/C2JM16828F
By using mushroom polysaccharides–protein complexes (PSP) as the capping agent, size controllable and highly stable selenium nanoparticles (SeNPs) have been successfully created in a simple redox system of sodium selenite and ascorbic acid. SeNPs were capped with PSP through strong physical adsorption of hydroxyl groups of polysaccharides and imino groups of proteins on the surface of SeNPs. PSP surface decoration significantly enhanced the cellular uptake of SeNPs through endocytosis. Treatment with PSP–SeNPs significantly inhibited the growth of MCF-7 human breast cacinoma cells through induction of apoptosis with the involvement of PARP cleavage and caspase activation. Moreover, PSP–SeNPs not only significantly induced dose-dependent disruption of mitochondrial membrane potential in MCF-7 cells after 24 h treatment, but it also enhanced reactive oxygen species (ROS) generation as early as 15 min, indicating that ROS-mediated mitochondrial dysfunction may play an important role in PSP–SeNPs-induced apoptosis. Our results suggest that PSP–SeNPs may be a candidate for further evaluation as a chemopreventive agent for human cancers, and the strategy to use PSP as a surface decorator could be a highly efficient way to enhance the cellular uptake and anticancer efficacy of nanomaterials.
Co-reporter:Bo Yu, Yibo Zhang, Wenjie Zheng, Cundong Fan, and Tianfeng Chen
Inorganic Chemistry 2012 Volume 51(Issue 16) pp:8956-8963
Publication Date(Web):August 9, 2012
DOI:10.1021/ic301050v
Surface charge plays a key role in cellular uptake and biological actions of nanomaterials. Selenium nanoparticles (SeNPs) are novel Se species with potent anticancer activity and low toxicity. This study constructed positively charged SeNPs by chitosan surface decoration to achieve selective cellular uptake and enhanced anticancer efficacy. The results of structure characterization revealed that hydroxyl groups in chitosan reacted with SeO32– ion to form special chain-shaped intermediates, which could be decomposed to form crystals upon reduction by ascorbic acid. The initial colloids nucleated and then assembled into spherical SeNPs. The positive charge of the NH3+ group on the outer surface of the nanoparticles contributed to the high stability in aqueous solutions. Moreover, a panel of four human cancer cell lines were found to be susceptible to SeNPs, with IC50 values ranging from 22.7 to 49.3 μM. Chitosan surface decoration of SeNPs significantly enhanced the selective uptake by endocytosis in cancer cells and thus amplified the anticancer efficacy. Treatment of the A375 melanoma cells with chitosan–SeNPs led to dose-dependent apoptosis, as evidenced by DNA fragmentation and phosphatidylserine translocation. Our results suggest that the use of positively charged chitosan as a surface decorator could be a simple and attractive approach to achieve selective uptake and anticancer action of nanomaterials in cancer cells.
Co-reporter:Cundong Fan, Jie Jiang, Xi Yin, Ka-Hing Wong, Wenjie Zheng, Tianfeng Chen
Food Chemistry 2012 Volume 134(Issue 1) pp:253-261
Publication Date(Web):1 September 2012
DOI:10.1016/j.foodchem.2012.02.130
A fast protein liquid chromatographic method for purification of selenium-containing allophycocyanin (Se-APC) from selenium-enriched Spirulina platensis was demonstrated in this study. The purification procedures included ammonium sulphate precipitation and hydroxylapatite chromatography. Highly pure Se-APC with Se concentration of 415.7 μg g−1 protein was finally obtained. In haemolysis assay, increase in MDA content and ROS generation were found in erythrocytes exposed to t-BOOH. Se-APC exhibited higher antioxidant activity and better protective effect than APC on erythrocytes against t-BOOH-induced oxidative damage. Morphological change of erythrocytes as detected by atomic force microscopy was effectively reversed by Se-APC. In the hepatoprotective model, cytotoxicity induced by t-BOOH in HepG2 cells was significantly attenuated by Se-APC. The studies on the mechanism revealed that Se-APC could block the t-BOOH-induced apoptosis and G2/M cell cycle arrest. The findings suggest that Se-APC is a promising seleno-protein with potential applications in treatment of diseases related with oxidative stress.Highlights► A FPLC method for purification of Se-APC has been demonstrated in this study. ► Se-APC exhibited higher antioxidant activity and better protective effect than APC. ► Se-APC showed novel hepatoprotective effect on HepG2 cells against t-BOOH.
Co-reporter:Wen Liu, Xiaoling Li, Yum-Shing Wong, Wenjie Zheng, Yibo Zhang, Wenqiang Cao, and Tianfeng Chen
ACS Nano 2012 Volume 6(Issue 8) pp:6578
Publication Date(Web):July 23, 2012
DOI:10.1021/nn202452c
A simple method for preparing 5-fluorouracil surface-functionalized selenium nanoparticles (5FU-SeNPs) with enhanced anticancer activity has been demonstrated in the present study. Spherical SeNPs were capped with 5FU through formation of Se–O and Se–N bonds and physical adsorption, leading to the stable structure of the conjugates. 5FU surface decoration significantly enhanced the cellular uptake of SeNPs through endocytosis. A panel of five human cancer cell lines was shown to be susceptible to 5FU-SeNPs, with IC50 values ranging from 6.2 to 14.4 μM. Despite this potency, 5FU-SeNP possesses great selectivity between cancer and normal cells. Induction of apoptosis in A375 human melanoma cells by 5FU-SeNPs was evidenced by accumulation of sub-G1 cell population, DNA fragmentation, and nuclear condensation. The contribution of the intrinsic apoptotic pathway to the cell apoptosis was confirmed by activation of caspase-9 and depletion of mitochondrial membrane potential. Pretreatment of cells with a general caspase inhibitor z-VAD-fmk significantly prevented 5FU-SeNP-induced apoptosis, indicating that 5FU-SeNP induced caspase-dependent apoptosis in A375 cells. Furthermore, 5FU-SeNP-induced apoptosis was found dependent on ROS generation. Our results suggest that the strategy to use SeNPs as a carrier of 5FU could be a highly efficient way to achieve anticancer synergism. 5FU-SeNPs may be a candidate for further evaluation as a chemopreventive and chemotherapeutic agent for human cancers, especially melanoma.Keywords: 5-fluorouracil; apoptosis; cellular uptake; selenium nanoparticles; synergistic effects
Co-reporter:Jun-Sheng Zheng, Shan-Yuan Zheng, Yi-Bo Zhang, Bo Yu, Wenjie Zheng, Fang Yang, Tianfeng Chen
Colloids and Surfaces B: Biointerfaces 2011 Volume 83(Issue 1) pp:183-187
Publication Date(Web):1 March 2011
DOI:10.1016/j.colsurfb.2010.11.023
A simple method for fabrication of sialic acid surface-decorated selenium nanoparticles (SA–Se–NPs) with enhanced cancer-targeting and cell-penetrating abilities has been demonstrated in the present study. Monodisperse and homogeneous spherical SA–Se–NPs with striking stability were prepared under the optimized conditions. SA surface decoration significantly increased the cellular uptake and cytotoxicity of Se–NPs in HeLa human cervical carcinoma cells. Treatments of SA–Se–NPs induced dose-dependent apoptosis in HeLa cells, as evidenced by increase in sub-G1 cell populations, nuclear condensation and formation of apoptotic bodies. Further investigation on molecular mechanisms reveals that SA–Se–NPs triggered cancer cell apoptosis through activation of caspase-3 and subsequent cleavage of PARP.Graphical abstractSialic acid surface-decorated selenium nanoparticles (SA–Se–NPs) with enhanced cancer-targeting and cell-penetrating abilities have been fabricated in the present study. SA surface decoration significantly increased the cellular uptake and cytotoxicity of Se–NPs in HeLa human cervical carcinoma cells. Treatments of SA–Se–NPs induced dose-dependent apoptosis in HeLa cells through activation of caspase-3 and subsequent cleavage of PARP.Research highlights▶ A simple method for fabrication of sialic acid surface-decorated selenium nanoparticles (SA–Se–NPs) with enhanced cancer-targeting and cell-penetrating abilities has been demonstrated. ▶ SA surface decoration significantly increased the cellular uptake and cytotoxicity of Se–NPs in HeLa human cervical carcinoma cells. ▶ SA–Se–NPs induced dose-dependent apoptosis in HeLa cells through activation of caspase-3 and subsequent cleavage of PARP.
Co-reporter:Yinghua Li, Xiaoling Li, Yum-Shing Wong, Tianfeng Chen, Haobin Zhang, Chaoran Liu, Wenjie Zheng
Biomaterials 2011 32(34) pp: 9068-9076
Publication Date(Web):
DOI:10.1016/j.biomaterials.2011.08.001
Co-reporter:Qian Li, Tianfeng Chen, Fang Yang, Jie Liu, Wenjie Zheng
Materials Letters 2010 Volume 64(Issue 5) pp:614-617
Publication Date(Web):15 March 2010
DOI:10.1016/j.matlet.2009.12.019
A simple and solution-phase approach for large-scale synthesis of selenium nanoparticles (Nano-Se) by reducing sodium selenite (Na2SeO3) with l-cysteine has been demonstrated in this study. l-cysteine was used as both the reducing agent and surface modifier to control the formation of Nano-Se. The effects of reactant concentrations and ratios, and reaction time on the size and stability of Nano-Se were also investigated. The morphology and chemical composition of Nano-Se were characterized using various spectroscopic and microscopic methods. The results showed that varying the concentration ratio of l-cysteine to Na2SeO3 could control the diameter and morphology of Nano-Se, but not affecting their crystalline phases and chemical compositions. Monodisperse and homogeneous spherical Nano-Se with an average diameter of about 100 nm could be synthesized with the concentration ratio of l-cysteine to Na2SeO3 at 4:1. A striking feature of the as-synthesized Nano-Se was their good stability when dispersed in the reaction solutions, which indicates their potential in medical applications.
Co-reporter:Yanyu Huang, Wei Huang, Leung Chan, Binwei Zhou, Tianfeng Chen
Biomaterials (October 2016) Volume 103() pp:183-196
Publication Date(Web):October 2016
DOI:10.1016/j.biomaterials.2016.06.053
The use of metal complexes in cancer treatment is hampered by the insufficient accumulation in tumor regions and observable systemic toxicity due to their nonspecificity in vivo. Herein we present a cancer-targeted DNA origami as biocompatible nanocarrier of metal complexes to achieve advanced antitumor effect. The formation of unique tetrahedral nanostructure of DNA cages effectively enhances the interaction between ruthenium polypyridyl complexes (RuPOP) and the cages, thus increasing the drug loading efficacy. Conjugation of biotin to the DNA-based nanosystem (Bio-cage@Ru) enhances its specific cellular uptake, drug retention and cytotoxicity against HepG2 cells. Different from free RuPOP and the cage itself, Bio-cage@Ru translocates to cell nucleus after internalization, where it undergoes self-immolative cleavage in response to DNases, leading to triggered drug release and induction of ROS-mediated cell apoptosis. Moreover, in the nude mice model, the nanosystem specifically accumulates in tumor sites, thus exhibits satisfactory in vivo antitumor efficacy, and alleviates the damage of liver, kidney, lung and heart function of nude mice induced by RuPOP and tumor xenografts. Collectively, this study demonstrates a strategy for construction of biocompatible and cancer-targeted DNA origami with enhanced anticancer efficacy and reduced toxicity for next-generation cancer therapy.Herein we present a multifunctional DNA origami as biocompatible nanocarrier of ruthenium complexes (RuPOP) for advanced cancer therapeutics. The tetrahedral Bio-cage with cancer-targeted ability increases the loading efficacy of RuPOP and drastically promotes its tumoral accumulation. Bio-cage@Ru undergoing safe circulation in blood efficiently targets nucleus and strengthens enhanced antitumoral effects without causing systemic toxicities.
Co-reporter:Yanyu Huang, Wei Huang, Leung Chan, Binwei Zhou, Tianfeng Chen
Biomaterials (October 2016) Volume 103() pp:183-196
Publication Date(Web):October 2016
DOI:10.1016/j.biomaterials.2016.06.053
Co-reporter:Hongzhi He, Yongjun Li, Tianfeng Chen, Xiaolong Huang, Qiu Guo, Shufeng Li, Tianhong Yu, Huashou Li
Pesticide Biochemistry and Physiology (March 2013) Volume 105(Issue 3) pp:224-230
Publication Date(Web):1 March 2013
DOI:10.1016/j.pestbp.2013.02.009
Highlights•Butachlor induces some physiological and biochemical changes in Nostoc sp.•High levels of butachlor inhibit the growth, pigments synthesis, and PSII activity.•High levels of butachlor trigger dramatic intracellular antioxidant response.Butachlor has been widely applied in rice field in China. However, concerns are also raised about its potential adverse impacts on non-target organisms. In the present study, butachlor was found be able to induce toxic effects on a rice field biofertilizer cyanobacterium Nostoc sp. When treated with 80 mg L−1 butachlor, significant decline in the growth rate, concentrations of chlorophyll a (Chla), carotenoids (Cars), phycobiliproteins (PBPs) and; the minimal fluorescence yield (F0), fluorescence intensity at the J-step of OJIP (Fj), the maximum fluorescence yield (Fm), the potential quantum yield (Qy), the quantum yield of electron transport (ΦE0), the maximum quantum yield of primary photochemistry (ΦP0), and the performance index on absorption basis (PIABS) (14.2%, 39.5%, 55.5%, 34.8%, 38.5%, 19.8%, 18.7%, 20.4%, 10.1%, 10.3%, and 26.4%, respectively) was observed in Nostoc sp. In contrast, significant increase in Cars/Chla, PBPs/Chla, the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD) and, glutathione reductase (GR), content of malonaldehyde (MDA), the absorption flux per reaction center (ABS/RC) and the effective dissipation per reaction center (DI0/RC) for 0.45, 0.65, 2.36, 2.47, 1.08, 1.16, 0.87, 0.122 and 0.205 fold was also detected by comparing with the control group. These results demonstrated that high concentration of butachlor could inhibit the growth, synthesis of pigments, and photosystem II (PSII) activities of Nostoc sp., and trigger dramatic intracellular antioxidant response in the cells. Taken together, this study may provide important information on the understanding of the changes induced by butachlor stress in nitrogen-fixing cyanobacteria and the adaptive strategy of the alga.Graphical abstractDownload full-size image
Co-reporter:Yibo Zhang, Xiaoling Li, Zhi Huang, Wenjie Zheng, Cundong Fan, Tianfeng Chen
Nanomedicine: Nanotechnology, Biology and Medicine (January 2013) Volume 9(Issue 1) pp:74-84
Publication Date(Web):1 January 2013
DOI:10.1016/j.nano.2012.04.002
A simple method for preparation of adenosine triphosphate (ATP) surface-functionalized selenium nanoparticles (SeNPs@ATP) with enhanced cell permeabilization and anticancer activity has been demonstrated in the study reported in this article. Spherical SeNPs were decorated with ATP by strong adsorption through an Se-N bond, leading to the highly stable structure of the conjugates. ATP surface decoration significantly enhanced the cellular uptake and anticancer activity of SeNPs. Induction of apoptosis in HepG2 human hepatocellular carcinoma cells by SeNPs@ATP was evidenced by accumulation of the sub-G1 cell population, phosphatidylserine exposure, DNA fragmentation, PARP cleavage and caspase activation. Further studies found that SeNPs@ATP treatment triggered the depletion of mitochondrial membrane potential and reactive oxygen species (ROS) overproduction. Our results demonstrate that the use of ATP as a surface decorator of SeNPs is a novel strategy to achieve anticancer synergy. SeNPs@ATP may be a candidate for further evaluation as a chemotherapeutic agent for human cancers.From the Clinical EditorIn this paper, adenosine triphosphate (ATP) surface-functionalized selenium nanoparticles are discussed as cell-penetrating anticancer agents. Conjugates are stable and ATP functionalization greatly enhances the apoptosis induction properties of the selenium nanoparticles in HepG2 human hepatocellular carcinoma cells.ATP surface decoration significantly enhances the cellular uptake and anticancer activity of SeNPs. Induction of apoptosis was the major mode of cancer cell death induced by SeNPs@ATP. Our results demonstrate that it is a novel strategy to use ATP as a surface decorator of SeNPs to achieve anticancer synergism. SeNPs@ATP may be a candidate for further evaluation as a therapeutic agent for human cancers.Download high-res image (163KB)Download full-size image
Co-reporter:Qiang Xie, Shenggui Liu, Xiaoling Li, Qiong Wu, Zuandi Luo, Xiaoyan Fu, Wenqiang Cao, Guoqiang Lan, Dan Li, Wenjie Zheng and Tianfeng Chen
Dalton Transactions 2014 - vol. 43(Issue 19) pp:NaN6976-6976
Publication Date(Web):2014/03/03
DOI:10.1039/C4DT00198B
Herein we demonstrated that dinuclear zinc complexes could overcome drug resistance in R-HepG2 drug resistance hepatocellular carcinoma cells through induction of mitochondria-mediated apoptosis or by triggering mitochondria fragmentation, depletion of the membrane potential and intracellular ATP levels.
Co-reporter:Yuanyuan You, Liye Yang, Lizhen He and Tianfeng Chen
Journal of Materials Chemistry A 2016 - vol. 4(Issue 36) pp:NaN5990-5990
Publication Date(Web):2016/08/10
DOI:10.1039/C6TB01329E
Cancer-targeted drug delivery systems with permeability of the blood–brain barrier (BBB) have become of great interest for the rational design of high-efficiency anticancer agents. Herein, a tailored mesoporous silica nanoparticles (MSNs) nanosystem modified by RGD (arginine–glycine–aspartate) peptide was designed and tested for use as a carrier of anticancer agents, by using a novel organic selenium compound BSeC as a model molecule. As expected, the nanosystem (BSeC@MSNs-RGD) could effectively enhance the BBB permeability and the cellular uptake of BSeC in tumor cells. The internalized BSeC@MSNs-RGD triggered mitochondrial dysfunction and intracellular ROS overproduction, which subsequently activated the p53 and MAPKs pathways. Moreover, the nanosystem could inhibit the U87 tumor spheroids growth, significantly prolong the blood circulation time of the loaded drug in vivo and effectively reduce its in vivo toxicity. Taken together, this study provides a strategy for the rational design of a tailored nanomedicine with enhanced BBB permeability to treat human brain glioma.
Co-reporter:Yanyu Huang, Lizhen He, Zhenhuan Song, Leung Chan, Jintao He, Wei Huang, Binwei Zhou and Tianfeng Chen
Journal of Materials Chemistry A 2017 - vol. 5(Issue 18) pp:NaN3314-3314
Publication Date(Web):2017/03/28
DOI:10.1039/C7TB00287D
Resistance to chemotherapy remains the primary obstacle for the successful treatment of cancers. Nanotechnology-based studies have developed many smart nanomedicines and efficient strategies to overcome multidrug resistance (MDR), which have brought new horizons to cancer therapy. Among them, protein-based nanomedicine represents an appealing drug delivery platform to realize safe and superior therapeutic effects due to its paramount biocompatibility with minimized toxicity. Herein we describe the rational design and construction of a novel protein-based nanocarrier using the naturally-occurring protein phycocyanin (PC) as the base material, to achieve safe and tumor-specific drug delivery. This cancer-targeting nanosystem (FA-PCNP@DOX) with bio-responsive properties exhibits positive targeting accumulation in resistant cancer cells and overcomes drug efflux by enhancing cellular uptake and retention time. Specifically, FA-PCNP@DOX inhibits the function of pumping proteins of the ABC family and triggers ROS-mediated apoptotic signaling pathways, thereby attaining highly efficient anticancer efficacy and overcoming drug resistance. Pharmaceutical studies demonstrate that FA-PCNP@DOX overwhelms DOX by sustained release in the blood, which verifies its prolonged circulation in vivo. Moreover, FA-PCNP@DOX efficiently accumulates in tumors and strengthens the tumor inhibitory effect of DOX by enhanced tumoral penetration. Importantly, FA-PCNP@DOX effectively reduces the hepatic, pulmonary, renal and cardiac toxicity caused by DOX. Therefore, as a new nanocarrier, this novel nanosystem could be further exploited as a safe and versatile nanoplatform for next-generation cancer therapy.
Co-reporter:Lizhen He, Lilan Zeng, Xiaoxuan Mai, Changzheng Shi, Liangping Luo and Tianfeng Chen
Journal of Materials Chemistry A 2017 - vol. 5(Issue 16) pp:NaN3034-3034
Publication Date(Web):2017/03/22
DOI:10.1039/C6TB03365B
Glioblastoma is considered as the most lethal cancer, due to the inability of chemotherapeutic agents to reach the glioma core as well as the infiltration zone of the invasive glioma cells. Nanotechnology based delivery systems bring new hope to cancer targeted therapy and diagnosis owing to their enhancement of selective cellular uptake and cytotoxicity to cancer cells through various smart designs. We prepared a novel selenium-based composite nanosystem (QDs/Se@Ru(A)) surface functionalized with the AS1411 aptamer and loaded with quantum dots to realize selectivity against glioblastoma and enhance theranostic effects. This cancer targeted nanosystem significantly enhanced the cellular uptake in glioma cells through nucleolin mediated endocytosis, and increased selectivity between cancer and normal cells. The QDs/Se@Ru(A) nanosystem can also be used for spontaneous fluorescence of biological probes to explore their localization in cancer cells, because of the green fluorescent quantum dots loaded into the selenium nanoparticles. QDs/Se@Ru(A) promotes excess reactive oxygen species (ROS) production in glioma cells to induce DNA damage, thus activating diverse downstream signaling pathways, and inhibiting proliferation of U87 cells through the G2/M phase cycle. Thus, this study provides an effective strategy to design a theranostic agent to simultaneously realize cell imaging and therapy for glioblastoma treatment.
Co-reporter:Xueyang Fang, Wenting Jiang, Yanyu Huang, Fang Yang and Tianfeng Chen
Journal of Materials Chemistry A 2017 - vol. 5(Issue 5) pp:NaN952-952
Publication Date(Web):2016/12/08
DOI:10.1039/C6TB02361D
Multidrug resistance is one of the main causes leading to failure of chemotherapy. Therefore, the rational design of targeting drug systems to reverse multidrug resistance is becoming an important strategy for cancer therapy. Herein, we present a novel copolymer-based nanoparticle that was size changeable and could realize the goal of precise drug controlled release under acidic conditions, and could overcome the multidrug resistance in breast cancer cells. This PCP/uPA nanosystem was formed through the crosslinking between chitosan (CS) and poly(N-isopropylacrylamide) (PNIPAM), followed by surface decoration with polyethylene glycol (mPEG) and a breast cancer targeting peptide uPA, which was then used to encapsulate metal complexes (RuPOP and Fe(PiP)3) to solve their bottleneck of low solubility and stability under physiological conditions. These multifunctional nanosystems (PCP-Ru/uPA and PCP-Fe/uPA) exhibited remarkable anticancer activity and could overcome the poor stability and low solubility of RuPOP and Fe(PiP)3. Noticeably, PCP-Ru/uPA reversed the multidrug resistance of drug-resistant MCF-7 (MCF-7R) human breast cancer cells by enhancing the cellular uptake of RuPOP by MCF-7R cells and inhibiting the expression of ABC family proteins. Furthermore, when PCP-Ru/uPA was at pH 5.3 with lysozyme, the release amount of RuPOP is the largest compared with pH at 5.3 or 7.4, and the release rate of RuPOP reached 75% at 48 h. In other words, the nanosystem with a pH-responsive effect swelled in an acidic environment and released free RuPOP in the lysosome of cancer cells efficiently, which triggered ROS up-regulation and induced apoptosis in MCF-7R cells. Taken together, this study presents a novel size changeable nanosystem for precise drug controlled release and efficient overcoming of cancer multidrug resistance.
Co-reporter:Yahui Yang, Shulin Deng, Qinsong Zeng, Weilie Hu and Tianfeng Chen
Dalton Transactions 2016 - vol. 45(Issue 46) pp:NaN18475-18475
Publication Date(Web):2016/09/05
DOI:10.1039/C6DT02045C
Bladder cancer is still a common malignancy of the urinary tract due to the high metastasis rate and unexpected side effects of drug treatments. The acidic environment of the urinary bladder also strongly limits the efficacy of the chemotherapeutic agents during the treatment of bladder cancer. In this study, a series of selenadiazole derivatives (SeDs) have been rationally designed and synthesized and could actively suppress the progression and metastasis of bladder cancer cells. SeDs demonstrated better antiproliferative activity and higher stability under different physiological conditions, especially in an acidic urocystic environment, than mitomycin, a clinically used anti-bladder cancer drug. In particular, compound 1b displayed better selectivity between cancer and normal cells in comparison with other compounds. Studies on the structure–activity relationship revealed that the introduction of strong electron donating substituents, such as the methoxy group, resulted in a dramatic enhancement in the anticancer efficacy. Furthermore, 1b induced anti-migration and anti-invasion activities against bladder cancer cells. Mechanistic investigation revealed that compound 1b was able to enter the cells through endocytosis and then trigger reactive oxygen species (ROS) overproduction, further causing DNA damage-mediated p53 phosphorylation and promoting cancer cell apoptosis by regulating the AKT and MAPKs signaling pathways. Altogether, the study provides a strategy for rational design of selenadiazole derivatives with improved stability to antagonize bladder cancer.
Co-reporter:Zhennan Zhao, Zuandi Luo, Qiong Wu, Wenjie Zheng, Yanxian Feng and Tianfeng Chen
Dalton Transactions 2014 - vol. 43(Issue 45) pp:NaN17028-17028
Publication Date(Web):2014/07/17
DOI:10.1039/C4DT01392A
Ruthenium (Ru) polypyridyl complexes have emerged as leading players among the potential metal-based candidates for cancer treatment. However, the roles of cellular translocation in their action mechanisms remain elusive. Herein we present the synthesis and characterization of a series of ruthenium (Ru) complexes containing phenanthroline derivatives with varying lipophilicities, and examine their mechanism of anticancer action. Results showed that increasing the lipophilicity of complexes can enhance the rates of cellular uptake. The in vitro anticancer efficacy of these complexes depended on the levels of ROS overproduction, rather than on cellular Ru uptake levels. The introduction of a phenolic group on the ligand effectively enhanced their intracellular ROS generation and anticancer activities. In particular, complex 4, with an ortho-phenolic group on the ligand, exhibited better selectivity between cancer and normal cells in comparison with cisplatin. Notably, complex 4 entered the cancer cells partially through transferrin receptor-mediated endocytosis, and then it translocated from lysosomes to the mitochondria, where it activated mitochondrial dysfunction by regulation of Bcl-2 family proteins, thus leading to intracellular ROS overproduction. Excess ROS amplified apoptotic signals by activating many downstream pathways such as p53 and MAPK pathways to promote cell apoptosis. Overall, this study provides a drug design strategy for discovery of Ru-based apoptosis inducers, and elucidates the intracellular translocation of these complexes.
Co-reporter:Tianqi Nie, Hualian Wu, Ka-Hing Wong and Tianfeng Chen
Journal of Materials Chemistry A 2016 - vol. 4(Issue 13) pp:NaN2358-2358
Publication Date(Web):2016/02/23
DOI:10.1039/C5TB02710A
Selenium nanoparticles (SeNPs) have attracted increasing attention due to their potential application as an effective drug delivery system. However, the conventional synthetic methods are mostly confined to solution-based synthesis that are time consuming and with low efficiency. Herein, we demonstrate the facile synthesis of highly uniform SeNPs using glucose as the reductant and surface decorator (Glu–SeNPs) that could induce cancer cell apoptosis. Glucose was used as the reducing agent to reduce sodium selenite (Na2SeO3) at high temperature (115 °C), which also acted as the surface decorator of SeNPs to prevent aggregation in an aqueous solution, thus enhancing its stability under physiological conditions. The functionalized nanoparticles demonstrated high hemocompatibility and showed selective cytotoxicity towards various human cancer cells, but not normal cells, through induction of apoptosis by initiating both intrinsic and extrinsic pathways. Furthermore, studies on the action mechanisms revealed that internalized Glu–SeNPs significantly and rapidly triggered intracellular ROS overproduction and mitochondria dysfunction to regulate the cell fate. Taken together, this study provides a new and effective method for facile synthesis of SeNPs possessing potent anticancer efficacy.
Co-reporter:Leung Chan, Yanyu Huang and Tianfeng Chen
Journal of Materials Chemistry A 2016 - vol. 4(Issue 26) pp:NaN4525-4525
Publication Date(Web):2016/05/24
DOI:10.1039/C6TB00514D
Cancer targeting delivery and controlled release of metal complexes may offer a new approach to improve their anticancer efficacy with eliminated systemic toxicities. Herein, a biotin-conjugated tri-block polymer delivery system was designed and used as a carrier of potent ruthenium polypyridyl (RuPOP) complexes to achieve superior biocompatibility, higher water solubility and cancer-targeting ability. Biotin was used as a targeting molecule to enhance the cellular uptake and retention of RuPOP in diverse carcinoma cells. Furthermore, the nanosystem (Bio-PLGA@Ru) was efficiently internalized by cancer cells by the lipid raft-mediated endocytosis pathway, triggered ROS overproduction and activated p53-mediated apoptosis in cancer cells. Moreover, the nanosystem effectively accumulated in tumor tissue and alleviated the damage of the metal complex to the organs. Taken together, this study demonstrates a smart strategy for the fabrication of a biocompatible and cancer-targeted PLGA-based copolymer nanosystem to achieve superior tumor cell localization and anticancer ability with eliminated systemic toxicities.
Co-reporter:Yinghua Li, Xiaoling Li, Wenjie Zheng, Cundong Fan, Yibo Zhang and Tianfeng Chen
Journal of Materials Chemistry A 2013 - vol. 1(Issue 46) pp:NaN6372-6372
Publication Date(Web):2013/10/01
DOI:10.1039/C3TB21168A
The most frequent adverse effect of cisplatin-based chemotherapy is nephrotoxicity. Oxidative stress has been implicated as an important mechanism in the pathogenesis of cisplatin-induced nephrotoxicity. In the present study, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox) surface-functionalized selenium nanoparticles (Se@Trolox) with enhanced antioxidant activity have been prepared by self-assembly of trolox on the surface of the nanoparticles, and their nephroprotective effects have been investigated. Functionalization by trolox significantly enhanced cell uptake and in vitro antioxidant activities of the nanoparticles. In addition, pretreatment with Se@Trolox dose-dependently blocked cisplatin-induced cell growth inhibition against HK-2 cells. Mechanistic investigation suggested that Se@Trolox markedly prevented cisplatin-induced apoptosis in HK-2 cells, as evidenced by inhibition of chromatin condensation, DNA fragmentation, PARP cleavage and activation of caspase-3. Furthermore, Se@Trolox effectively blocked the cisplatin-induced reactive oxygen species (ROS) accumulation, activation of AKT and MAPK signaling and DNA damage-mediated p53 phosphorylation in HK-2 cells. Taken together, our findings suggest that Se@Trolox is a promising Se species with potential application in prevention of cisplatin-induced renal injury.
Co-reporter:Lizhen He, Shengbin Ji, Haoqiang Lai and Tianfeng Chen
Journal of Materials Chemistry A 2015 - vol. 3(Issue 42) pp:NaN8393-8393
Publication Date(Web):2015/09/14
DOI:10.1039/C5TB01501D
The lack of early and timely diagnosis of tumors and the monitoring of their response to therapeutics have limited the successful cancer treatments. Theranostic agents are expected to realize the dual-purpose of simultaneous diagnosis and therapy for treatments of cancers. In the present study, we have examined the effects of the chemical structure of selenadiazole derivatives (SeDs) on their anticancer efficacy and radio-sensitization against clinically used X-rays. The results showed that the introduction of a nitro group (–NO2) into SeD-3 significantly enhanced the anticancer activity of SeDs. The higher lipophilicity endowed SeD-3 with higher cellular internalization ability, resulting in higher cellular uptake and anticancer efficacy. Specifically, the capacity of autofluorescence allowed the use of SeD-3 as a promising theranostic agent to directly monitor the cellular uptake, localization and biodistribution in vitro and in vivo. Interestingly, SeD-3 also significantly enhanced the sensitivity of HeLa cervical cells to X-ray-induced apoptosis by targeting the inhibition of TrxR and promoting intracellular ROS overproduction, which activated the downstream ROS-mediated signaling pathways to regulate cell apoptosis. Furthermore, SeD-3 exhibited satisfactory in vivo antitumor efficacy through the inhibition of tumor proliferation and induction of tumor cell apoptosis, and showed no toxicity to the main organs. Moreover, from the results of hematological analysis, we found that not only inhibiting the tumor growth, treatment of SeD-3 also alleviated the damage of liver, kidney and heart function of nude mice induced by HeLa xenografts. Taken together, this study demonstrates that SeDs could be further developed as an effective and safe theranostic agent for simultaneous cancer chemo-/radiotherapy.
Co-reporter:Yifan Wang, Wenying Li, Yahui Yang, Qinsong Zeng, Ka-Hing Wong, Xiaoling Li and Tianfeng Chen
Journal of Materials Chemistry A 2015 - vol. 3(Issue 48) pp:NaN9382-9382
Publication Date(Web):2015/11/05
DOI:10.1039/C5TB01929J
The development of novel therapeutics for patients with bladder cancer is an important area of research, particularly considering the rather limited treatment options currently available. In this study, we designed and synthesized a conjugate of cancer-targeting selenadiazole derivative BSeC (benzo[1,2,5]selenadiazole-5-carboxylic acid) and the RGD (arginine–glycine–aspartate) peptide, which was used as a targeting molecule, using a PEI polymer as a linker. The results showed that BSeC–PEI–RGD formed core–shell spherical nanoparticles with improved stability in physiological and low pH solutions. The cancer-targeting design significantly enhanced cellular uptake of BSeC–PEI–RGD and decreased its cytotoxicity to normal cells. The nanoparticles could inhibit the migration and invasion of EJ and T24 bladder cancer cell and reduce cancer cell proliferation through the induction of reactive oxygen species (ROS)-dependent apoptosis and mitochondrial dysfunction. Further mechanistic studies using western blotting showed that BSeC–PEI–RGD triggered bladder cancer cell apoptosis by activating p38, JNK and p53 and by inactivating AKT and ERK. In summary, this study demonstrates the rational design of a polymer-based cancer-targeting nanosystem as a carrier of the selenadiazole derivative to treat bladder cancer.
Co-reporter:Hualian Wu, Xiaoling Li, Wen Liu, Tianfeng Chen, Yinghua Li, Wenjie Zheng, Cornelia Wing-Yin Man, Man-Kin Wong and Ka-Hing Wong
Journal of Materials Chemistry A 2012 - vol. 22(Issue 19) pp:NaN9610-9610
Publication Date(Web):2012/04/04
DOI:10.1039/C2JM16828F
By using mushroom polysaccharides–protein complexes (PSP) as the capping agent, size controllable and highly stable selenium nanoparticles (SeNPs) have been successfully created in a simple redox system of sodium selenite and ascorbic acid. SeNPs were capped with PSP through strong physical adsorption of hydroxyl groups of polysaccharides and imino groups of proteins on the surface of SeNPs. PSP surface decoration significantly enhanced the cellular uptake of SeNPs through endocytosis. Treatment with PSP–SeNPs significantly inhibited the growth of MCF-7 human breast cacinoma cells through induction of apoptosis with the involvement of PARP cleavage and caspase activation. Moreover, PSP–SeNPs not only significantly induced dose-dependent disruption of mitochondrial membrane potential in MCF-7 cells after 24 h treatment, but it also enhanced reactive oxygen species (ROS) generation as early as 15 min, indicating that ROS-mediated mitochondrial dysfunction may play an important role in PSP–SeNPs-induced apoptosis. Our results suggest that PSP–SeNPs may be a candidate for further evaluation as a chemopreventive agent for human cancers, and the strategy to use PSP as a surface decorator could be a highly efficient way to enhance the cellular uptake and anticancer efficacy of nanomaterials.
Co-reporter:Bo Yu, Xiaoling Li, Wenjie Zheng, Yanxian Feng, Yum-Shing Wong and Tianfeng Chen
Journal of Materials Chemistry A 2014 - vol. 2(Issue 33) pp:NaN5418-5418
Publication Date(Web):2014/06/10
DOI:10.1039/C4TB00399C
Selenium nanoparticles (SeNPs) have been widely used in various biomedical applications, including cancer therapy, diagnosis and drug delivery. Herein, we fabricated a novel type of structure-transformable capsules by decoration of SeNPs with folate-chitosan to form smart-shell nanocapsules (FAC@CurP–SeNPs). The shrink particles could target cancer cells over expressing folate receptor and enter the cells via folate receptor-mediated endocytosis. FAC@CurP–SeNPs were expanded to snowflake particles under acidifying stimulus (pH 5.3), which led to enhanced drug-release over prolonged periods. Treatment with FAC@CurP–SeNPs significantly inhibited the growth of MCF-7 human breast carcinoma cells through induction of apoptosis, which was evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. The contribution of extrinsic and intrinsic apoptotic pathways to the cell apoptosis was confirmed by activation of caspase-9 and caspase-8. Internalized FAC@CurP–SeNPs triggers intracellular ROS overproduction, thus activates p53, MAPKs pathways and inhibits NFκB and to promote cell apoptosis. Our results suggest that FAC@CurP–SeNPs may be a candidate for further evaluation as a agent for human cancers, and the strategy to use transformable nanocapsules could be a highly efficient way to enhance controlled drug release and anticancer efficacy.
Co-reporter:Hao Hu, Yuanyuan You, Lizhen He and Tianfeng Chen
Journal of Materials Chemistry A 2015 - vol. 3(Issue 30) pp:NaN6346-6346
Publication Date(Web):2015/06/22
DOI:10.1039/C5TB00612K
Angiogenesis is essential for tumorous progression and metastasis. The RGD (Arg–Gly–Asp acid) peptide has been demonstrated to be a remarkable targeting reagent and can be distinguished by the integrin receptor overexpressed in various human tumor cells. Mesoporous silica nanoparticles (MSNs) are one of the most promising carriers applied for delivery of drugs or genes. It is well known that NAMI-A is an excellent drug for antimigration of tumor cells. Targeting the tumor vasculature with RGD-modified nanomaterials is expected to be a promising strategy for cancer therapy. Herein we have investigated the antiangiogenic activity of NAMI-A-loaded and RGD peptide surface decorated mesoporous silica nanoparticles in vitro and in vivo. The results revealed that NAMI-A@MSN-RGD remarkably enhanced the cellular uptake and antiangiogenic efficacy in contrast to bare NAMI-A in vitro. The nanosystem of NAMI-A@MSN-RGD also exhibited inspiring antiangiogenic action in vivo. Furthermore, the RGD-functionalized nanodrug inhibited angiogenesis by means of apoptosis by triggering ROS-mediated DNA damage in human umbilical vein endothelial cells (HUVECs). Our results suggested that the use of RGD-peptide modified MSNs as a vehicle of anticancer drugs is an efficient way to construct cancer-targeted nanosystems with antiangiogenic activity.
Co-reporter:Lilan Zeng, Jingjing Chen, Shengbin Ji, Leung Chan, Wenjie Zheng and Tianfeng Chen
Journal of Materials Chemistry A 2015 - vol. 3(Issue 21) pp:NaN4354-4354
Publication Date(Web):2015/04/16
DOI:10.1039/C4TB02010C
Multidrug resistance has been identified as a major cause of failure of cancer treatment. Due to their relative non-toxicity, selenium nanoparticles (SeNPs) have been reported as excellent cancer therapeutic nanodrugs. In this study, we designed and prepared a novel nanosystem with borneol surface-functionalized and liver targeting to overcome the multidrug resistance. Borneol (Bor)-modified SeNPs can significantly improve the stability of SeNPs and their anticancer activity. Fe(PiP)3 (PiP = 2-phenylimidazo [4,5-f][1,10] phenanthroline) is a novel anticancer agent with low solubility and stability. In this study, we have constructed a functionalized SeNPs (GAL/Bor@SeNPs) by the surface decoration of galactosamine (GAL), which is a liver targeting ligand that significantly enhanced the cellular uptake of Fe(PiP)3-loaded nanosystem via dynamin-mediated lipid raft endocytosis and clathrin-mediated endocytosis in liver cancer cells overexpressing asialoglycoprotein receptor, thus achieving amplified anticancer efficacy. This multifunctional nanosystem exhibited excellent hemocompatibility and anticancer activity comparing with Fe(PiP)3 or SeNPs alone. Remarkably, GAL/Bor@SeNPs antagonized the multidrug resistance in R-HepG2 cells by inhibiting the expression of ABC family proteins, resulting in enhanced drug accumulation and retention. Internalized nanoparticles released free iron complexes into the cytoplasm, which triggered ROS down-regulation and induced apoptosis through activating AKT and MAPKs pathways. Moreover, this nanosystem effectively prolonged the circulation time of encapsulated drugs. Taken together, this study suggests that GAL and Bor functionalization could be an effective strategy to design cancer-targeted nanomaterials to antagonize multidrug resistance in cancers.
Co-reporter:Bo Yu, Hong Li, Jinhui Zhang, Wenjie Zheng and Tianfeng Chen
Journal of Materials Chemistry A 2015 - vol. 3(Issue 12) pp:NaN2504-2504
Publication Date(Web):2015/02/03
DOI:10.1039/C4TB02146K
The rational design and fabrication of nanodelivery systems to encapsulate drugs has been proven to be a promising and effective strategy for cancer therapy. Selenocystine (SeC), a naturally occurring selenoamino acid, has received more and more attention due to its novel pharmacological properties in the treatments of cancers. In this study, we fabricated a cancer-targeted nanodrug delivery system by encapsulating SeC into chitosan (CS) nanoparticles with folate surface decoration (FA–SeC–CSNPs) and evaluated its antiproliferative activities. The nanosystem entered the cells through endocytosis and released SeC in lysosomes under an acidic environment. Compared with SeC–CSNPs and SeC, FA–SeC–CSNPs significantly inhibited the growth of HeLa human cervical cancer cells that overexpressed folate receptors through the induction of apoptosis with the involvement of PARP cleavage and caspase activation. Moreover, FA–SeC–CSNPs also significantly suppressed the migration and invasion of HeLa cells in a dose-dependent manner. Furthermore, the intracellular nanosystem triggered the overproduction of reactive oxygen species (ROS) as early as 25 min after treatment, which activated various downstream signaling pathways such as p53, AKT and MAPKs to induce the cell death. Taken together, this study demonstrates a strategy for rational design of a cancer-targeted nanosystem loaded with selenocompounds to achieve selective cellular uptake and enhanced anticancer efficacy.
Co-reporter:Mingxian Liu, Yanzhou Chang, Jing Yang, Yuanyuan You, Rui He, Tianfeng Chen and Changren Zhou
Journal of Materials Chemistry A 2016 - vol. 4(Issue 13) pp:NaN2263-2263
Publication Date(Web):2016/03/01
DOI:10.1039/C5TB02725J
Halloysite nanotubes (HNTs) have a unique tubular structure in nanoscale, and have shown potential as novel carriers for various drugs. Coating the nanotubes with a hydrophilic polymer shell can significantly decrease the toxicity and provide colloidal stability during blood circulation. Here, we synthesized chitosan grafted HNTs (HNTs-g-CS) and investigated their potential as a nano-formulation for the anticancer drug curcumin. The structure and properties of HNTs-g-CS were characterized using water contact angle, zeta-potential, Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), and transmission electron microscopy (TEM) techniques. HNTs-g-CS exhibit a maximum 90.8% entrapment efficiency and 3.4% loading capacity of curcumin, which are higher than those of raw HNTs. HNTs-g-CS also show no obvious hemolytic phenomenon and good stability in serum. The cumulative release ratio of curcumin from HNTs-g-CS/curcumin at cell lysate after 48 hours is 84.2%. The curcumin loaded HNTs-g-CS show specific toxicity to various cancer cell lines, including HepG2, MCF-7, SV-HUC-1, EJ, Caski and HeLa, and demonstrate an inhibition concentration of IC50 at 5.3–192 μM as assessed by cytotoxicity studies. The anticancer activity of this nanoformulation is extremely high in EJ cells compared with the other cancer cell lines. The cell uptake of HNTs-g-CS is confirmed by fluorescence microscopy. Flow cytometric analysis of curcumin loaded HNTs-g-CS shows that curcumin loaded HNTs-g-CS increase apoptosis on EJ cells. The content of ROS created by HNTs-g-CS/curcumin is more than that of free curcumin. All these results suggest that HNTs-g-CS are potential nanovehicles for anticancer drug delivery in cancer therapy.
Co-reporter:Shenggui Liu, Wenqiang Cao, Lianling Yu, Wenjie Zheng, Linlin Li, Cundong Fan and Tianfeng Chen
Dalton Transactions 2013 - vol. 42(Issue 16) pp:NaN5940-5940
Publication Date(Web):2013/02/08
DOI:10.1039/C3DT33077J
In the present study, two zinc(II) complexes containing bis-benzimidazole derivatives, Zn(bpbp)Cl2 (1) and [Zn(bpbp)2](ClO4)2·CH3CH2OH·H2O (2) (bpbp = 2,6-bis(1-phenyl-1H-benzo[d]imidazol-2-yl)pyridine), have been designed, synthesized and evaluated for their in vitro anticancer activities. The underlying molecular mechanisms through which they caused the cancer cell death were also elucidated. The complexes were identified as potent antiproliferative agents against a panel of five human cancer cell lines by comparing with cisplatin. Complex 2 demonstrated dose-dependent growth inhibition on MCF-7 human breast carcinoma cells with IC50 at 2.9 μM. Despite this potency, the complexes possessed great selectivity between human cancer cells and normal cells. Induction of apoptosis in MCF-7 cells by complex 2 was evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Further investigation on intracellular mechanisms revealed that complex 2 was able to induce p53-dependent apoptosis in cancer cells by triggering DNA damage. On the basis of this evidence, we suggest that Zn(II) complexes containing bis-benzimidazole derivatives may be candidates for further evaluation as chemotherapeutic agents for human cancers.
Co-reporter:Yanxian Feng, Jianyu Su, Zhennan Zhao, Wenjie Zheng, Hualian Wu, Yibo Zhang and Tianfeng Chen
Dalton Transactions 2014 - vol. 43(Issue 4) pp:NaN1861-1861
Publication Date(Web):2013/11/01
DOI:10.1039/C3DT52468J
The use of selenium for anticancer therapy has been heavily explored during the last decade. Amino acids (AAs) play central roles both as building blocks of proteins and intermediates in metabolism. In the present study, AAs-modified selenium nanoparticles (SeNPs@AAs) have been successfully synthesized in a simple redox system. Typical neutral (valine), acidic (aspartic acid) and basic (lysine) amino acids were used to decorate SeNPs, and the stable and homodisperse nanoparticles were characterized by zeta potential and transmission electron microscope. The result of X-ray photoelectron spectra (XPS) showed that the interaction of –NH3+ groups of the amino acids with negative-charged SeNPs could be a driving force for dispersion of the nanoparticles. The screening of in vitro anticancer activities demonstrated that SeNPs@AAs exhibited differential growth inhibitory effects on various human cancer cell lines. Among them, SeNPs decorated by Lys displayed higher anticancer efficacy than those of valine and aspartic acid. The studies on the in vitro cellular uptake mechanisms revealed that SeNPs@AAs were internalized by cancer cells through endocytosis. Flow cytometric analysis and the determination of caspase activity indicated that treatment of the MCF-7 breast adenocarcinoma cells with SeNPs@AAs led to a dose-dependent increase in apoptosis. Moreover, it was found that SeNPs@AAs-induced ROS overproduction could be the upstream signal of caspase activation and mitochondrial dysfunction in cancer cells. Taken together, our results suggest that these amino acid biocompatible nanoparticles might have potential application as chemopreventive and chemotherapeutic agents for human cancers.
Co-reporter:Zhiqin Deng, Lianling Yu, Wenqiang Cao, Wenjie Zheng and Tianfeng Chen
Chemical Communications 2015 - vol. 51(Issue 13) pp:NaN2640-2640
Publication Date(Web):2015/01/02
DOI:10.1039/C4CC07926D
A novel selenium-containing ruthenium complex Ru(phtpy)(phenSe)Cl(ClO4) (phtpy = 4-phenyl-2,2′:6′,2′′-terpyridine, phenSe = 2-selenicimidazole[4,5-f]1,10-phenanthroline) has been synthesized and found be able to enhance radiation-induced DNA damage through superoxide overproduction, which leads to G2/M arrest and apoptosis in cancer cells by activating ROS-mediated pathways.
![Benzoic acid, 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-](/data/chemimg/131300/865169-07-9.png)
![Benzoic acid, 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-](/data/chemimg/131300/865169-07-9_b.png)
![Selenazolo[5,4-b]pyridin-2-amine, N-phenyl-](http://img.cochemist.com/ccimg/682800/682740-77-8.png)
![Selenazolo[5,4-b]pyridin-2-amine, N-phenyl-](http://img.cochemist.com/ccimg/682800/682740-77-8_b.png)
![1H-Imidazo[4,5-f][1,10]phenanthroline, 2-(4-methylphenyl)-](http://img.cochemist.com/ccimg/608600/608521-18-2.png)
![1H-Imidazo[4,5-f][1,10]phenanthroline, 2-(4-methylphenyl)-](http://img.cochemist.com/ccimg/608600/608521-18-2_b.png)
![Phenol, 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-](/data/chemimg/3726600/256525-24-3.png)
![Phenol, 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-](/data/chemimg/3726600/256525-24-3_b.png)
![1H-Imidazo[4,5-f][1,10]phenanthroline, 2-(4-methoxyphenyl)-](/data/chemimg/3108700/219615-28-8.png)
![1H-Imidazo[4,5-f][1,10]phenanthroline, 2-(4-methoxyphenyl)-](/data/chemimg/3108700/219615-28-8_b.png)
![1H-Imidazo[4,5-f][1,10]phenanthroline, 2-(2-chlorophenyl)-](http://img.cochemist.com/ccimg/215700/215601-93-7.png)
![1H-Imidazo[4,5-f][1,10]phenanthroline, 2-(2-chlorophenyl)-](http://img.cochemist.com/ccimg/215700/215601-93-7_b.png)
![N-[4-[[(2-amino-3,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-Glutamic acid 5-(2,5-dioxo-1-pyrrolidinyl) ester](http://img.cochemist.com/ccimg/153500/153445-05-7.png)
![N-[4-[[(2-amino-3,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-Glutamic acid 5-(2,5-dioxo-1-pyrrolidinyl) ester](http://img.cochemist.com/ccimg/153500/153445-05-7_b.png)
![Butanedinitrile,2,3-bis[amino[(2-aminophenyl)thio]methylene]-](http://img.cochemist.com/ccimg/109600/109511-58-2.png)
![Butanedinitrile,2,3-bis[amino[(2-aminophenyl)thio]methylene]-](http://img.cochemist.com/ccimg/109600/109511-58-2_b.png)
![2-[4-(aminoiminomethyl)phenyl]-1H-Indole-6-carboximidamide](http://img.cochemist.com/ccimg/47200/47165-04-8.png)
![2-[4-(aminoiminomethyl)phenyl]-1H-Indole-6-carboximidamide](http://img.cochemist.com/ccimg/47200/47165-04-8_b.png)
![6-(1,3-dihydro-2H-phenanthro[9,10-d]imidazol-2-ylidene)cyclohexa-2,4-dien-1-one](http://img.cochemist.com/ccimg/24300/24293-67-2.png)
![6-(1,3-dihydro-2H-phenanthro[9,10-d]imidazol-2-ylidene)cyclohexa-2,4-dien-1-one](http://img.cochemist.com/ccimg/24300/24293-67-2_b.png)
![1H-Imidazo[4,5-f][1,10]phenanthroline](/data/chemimg/129500/171565-43-8.png)
![1H-Imidazo[4,5-f][1,10]phenanthroline](/data/chemimg/129500/171565-43-8_b.png)
![Phenol, 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-](/data/chemimg/104700/185129-91-3.png)
![Phenol, 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-](/data/chemimg/104700/185129-91-3_b.png)
![1H-Imidazo[4,5-f][1,10]phenanthroline, 2-phenyl-](/data/chemimg/133600/171565-44-9.png)
![1H-Imidazo[4,5-f][1,10]phenanthroline, 2-phenyl-](/data/chemimg/133600/171565-44-9_b.png)
