Co-reporter:Yujie Zhang, Yifei Lu, Yu Zhang, Xi He, Qinjun Chen, Lisha Liu, Xinli Chen, Chunhui Ruan, Tao Sun, and Chen Jiang
Molecular Pharmaceutics October 2, 2017 Volume 14(Issue 10) pp:3409-3409
Publication Date(Web):August 23, 2017
DOI:10.1021/acs.molpharmaceut.7b00430
Most small molecular chemotherapeutics have poor water solubility and unexpected pharmacokinetics and toxicity to normal tissues. A series of nano drug delivery systems have been developed to solve the problems, among which a micelle based on linear–dendritic polymer–drug conjugates (LDPDCs) is a promising strategy to deliver hydrophobic chemotherapeutics due to its small size, fine stability in blood circulation, and high drug loading capacity. In this work we synthesized a novel amphiphilic linear–dendritic PEG–PTX8 conjugate which can also encapsulate extra free PTX and self-assemble into uniform ultrasmall micelles with a hydrated diameter of 25.50 ± 0.27 nm. To realize efficient drug delivery to tumor sites, a cyclic tumor homing and penetrating peptide iNGR was linked to the PEG–PTX8 conjugate. The biological evaluation was performed on a human triple negative breast cancer model. PTX accumulation in tumor at 24 h of the TNBC-bearing mice treated with iNGR–PEG–PTX8/PTX micelles was significantly enhanced (P < 0.001, two-way ANOVA) compared to that of Taxol and untargeted MeO–PEG–PTX8/PTX micelles. Furthermore, iNGR–PEG–PTX8/PTX micelles showed an obvious strong antitumor effect, and the median survival time of TNBC bearing mice treated with iNGR-modified micelles was significantly extended compared to Taxol. Therefore, this smart micelle system may be a favorable platform for effective TNBC therapy.Keywords: linear−dendritic; micelle; polymer−drug conjugates; triple negative breast cancer; tumor targeting;
Co-reporter:Tao Sun, Xutao Jiang, Qingbing Wang, Qinjun Chen, Yifei Lu, Lisha Liu, Yu Zhang, Xi He, Chunhui Ruan, Yujie Zhang, Qin Guo, Yaohua Liu, and Chen Jiang
ACS Applied Materials & Interfaces October 11, 2017 Volume 9(Issue 40) pp:34603-34603
Publication Date(Web):September 19, 2017
DOI:10.1021/acsami.7b05997
Currently, glioblastoma (glioma) is described as the deadliest brain tumor for its invasive natural with exceeding difficulty in surgical excision. Blood-brain barrier (BBB) can restrict the penetration of most therapeutic reagents including platinum (Pt)-based drugs-the most widely used reagents in clinical trials for their revolutionized cancer chemotherapy against a broad range of tumors. Nanomedicine represents a promising strategy for the intravenous delivery of Pt-based drugs into the brain. In this research, with the aim of malignant glioma treatment by Pt-based drugs, a novel nano drug carrier was developed: dendrigraft poly-L-lysines (DGLs) was PEGylated, linked with diethylenetriaminpentaacetic acid (DTPA) to complex (1,2-diaminocyclohexane)platinum(II) (DACHPt), and modified with Substance P (SP) as a BBB/glioma dual-targeting moiety. The preparation and characterization of the platform were exhibited in detail. The increased targeting capability and antitumor effect was found both in vitro and in vivo. The well-defined chemical composition, rigorously nanoscaled size and the first attempt of using SP as a BBB/glioma dual-targeting group were highlighted. The combined results suggest this strategy may serve as novel formulation for Pt-based drugs with the aim of clinical glioma treatment.Keywords: blood-brain barrier; drug delivery; glioma; platinum drug; Substance P;
Co-reporter:Lisha Liu, Yunke Bi, Muru Zhou, Xinli Chen, Xi He, Yujie Zhang, Tao Sun, Chunhui Ruan, Qingjun Chen, Hao Wang, and Chen Jiang
ACS Applied Materials & Interfaces March 1, 2017 Volume 9(Issue 8) pp:
Publication Date(Web):February 2, 2017
DOI:10.1021/acsami.6b14390
Triple-negative breast cancers (TNBCs), devoid of hormone receptors and human epidermal growth-factor receptor-2/Neu expression, bring about poor prognosis and induce a high rate of systematic metastases. The ineffectiveness of current therapies on TNBCs could be attributed to the lack of efficient targeted therapy. Paclitaxel (PTX) is considered one of first-line chemotherapeutics for TNBC treatment but, due to its low aqueous solubility and nonspecific accumulation, results in poor antitumor efficacy. The present study is aimed at enhancing the chemotherapeutic potency of PTX by improving the stability and targeting efficiency of PTX-loaded nanoparticulate drug carriers. Here, PTX was incorporated in nontoxic and endogenous material, human serum albumin (HSA), via an innovative disulfide reduction method to construct HSA-based PTX nanoparticle (HSA-PTX NP) to not only realize redox-responsive drug release but also improve in vivo stability. Besides, W peptide was selected as a target ligand to be conjugated with HSA-PTX NP for endowing active targeting ability. The resulting Wpep-HSA-PTX NP possessed a spherical structure (118 nm), 9.87% drug-loading content, and 86.3% entrapment efficiency. An in vitro drug release test showed that PTX release from Wpep-HSA-PTX NP was of a redox-responsive manner. Furthermore, cellular uptake of Wpep-HSA-PTX NP was significantly enhanced, exhibiting the improved antiproliferation and antitube formation effects of PTX in vitro. In comparison with those commercial formulations and conventional HSA NP, Wpep-HSA-PTX NP exhibited better pharmacokinetic behaviors and tumor homing characteristics. The antitumor efficacy of Wpep-HSA-PTX NP was further confirmed by the strong pro-apoptotic effect and reduced tumor burden. In a word, this evidence highlighted the proof of concept for Wpep-HSA NP as a promising conqueror to the ineffectiveness of TNBC therapy.Keywords: disulfide reduction; drug delivery; human serum albumin; triple-negative breast cancer; W peptide;
Co-reporter:Yu Zhang, Qin Guo, Sai An, Yifei Lu, Jianfeng Li, Xi He, Lisha Liu, Yujie Zhang, Tao Sun, and Chen Jiang
ACS Applied Materials & Interfaces April 12, 2017 Volume 9(Issue 14) pp:12227-12227
Publication Date(Web):March 28, 2017
DOI:10.1021/acsami.6b16815
Tumor microenvironment plays a vital role in the process of tumor development, proliferation, invasion, and metastasis. It is well acknowledged that reduction in pH, reactive oxygen species (ROS), and increased level of glucose transporter 1 (GLUT1) have become featured intracellular and extracellular biochemical markers of cancer owing to oncogenic transformation and abnormal metabolism. To establish a distinctive drug delivery system directed against the tumor microenvironment features, we develop a newly engineered polymeric nanoplatform for efficient doxorubicin (DOX) delivery with reduced systemic toxicity and high antitumor efficiency. A thioketal cross-linker is used to improve the formulation’s stability during circulation and to foster quick intracellular drug release in response to tumor’s ROS potential. Furthermore, the low drug loading efficiency of conventional micelles is ameliorated in this polymeric nanoplatform via a drug-conjugation strategy with an acid-labile chemical bond. The optimized formulation, MPLs-sB-DOX micelles, possesses a high drug-loading efficiency (31%) within nanosize diameter (37.8 nm). In addition, this formulation shows significant improvement in the pharmacokinetics and biodistribution profiles with a 2.69-fold increase of tumor accumulation, while with largely reduced systemic toxicity in comparison with free DOX. With advantages of efficient cellular uptake, preferential tumor accumulation, and controlled release behaviors, MPLs-sB-DOX micelles demonstrate good tumor-targeting ability with reduced systemic toxicity, proving to be a promising formulation for breast cancer therapy.Keywords: controlled release; drug delivery; polymeric nanoplatform; ROS responsive; tumor microenvironment;
Co-reporter:Tao Sun;Qingbing Wang;Yunke Bi;Xinli Chen;Lisha Liu;Chunhui Ruan;Zhifeng Zhao
Journal of Materials Chemistry B 2017 vol. 5(Issue 14) pp:2644-2654
Publication Date(Web):2017/04/05
DOI:10.1039/C6TB03272A
Herein we report a novel “supra-prodrug-type” superamphiphile design: via a redox-sensitive self-immolative linker, a hydrophobic drug molecule was labeled with an azobenzene moiety, which was designed to be capped by a hydrophilic cyclodextrin (CD) molecule. Four clinical hydrophobic drugs, 7-ethyl-10-hydroxycamptothecin (SN-38), doxorubicin (DOX), phenytoin and aliskiren, were investigated to directly participate in building a novel class of superamphiphile, in which the CD moiety plays as the hydrophilic head and the drug as the hydrophobic tail. This novel type of superamphiphile can further self-assemble into vesicular or tubular structures, characterized by transmission electron microscope (TEM), scanning electron microscope (SEM) and dynamic light scattering (DLS). The possible self-assembly mechanism is given based on multiple pieces of evidence, including nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and Ultraviolet-visible spectroscopy (UV-vis) results. The reconversion kinetics of the prodrug as a function of glutathione (GSH) in the presence or absence of UV irradiation is presented. Cell experiments indicate that the “supra-prodrug” can be facially endowed with a function by a simple substitution with another functionalized host. We hope this work can provide new reference in the field of drug screening, formulation and delivery.
Co-reporter:Yunke Bi, Lisha Liu, Yifei Lu, Tao Sun, Chen Shen, Xinli Chen, Qinjun Chen, Sai An, Xi He, Chunhui Ruan, Yinhao Wu, Yujie Zhang, Qin Guo, Zhixing Zheng, Yaohua Liu, Meiqing Lou, Shiguang Zhao, and Chen Jiang
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 41) pp:27465
Publication Date(Web):July 28, 2016
DOI:10.1021/acsami.6b05572
Glioma is regarded as the deadliest and most common brain tumor because of the extremely difficult surgical excision ascribed from its invasive nature. In addition, the natural blood-brain barrier (BBB) greatly restricts the therapeutics’ penetration into the central nervous system. Carmustine (BCNU) is a widely used antiglioma drug in clinical applications. However, its serious complications prevent it from being applied in a clinical setting to some extent. Thus, it is urgent to explore novel BCNU delivery systems specially designed for glioma. Development of polymeric nanoparticles offers a favorable alternative to serve this purpose. Particularly, use of poly(lactic-co-glycolic acid) (PLGA) has been shown to be advantageous for its favorable biodegradability and biocompatibility, which ensure safe therapies. In this study, T7 peptide-conjugated, BCNU-loaded micelles were constructed successfully via the emulsion-solvent evaporation method. The micelles were characterized by transmission electron microscopy and dynamic light scattering in detail, and the capacity of BBB crossing was studied. The in vivo detecting results of the targeting effect using the BODIPY probe evidenced that T7-modified micelles showed a more pronounced accumulation and accumulated in the tumor more efficiently than in the unconjugated probe. Meanwhile, the targeting group exhibited the best curative effect accompanied with the lowest loss in body weight, the smallest tumor size, and an obviously prolonged survival time among the groups. In the near future, we believe the targeted delivery system specially designed for BCNU is expected to provide sufficient evidence to proceed to clinical trials.Keywords: BCNU; blood-brain barrier; glioma; micelle; receptor-mediated endocytosis; transferrin receptor
Co-reporter:Yuyang Kuang; Xutao Jiang; Yu Zhang; Yifei Lu; Haojun Ma; Yubo Guo; Yujie Zhang; Sai An; Jianfeng Li; Lisha Liu; Yinhao Wu; Jianying Liang
Molecular Pharmaceutics 2016 Volume 13(Issue 5) pp:1599-1607
Publication Date(Web):April 8, 2016
DOI:10.1021/acs.molpharmaceut.6b00051
Compared with peripheral tumors, glioma is very difficult to treat, not only because it has general features of tumor but also because the therapy has been restricted by the brain–blood barrier (BBB). The two main features of tumor growth are angiogenesis and proliferation of tumor cells. RNA interference (RNAi) can downregulate VEGF overexpression to inhibit tumor neovascularization. Meanwhile, doxorubicin (DOX) has been used for cytotoxic chemotherapy to kill tumor cells. Thus, combining RNAi and chemotherapy has been regarded as a potential strategy for cancer treatment. However, the BBB limits the shVEGF-DOX codelivery system to direct into glioma. Here, a smart drug delivery system modified with a dual functional peptide was established, which could target to transferrin receptor (TfR) overexpressing on both the BBB and glioma. It showed that the dual-targeting delivery system had high tumor targeting efficiency in vitro and in vivo.
Co-reporter:Tao Sun, Lan Shu, Jian Shen, Chunhui Ruan, Zhifeng Zhao and Chen Jiang
RSC Advances 2016 vol. 6(Issue 57) pp:52189-52200
Publication Date(Web):03 May 2016
DOI:10.1039/C6RA05808F
Superamphiphiles are considered as a promising approach for fabricating stimuli-responsive materials. Sensitivity to more than one stimulus can improve the system's versatile performance. In this study, we proposed a facile dual-responsive vesicle constructed from Bola-type superamphiphiles. An azobenzene dimer linked by a disulfide bond was synthesized. As the guest molecule, the azobenzene dimer can be included into the β-cyclodextrin's cavity from both ends to form a novel Bola-type superamphiphile, which can further assemble into a vesicular structure in aqueous solution. The vesicles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The formation mechanism of the vesicular structure was suggested based on the NMR, Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) results. The photo and redox responsiveness of the vesicles was studied. The vesicles were found able to carry mitomycin C (MMC) and the drug-release can be greatly promoted upon UV irradiation or reduction.
Co-reporter:Kaimin Cai; Xi He; Ziyuan Song; Qian Yin; Yanfeng Zhang; Fatih M. Uckun; Chen Jiang;Jianjun Cheng
Journal of the American Chemical Society 2015 Volume 137(Issue 10) pp:3458-3461
Publication Date(Web):March 5, 2015
DOI:10.1021/ja513034e
Encapsulation of small-molecule drugs in hydrophobic polymers or amphiphilic copolymers has been extensively used for preparing polymeric nanoparticles (NPs). The loadings and loading efficiencies of a wide range of drugs in polymeric NPs, however, tend to be very low. In this Communication, we report a strategy to prepare polymeric NPs with exceptionally high drug loading (>50%) and quantitative loading efficiency. Specifically, a dimeric drug conjugate bearing a trigger-responsive domain was designed and used as the core-constructing unit of the NPs. Upon co-precipitation of the dimeric drug and methoxypoly(ethylene glycol)-block-polylactide (mPEG-PLA), NPs with a dimeric drug core and a polymer shell were formed. The high-drug-loading NPs showed excellent stability in physiological conditions. No premature drug or prodrug release was observed in PBS solution without triggering, while external triggering led to controlled release of drug in its authentic form.
Co-reporter:Yubo Guo, Yujie Zhang, Jianfeng Li, Yu Zhang, Yifei Lu, Xutao Jiang, Xi He, Haojun Ma, Sai An, and Chen Jiang
ACS Applied Materials & Interfaces 2015 Volume 7(Issue 9) pp:5444
Publication Date(Web):February 16, 2015
DOI:10.1021/am5091462
In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as their serious systemic toxicity. In this work, we developed actively tumor-targeting trilayer micelles with microenvironment-sensitive cross-links as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable PEG-pLys-pPhe polymers, in which pLys could react with a disulfide-containing agent to form redox-responsive cross-links. In vitro drug release and pharmacokinetics studies showed that these cross-links were stable in physiological condition whereas cleaved once internalized into cells due to the high level of glutathione, resulting in facilitated intracellular doxorubicin release. In addition, dehydroascorbic acid (DHAA) was decorated on the surface of micelles for specific recognition of tumor cells via GLUT1, a member of glucose transporter family overexpressed on hepatocarcinoma cells. Moreover, DHAA exhibited a “one-way” continuous accumulation within tumor cells. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.Keywords: cross-link; dehydroascorbic acid; GLUT1; hepatocellular carcinoma; polymer micelle; redox-responsive
Co-reporter:Jianfeng Li, Huiying Yang, Yujie Zhang, Xutao Jiang, Yubo Guo, Sai An, Haojun Ma, Xi He, and Chen Jiang
ACS Applied Materials & Interfaces 2015 Volume 7(Issue 38) pp:21589
Publication Date(Web):September 10, 2015
DOI:10.1021/acsami.5b07045
Ligand-mediated polymeric micelles have enormous potential for improving the efficacy of glioma therapy. Linear–dendritic drug–polymer conjugates composed of doxorubicin (DOX) and polyethylene glycol (PEG) were synthesized with or without modification of choline derivate (CD). The resulting MeO–PEG–DOX8 and CD–PEG–DOX8 could self-assemble into polymeric micelles with a nanosized diameter around 30 nm and a high drug loading content up to 40.6 and 32.3%, respectively. The optimized formulation 20% CD–PEG–DOX8 micelles had superior cellular uptake and antitumor activity against MeO–PEG–DOX8 micelles. The subcellular distribution using confocal study revealed that 20% CD–PEG–DOX8 micelles preferentially accumulated in the mitochondria. Pharmacokinetic study showed area under the plasma concentration–time curve (AUC0–t) and Cmax for 20% CD–PEG–DOX8 micelles and DOX solution were 1336.58 ± 179.43 mg/L·h, 96.35 ± 3.32 mg/L and 1.40 ± 0.19 mg/L·h, 1.15 ± 0.25 mg/L, respectively. Biodistribution study showed the DOX concentration of 20% CD–PEG–DOX8 micelles treated group at 48 h was 2.37-fold higher than that of MeO–PEG–DOX8 micelles treated group at 48 h and was 24 fold-higher than that of DOX solution treated group at 24 h. CD–PEG–DOX8 micelles (20%) were well tolerated with reduced cardiotoxicity, as evaluated in the body weight change and HE staining studies, while they induced most significant antitumor activity with longest media survival time in an orthotopic mouse model of U87-luci glioblastoma model as displayed in the bioluminescence imaging and survival curve studies. Our findings consequently indicated that 20% CD–PEG–DOX8 micelles are promising drug delivery system for glioma chemotherapy.Keywords: choline derivate; doxorubicin; drug−polymer conjugate; glioma; linear−dendritic; polymeric micelles
Co-reporter:Kun Shao;Yu Zhang;Ning Ding;Shixian Huang;Jiqin Wu;Jianfeng Li;Chunfu Yang;Qibin Leng;Liya Ye;Jinning Lou;Liping Zhu
Advanced Healthcare Materials 2015 Volume 4( Issue 2) pp:291-300
Publication Date(Web):
DOI:10.1002/adhm.201400214
Due to complication factors such as blood-brain barrier (BBB), integrating high efficiency of brain target ability with specific cargo releasing into one nanocarrier seems more important. A brain targeting nanoscale system is developed using dehydroascorbic acid (DHA) as targeting moiety. DHA has high affinity with GLUT1 on BBB. More importantly, the GLUT1 transportation of DHA represents a “one-way” accumulative priority from blood into brain. The artificial micelles are fabricated by a disulfide linkage, forming a bio-responsive inner barrier, which can maintain micelles highly stable in circulation and shield the leakage of entrapped drug before reaching the targeting cells. The designed micelles can cross BBB and be further internalized by brain cells. Once within the cells, the drug release can be triggered by high intracellular level of glutathione (GSH). Itraconazole (ITZ) is selected as the model drug because of its poor brain permeability and low stability in blood. It demonstrates that the functionalized nanoscale micelles can achieve highly effective direct drug delivery to targeting site. Based on the markedly increased stability in blood circulation and improved brain delivery efficiency of ITZ, DHA-modified micelles show highly effective in anti-intracranial infection. Therefore, this smart nanodevice shows a promising application for the treatment of brain diseases.
Co-reporter:Jianfeng Li, Xutao Jiang, Yubo Guo, Sai An, Yuyang Kuang, Haojun Ma, Xi He, and Chen Jiang
Bioconjugate Chemistry 2015 Volume 26(Issue 3) pp:418
Publication Date(Web):February 12, 2015
DOI:10.1021/acs.bioconjchem.5b00030
A new linear–dendritic copolymer composed of poly(ethylene glycol) (PEG) and all-trans-retinoic acid (ATRA) was synthesized as the anticancer drug delivery platform (PEG-G3-RA8). It can self-assemble into core–shell micelles with a low critical micelle concentration (CMC) at 3.48 mg/L. Paclitaxel (PTX) was encapsulated into PEG-G3-RA8 to form PEG-G3-RA8/PTX micelles for breast cancer treatment. The optimized formulation had high drug loading efficacy (20% w/w of drug copolymer ratio), nanosized diameter (27.6 nm), and narrow distribution (PDI = 0.103). Compared with Taxol, PEG-G3-RA8/PTX remained highly stable in the serum-containing cell medium and exhibited 4-fold higher cellular uptake. Besides, near-infrared fluorescence (NIR) optical imaging results indicated that fluorescent probe loaded micelle had a preferential accumulation in breast tumors. Pharmacokinetics and biodistribution studies (10 mg/kg) showed the area under the plasma concentration–time curve (AUC0-∞) and mean residence time (MRT0-∞) for PEG-G3-RA8/PTX and Taxol were 12.006 ± 0.605 mg/L h, 2.264 ± 0.041 h and 15.966 ± 1.614 mg/L h, 1.726 ± 0.097 h, respectively. The tumor accumulation of PEG-G3-RA8/PTX group was 1.89-fold higher than that of Taxol group 24 h postinjection. With the advantages like efficient cellular uptake and preferential tumor accumulation, PEG-G3-RA8/PTX showed superior therapeutic efficacy on MCF-7 tumor bearing mice compared to Taxol.
Co-reporter:Sai An, Xutao Jiang, Jiashu Shi, Xi He, Jianfeng Li, Yubo Guo, Yu Zhang, Haojun Ma, Yifei Lu, Chen Jiang
Biomaterials 2015 53() pp: 330-340
Publication Date(Web):
DOI:10.1016/j.biomaterials.2015.02.084
Co-reporter:Yang Liu, Xi He, Yuyang Kuang, Sai An, Chenyu Wang, Yubo Guo, Haojun Ma, Jinning Lou, and Chen Jiang
Molecular Pharmaceutics 2014 Volume 11(Issue 10) pp:3330-3341
Publication Date(Web):June 25, 2014
DOI:10.1021/mp500084s
Achieving effective gene therapy for glioma depends on gene delivery systems. The gene delivery system should be able to cross the blood–brain barrier (BBB) and further target glioma at its early stage. Active brain tumor targeted delivery can be achieved using the “Trojan horse” technology, which involves either endogenous ligands or extraneous substances that can recognize and bind to specific receptors in target sites. This method facilitates receptor-mediated endocytosis to cross the BBB and enter into glioma cells. Dendrigraft poly-l-lysines (DGLs), which are novel nonviral gene vectors, are conjugated to a peptide (sequence: EPRNEEK) derived from Streptococcus pneumonia, a pathogen causing meningitis. This process yields peptide-modified nanoparticles (NPs) after DNA loading. Cellular uptake and in vivo imaging results indicate that EPRNEEK peptide-modified NPs have a better brain tumor targeted effect compared with a pentapeptide derived from endogenous laminin after intravenous injection. The mechanism of this effect is further explored in the present study. Besides, EPRNEEK peptide-modified NPs also exhibited a prolonged median survival time. In conclusion, the EPRNEEK peptide-modified DGL NPs exhibit potential as a nonviral platform for efficient, noninvasive, and safe brain glioma dual-targeted gene delivery.Keywords: brain-targeted; gene delivery; laminin receptor; nanoparticles; tumor-targeted;
Co-reporter:Kun Shao, Ning Ding, Shixian Huang, Sumei Ren, Yu Zhang, Yuyang Kuang, Yubo Guo, Haojun Ma, Sai An, Yingxia Li, and Chen Jiang
ACS Nano 2014 Volume 8(Issue 2) pp:1191
Publication Date(Web):January 7, 2014
DOI:10.1021/nn406285x
Malignant glioma, a highly aggressive tumor, is one of the deadliest types of cancer associated with dismal outcome despite optimal chemotherapeutic regimens. One explanation for this is the failure of most chemotherapeutics to accumulate in the tumors, additionally causing serious side effects in periphery. To solve these problems, we sought to develop a smart therapeutic nanodevice with cooperative dual characteristics of high tumor-targeting ability and selectively controlling drug deposition in tumor cells. This nanodevice was fabricated with a cross-linker, containing disulfide linkage to form an inner cellular microenvironment-responsive “-S-S-” barrier, which could shield the entrapped drug leaking in blood circulation. In addition, dehydroascorbic acid (DHA), a novel small molecular tumor-specific vector, was decorated on the nanodevice for tumor-specific recognition via GLUT1, a glucose transporter highly expressed on tumor cells. The drug-loaded nanodevice was supposed to maintain high integrity in the bloodstream and increasingly to specifically bind with tumor cells through the association of DHA with GLUT1. Once within the tumor cells, the drug release was triggered by a high level of intracellular glutathione. When these two features were combined, the smart nanodevice could markedly improve the drug tumor-targeting delivery efficiency, meanwhile decreasing systemic toxicity. Herein, this smart nanodevice showed promising potential as a powerful platform for highly effective antiglioma treatment.Keywords: antiglioma; cellular microenvironment; dehydroascorbic acid; GLUT1; glutathione triggered; polymeric micelles; U87 xenograft model
Co-reporter:Liang Han, Mingming Liu, Deyong Ye, Ning Zhang, Ed Lim, Jing Lu, Chen Jiang
Biomaterials 2014 35(9) pp: 2952-2960
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.12.020
Co-reporter:Liang Han;Haojun Ma;Yubo Guo;Yuyang Kuang;Xi He
Advanced Healthcare Materials 2013 Volume 2( Issue 11) pp:1435-1439
Publication Date(Web):
DOI:10.1002/adhm.201300013
Co-reporter:Shixian Huang, Kun Shao, Yuyang Kuang, Yang Liu, Jianfeng Li, Sai An, Yubo Guo, Haojun Ma, Xi He, Chen Jiang
Biomaterials 2013 34(21) pp: 5294-5302
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.03.043
Co-reporter:Jianfeng Li, Yubo Guo, Yuyang Kuang, Sai An, Haojun Ma, Chen Jiang
Biomaterials 2013 34(36) pp: 9142-9148
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.08.030
Co-reporter:Sai An, Yuyang Kuang, Teng Shen, Jianfeng Li, Haojun Ma, Yubo Guo, Xi He, Chen Jiang
Biomaterials 2013 34(35) pp: 8949-8959
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.07.060
Co-reporter:Rongqin Huang;Haojun Ma;Yubo Guo;Shuhuan Liu;Yuyang Kuang
Pharmaceutical Research 2013 Volume 30( Issue 10) pp:2549-2559
Publication Date(Web):2013 October
DOI:10.1007/s11095-013-1005-8
To prepare an angiopep-conjugated dendrigraft poly-L-lysine (DGL)-based gene delivery system and evaluate the neuroprotective effects in the rotenone-induced chronic model of Parkinson’s disease (PD).Angiopep was applied as a ligand specifically binding to low-density lipoprotein receptor-related protein (LRP) which is overexpressed on blood-brain barrier (BBB), and conjugated to biodegradable DGL via hydrophilic polyethyleneglycol (PEG), yielding DGL-PEG-angiopep (DPA). In vitro characterization was carried out. The neuroprotective effects were evaluated in a chronic parkinsonian model induced by rotenone using a regimen of multiple dosing intravenous administrations.The successful synthesis of DPA was demonstrated via 1H-NMR. After encapsulating the therapeutic gene encoding human glial cell line-derived neurotrophic factor (hGDNF), DPA/hGDNF NPs showed a sphere-like shape with the size of 119 ± 12 nm and zeta potential of 8.2 ± 0.7 mV. Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart. The pharmacodynamic results showed that rats in the group with five injections of DPA/hGDNF NPs obtained best improved locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups.This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.
Co-reporter:Shixian Huang, Kun Shao, Yang Liu, Yuyang Kuang, Jianfeng Li, Sai An, Yubo Guo, Haojun Ma, and Chen Jiang
ACS Nano 2013 Volume 7(Issue 3) pp:2860
Publication Date(Web):March 1, 2013
DOI:10.1021/nn400548g
Tumor microenvironment, such as the lowered tumor extracellular pH (pHe) and matrix metalloproteinase 2 (MMP2), has been extensively explored, which promotes the development of the microenvironment-responsive drug delivery system. Utilizing these unique features, an activatable cell-penetrating peptide (designated as dtACPP) that is dual-triggered by the lowered pHe and MMP2 has been constructed, and a smart nanoparticle system decorating with dtACPP has been successfully developed, which could dual-load gene drug and chemotherapeutics simultaneously. After systemic administration, dtACPP-modified nanoparticles possess passive tumor targetability via the enhanced permeability and retention effect. Then dtACPP would be activated to expose cell-penetrating peptide to drive the nanoparticles’ internalization into the intratumoral cells. As angiogenesis and tumor cells might be mutually improved in tumor growth, so combining antiangiogenesis and apoptosis is meaningful for oncotherapy. Vascular endothelial growth factor (VEGF) is significant in angiogenesis, and anti-VEGF therapy could decrease blood vessel density and delay tumor growth obviously. Chemotherapy using doxorubicin (DOX) could kill off tumor cells efficiently. Here, utilizing dtACPP-modified nanoparticles to co-deliver plasmid expressing interfering RNA targeting VEGF (shVEGF) and DOX (designated as dtACPPD/shVEGF–DOX) results in effective shutdown of blood vessels and cell apoptosis within the tumor. On the premise of effective drug delivery, dtACPPD/shVEGF–DOX has demonstrated good tumor targetability, little side effects after systemic administration, and ideal antitumor efficacy.Keywords: cell-penetrating peptide; chemotherapy; combination therapy; tumor microenvironment; tumor-targeting nanoparticles; VEGF
Co-reporter:Yang Liu, Yuzhi Hu, Yubo Guo, Haojun Ma, Jianfeng Li, Chen Jiang
Journal of Controlled Release 2012 Volume 163(Issue 2) pp:203-210
Publication Date(Web):28 October 2012
DOI:10.1016/j.jconrel.2012.09.001
The activation of caspase-3 mediated neuron death is a common process in neurodegenerative diseases. Efficient activated caspase-3 imaging in brain would be helpful to monitor the potential lesion and intervene promptly. However, the blood–brain barrier (BBB) is the major obstacle that hinders the delivery of diagnostic agents into the brain. Herein, the fluorescence resonance energy transfer (FRET) was successfully applied to detect in vivo activated caspase-3 in apoptotic neuron with a brain-targeted nano-device, which was based on dendrigraft poly-l-lysines (DGLs) and linked with a brain-targeted peptide RVG29 as well as the caspase-3 cleavable peptide linker (DEVD). This nano-device could detect the level of caspase-3 activation in accordance with the degree of apoptosis in rat brain; meanwhile normal rat showed no fluorescence signal. The location of fluorescence signal was confirmed to accumulate more in caspase-3 activated neurons. Taken together, our nano-device would help to image activated caspase-3 in vivo and hold great promise in early diagnosis of neurodegenerative diseases.
Co-reporter:Kun Shao, Jiqin Wu, Zhongqing Chen, Shixian Huang, Jianfeng Li, Liya Ye, Jinning Lou, Liping Zhu, Chen Jiang
Biomaterials 2012 33(28) pp: 6898-6907
Publication Date(Web):
DOI:10.1016/j.biomaterials.2012.06.050
Co-reporter:Shuhuan Liu, Yubo Guo, Rongqin Huang, Jianfeng Li, Shixian Huang, Yuyang Kuang, Liang Han, Chen Jiang
Biomaterials 2012 Volume 33(Issue 19) pp:4907-4916
Publication Date(Web):June 2012
DOI:10.1016/j.biomaterials.2012.03.031
The combination of gene therapy and chemotherapy is a promising treatment strategy for brain gliomas. In this paper, we designed a co-delivery system (DGDPT/pORF-hTRAIL) loading chemotherapeutic drug doxorubicin and gene agent pORF-hTRAIL, and with functions of pH-trigger and cancer targeting. Peptide HAIYPRH (T7), a transferrin receptor-specific peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. T7-modified co-delivery system showed higher efficiency in cellular uptake and gene expression than unmodified co-delivery system in U87 MG cells, and accumulated in tumor more efficiently in vivo. DOX was covalently conjugated to carrier though pH-trigged hydrazone bond. In vitro incubation of the conjugates in buffers led to a fast DOX release at pH 5.0 (intracellular environment) while at pH 7.4 (blood) the conjugates are relatively stable. The combination treatment resulted in a synergistic growth inhibition (combination index, CI < 1) in U87 MG cells. The synergism effect of DGDPT/pORF-hTRAIL was verified in vitro and in vivo. In vivo anti-glioma efficacy study confirmed that DGDPT/pORF-hTRAIL displayed anti-glioma activity but was less toxic.
Co-reporter:Jianfeng Li;Lu Zhou;Deyong Ye;Shixian Huang;Kun Shao;Rongqin Huang;Liang Han;Yang Liu;Shuhuan Liu;Liya Ye;Jinning Lou
Advanced Materials 2011 Volume 23( Issue 39) pp:4516-4520
Publication Date(Web):
DOI:10.1002/adma.201101899
Co-reporter:Liang Han, Rongqin Huang, Jianfeng Li, Shuhuan Liu, Shixian Huang, Chen Jiang
Biomaterials 2011 32(4) pp: 1242-1252
Publication Date(Web):
DOI:10.1016/j.biomaterials.2010.09.070
Co-reporter:Rongqin Huang, Weilun Ke, Liang Han, Jianfeng Li, Shuhuan Liu, Chen Jiang
Biomaterials 2011 32(9) pp: 2399-2406
Publication Date(Web):
DOI:10.1016/j.biomaterials.2010.11.079
Co-reporter:Liang Han, Jianfeng Li, Shixian Huang, Rongqin Huang, Shuhuan Liu, Xing Hu, Peiwei Yi, Dai Shan, Xuxia Wang, Hao Lei, Chen Jiang
Biomaterials 2011 32(11) pp: 2989-2998
Publication Date(Web):
DOI:10.1016/j.biomaterials.2011.01.005
Co-reporter:Rongqin Huang, Liang Han, Jianfeng Li, Shuhuan Liu, Kun Shao, Yuyang Kuang, Xing Hu, Xuxia Wang, Hao Lei, Chen Jiang
Biomaterials 2011 32(22) pp: 5177-5186
Publication Date(Web):
DOI:10.1016/j.biomaterials.2011.03.075
Co-reporter:Shixian Huang, Jianfeng Li, Liang Han, Shuhuan Liu, Haojun Ma, Rongqin Huang, Chen Jiang
Biomaterials 2011 32(28) pp: 6832-6838
Publication Date(Web):
DOI:10.1016/j.biomaterials.2011.05.064
Co-reporter:Kun Shao, Rongqin Huang, Jianfeng Li, Liang Han, Liya Ye, Jinning Lou, Chen Jiang
Journal of Controlled Release 2010 Volume 147(Issue 1) pp:118-126
Publication Date(Web):1 October 2010
DOI:10.1016/j.jconrel.2010.06.018
Amphotericin B (AmB) is a poorly water soluble antibiotic and is used to treat fungal infections of the central nervous system (CNS). However, AmB shows poor penetration into the CNS. Angiopep-2, the ligand of low-density lipoprotein receptor-related protein (LRP) present on the BBB, exhibits higher transcytosis capacity and parenchymal accumulation, which allowed us to consider the selectivity of it for receptor-mediated drug targeting to the brain. With this in mind, we prepared angiopep-2 modified PE-PEG based micellar drug delivery system loaded with the antifungal drug AmB to evaluate the efficiency of AmB accumulating into the brain. PE-PEG based micelles as nano-scaled drug carriers were investigated by incorporating AmB with high drug entrapping efficiency, improving solubilization of AmB and reducing its toxicity to mammalian cells. The AmB-incorporated angiopep-2 modified micelles showed highest efficiency in penetrating across the blood-brain barrier (BBB) than unmodified micelles and Fungizone (deoxycholate amphotericin B) in vitro and in vivo. Meanwhile, contrary to the free Rho 123, the enhancement of Rho 123-incorporated angiopep-2 modified micelles across the BBB can be explained by angiopep-2 modified polymeric micelles that have a potential to overcome the activity of efflux proteins expressed on the BBB such as P-glycoprotein. In conclusion, angiopep-2 modified polymeric micelles could be developed as a novel drug delivery system for brain targeting.
Co-reporter:Liang Han, Rongqin Huang, Shuhuan Liu, Shixian Huang, and Chen Jiang
Molecular Pharmaceutics 2010 Volume 7(Issue 6) pp:2156-2165
Publication Date(Web):September 21, 2010
DOI:10.1021/mp100185f
The purpose of this work was to evaluate the potential of HAIYPRH (T7) peptide as a ligand for constructing tumor-targeting drug delivery systems. T7 could target to transferrin-receptor (TfR) through a cavity on the surface of TfR and then transport into cells via endocytosis with the help of transferrin (Tf). In this study, T7-conjugated poly(ethylene glycol) (PEG)-modified polyamidoamine dendrimer (PAMAM) (PAMAM-PEG-T7) was successfully synthesized and further loaded with doxorubicin (DOX), formulating PAMAM-PEG-T7/DOX nanoparticles (NPs). In vitro, almost 100% of DOX was released during 2 h in pH 5.5, while only 55% of DOX was released over 48 h in pH 7.4. The cellular uptake of DOX could be significantly enhanced when treated with T7-modified NPs in the presence of Tf. Also, the in vitro antitumor effect was enhanced markedly. The IC50 of PAMAM-PEG-T7/DOX NPs with Tf was 231.5 nM, while that of NPs without Tf was 676.7 nM. T7-modified NPs could significantly enhance DOX accumulation in the tumor by approximately 1.7-fold compared to that of unmodified ones and by approximately 5.3-fold compared to that of free DOX. For in vivo antitumor studies, tumor growth of mice treated with PAMAM-PEG-T7/DOX NPs was significantly inhibited compared to that of mice treated with PAMAM-PEG/DOX NPs and saline. The study provides evidence that PAMAM-PEG-T7 can be applied as a potential tumor-targeting drug delivery system. T7 may be a promising ligand for targeted drug delivery to the tumor.Keywords: Doxorubicin; enhanced permeability and retention; HAIYPRH; PAMAM; receptor-mediated endocytosis; tumor-targeting;
Co-reporter:Yang Liu, Jianfeng Li, Kun Shao, Rongqin Huang, Liya Ye, Jinning Lou, Chen Jiang
Biomaterials 2010 31(19) pp: 5246-5257
Publication Date(Web):
DOI:10.1016/j.biomaterials.2010.03.011
Co-reporter:Weilun Ke;Yansong Zhao;Rongqin Huang;Yuanying Pei
Journal of Pharmaceutical Sciences 2008 Volume 97( Issue 6) pp:2208-2216
Publication Date(Web):
DOI:10.1002/jps.21155
Abstract
PAMAM dendrimers can permeate across intestinal epithelial barriers suggesting their potential as oral drug carriers. In the present study, we have developed a drug–PAMAM complex for oral administration. The loading of a model drug, doxorubicin into PAMAM, the cellular uptake and Pharmacokinetics of the doxorubicin–PAMAM complex were studied. As the results, the cellular uptake of doxorubicin in Caco-2 cells treated with the doxorubicin–PAMAM complex was increased significantly with an increase in concentration and time, as compared to that treated with free doxorubicin. And the transport efficiency of the doxorubicin–PAMAM complex from the mucosal side to the serosal side was 4–7 times higher than that of free doxorubicin in different segments of small intestines of rat. The doxorubicin–PAMAM complex led to the bioavailability that was more than 200-fold higher than that of free doxorubicin after oral administration. These results indicate that PAMAM dendrimer is a promising novel carrier to enhance the oral bioavailability of drug, especially for the P-glycoprotein (P-gp) substrates. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2208–2216, 2008
Co-reporter:Rong-qin Huang;Wei-lun Ke;Ying-hua Qu;Jian-hua Zhu
Journal of Biomedical Science 2007 Volume 14( Issue 1) pp:121-128
Publication Date(Web):2007 January
DOI:10.1007/s11373-006-9121-7
We present, herein, the evidence for lactoferrin (Lf) binding sites in brain endothelial capillary cells (BCECs) and mouse brain. The results from confocal microscopy showed the presence of Lf receptors on the surface of BCECs and the receptor-mediated endocytosis for Lf to enter the cells. Saturation binding analyses revealed that Lf receptors exhibited two classes of binding sites in BCECs (high affinity: dissociation constant (Kd) = 6.77 nM, binding site density (Bmax) = 10.3 fmol bound/μg protein; low affinity: Kd = 4815 nM, Bmax = 1190 fmol bound/μg protein) and membrane preparations of mouse brain (high affinity: Kd = 10.61 nM, Bmax = 410 fmol bound/μg protein; low affinity: Kd = 2228 nM, Bmax = 51641 fmol bound/μg protein). The distribution study indicated the effective uptake of 125I-Lf in brain after intravenous administration. The present study provides experimental evidence for the application of Lf as a novel ligand for brain targeting.
Co-reporter:Rong-qin Huang;Yuan-ying Pei
Journal of Biomedical Science 2007 Volume 14( Issue 5) pp:595-605
Publication Date(Web):2007 September
DOI:10.1007/s11373-007-9171-5
Brain capillary endothelial cells (BCECs) have been considered as one of the primary targets for cerebral gene therapy. However, the cells, well-known for their poor function of endocytosis, are difficult to be transfected by general non-viral vectors. The aim of this study was to enhance the efficiency of transfection and expression in BCECs of DNA/polymer nanoparticles with the modification of membrane-penetrating peptide, Antennapedia peptide (Antp) polyethylenimine (PEI) and polyamidoamine (PAMAM) were chosen to prepare Antp-modified DNA-loaded nanoparticles with a complex coacervation technique. After a 20-min transfection, the efficiency, in terms of transfection and expression, of DNA/PEI NP or DNA/PAMAM NP was enhanced significantly with the modification of Antp. After a 3-h transfection of DNA/Antp/PEI NP, there was no difference in cellular uptake but an enhancement in gene expression, compared to DNA/PEI NP alone. However, both the transfection and expression efficiency of DNA/PAMAM NP were enhanced using Antp. These observations suggest that Antp can increase the membrane-penetrating ability of DNA-loaded nanoparticles, which can be employed as novel non-viral gene vectors.
Co-reporter:Xinli Chen, Lisha Liu, Chen Jiang
Acta Pharmaceutica Sinica B (July 2016) Volume 6(Issue 4) pp:261-267
Publication Date(Web):July 2016
DOI:10.1016/j.apsb.2016.05.011
Co-reporter:Weilun Ke, Kun Shao, Rongqin Huang, Liang Han, Yang Liu, Jianfeng Li, Yuyang Kuang, Liya Ye, Jinning Lou, Chen Jiang
Biomaterials (December 2009) Volume 30(Issue 36) pp:
Publication Date(Web):December 2009
DOI:10.1016/j.biomaterials.2009.08.049
Angiopep targeting to the low-density lipoprotein receptor-related protein-1 (LRP1) was identified to exhibit high transcytosis capacity and parenchymal accumulation. In this study, it was exploited as a ligand for effective brain-targeting gene delivery. Polyamidoamine dendrimers (PAMAM) were modified with angiopep through bifunctional PEG, then complexed with DNA, yielding PAMAM–PEG–Angiopep/DNA nanoparticles (NPs). The angiopep-modified NPs were observed to be internalized by brain capillary endothelial cells (BCECs) through a clathrin- and caveolae-mediated energy-depending endocytosis, also partly through marcopinocytosis. Also, the cellular uptake of the angiopep-modified NPs were competed by angiopep-2, receptor-associated protein (RAP) and lactoferrin, indicating that LRP1-mediated endocytosis may be the main mechanism of cellular internalization of angiopep-modified NPs. And the angiopep-modified NPs showed higher efficiency in crossing blood–brain barrier (BBB) than unmodified NPs in an in vitro BBB model, and accumulated in brain more in vivo. The angiopep-modified NPs also showed higher efficiency in gene expressing in brain than the unmodified NPs. In conclusion, PAMAM–PEG–Angiopep showed great potential to be applied in designing brain-targeting drug delivery system.
Co-reporter:Tao Sun, Qingbing Wang, Yunke Bi, Xinli Chen, Lisha Liu, Chunhui Ruan, Zhifeng Zhao and Chen Jiang
Journal of Materials Chemistry A 2017 - vol. 5(Issue 14) pp:NaN2654-2654
Publication Date(Web):2017/03/06
DOI:10.1039/C6TB03272A
Herein we report a novel “supra-prodrug-type” superamphiphile design: via a redox-sensitive self-immolative linker, a hydrophobic drug molecule was labeled with an azobenzene moiety, which was designed to be capped by a hydrophilic cyclodextrin (CD) molecule. Four clinical hydrophobic drugs, 7-ethyl-10-hydroxycamptothecin (SN-38), doxorubicin (DOX), phenytoin and aliskiren, were investigated to directly participate in building a novel class of superamphiphile, in which the CD moiety plays as the hydrophilic head and the drug as the hydrophobic tail. This novel type of superamphiphile can further self-assemble into vesicular or tubular structures, characterized by transmission electron microscope (TEM), scanning electron microscope (SEM) and dynamic light scattering (DLS). The possible self-assembly mechanism is given based on multiple pieces of evidence, including nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and Ultraviolet-visible spectroscopy (UV-vis) results. The reconversion kinetics of the prodrug as a function of glutathione (GSH) in the presence or absence of UV irradiation is presented. Cell experiments indicate that the “supra-prodrug” can be facially endowed with a function by a simple substitution with another functionalized host. We hope this work can provide new reference in the field of drug screening, formulation and delivery.
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![Acetamide, 2-chloro-N-[2-(3,4-dihydroxyphenyl)ethyl]-](http://img.cochemist.com/ccimg/17700/17639-51-9.png)
![Acetamide, 2-chloro-N-[2-(3,4-dihydroxyphenyl)ethyl]-](http://img.cochemist.com/ccimg/17700/17639-51-9_b.png)
