Co-reporter:Ziwei Zhao, Zhe Zhang, Li Chen, Yue Cao, Chaoliang He, and Xuesi Chen
Langmuir October 22, 2013 Volume 29(Issue 42) pp:13072-13080
Publication Date(Web):September 26, 2013
DOI:10.1021/la402890k
Biodegradable stereocomplex micelles (SCMs) based on amphiphilic dextran-block-polylactide (Dex-b-PLA) were designed and used for efficient intracellular drug deliveries. The Dex-b-PLA copolymers were successfully synthesized by click reaction. The structures of the resultant copolymers were verified by 1H NMR and FT-IR spectra. The formation of stable micelles through self-assembly driven by the stereocomplexation between enantiomeric l- and d-PLA blocks was characterized by transmission electron microscopy (TEM), dynamic laser scattering (DLS), and fluorescence techniques. It was interesting to observe that the SCMs showed lower critical micelle concentration values (CMCs) because of the stereocomplex interaction between PLLA and PDLA. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis provided information on the thermal and crystal properties of the copolymers and SCMs. The improved stability of SCMs should be attractive for intracellular drug delivery. Thus, a model anticancer drug doxorubicin (DOX) was loaded into micelles, and the in vitro drug release in was also studied. The release kinetics of DOX showed DOX-loaded SCMs exhibited slower DOX release. Confocal laser scanning microscopy (CLSM) and flow cytometry studies also showed that the DOX-loaded SCMs exhibited a slower drug release behavior. Meanwhile, the MTT assay demonstrated that DOX-loaded SCMs show lower cellular proliferation inhibition against HepG2. In sum, the micelles through self-assembly driven by stereocomplex interaction would have great potential to be used as stable delivery vehicles for pharmaceutical and biomedical applications.
Co-reporter:Shuangjiang Yu, Dianliang Zhang, Chaoliang He, Wujin Sun, Rangjuan Cao, Shusen Cui, Mingxiao Deng, Zhen Gu, and Xuesi Chen
Biomacromolecules December 11, 2017 Volume 18(Issue 12) pp:4341-4341
Publication Date(Web):November 15, 2017
DOI:10.1021/acs.biomac.7b01374
In this study, a type of novel thermosensitive polypeptide-based hydrogel with tunable gelation behavior through changing the content of carboxyl groups was developed for the purpose of improving the cisplatin (CDDP) release behavior and enhancing the localized antitumor efficiency. The introduction of carboxyl groups in methoxy-poly(ethylene glycol)-b-(poly(γ-ethyl-l-glutamate-co-l-glutamic acid) (mPEG-b-P(ELG-co-LG)) not only led to adjustable mechanical properties of the hydrogel but also significantly reduced the burst release of the drug through the complexation between the carboxyl groups of polypeptide and CDDP. Furthermore, both the good biocompatibility and the biodegradable properties of mPEG-b-P(ELG-co-LG) hydrogel were observed in vivo. Interestingly, the CDDP-complexed mPEG-b-P(ELG-co-LG) hydrogel exhibited significantly enhanced antitumor efficacy in vivo compared to the mPEG-b-PELG hydrogel loaded with CDDP without complexation, although a lower cytotoxicity and IC50 of the CDDP-complexed hydrogel was observed in vitro. Overall, the new type of injectable CDDP-complexed hydrogel may serve as an efficient platform for sustained CDDP delivery in localized tumor therapy.
Co-reporter:Qinghua Xu, Zhen Zhang, Chunsheng Xiao, Chaoliang He, and Xuesi Chen
Biomacromolecules April 10, 2017 Volume 18(Issue 4) pp:1411-1411
Publication Date(Web):March 14, 2017
DOI:10.1021/acs.biomac.7b00142
Injectable hydrogels have been widely investigated for applications in biomedical fields, for instance, as biomimetic scaffolds mimicking the extracellular matrix (ECM). In addition to as scaffolds for mechanical support and transferring of nutrients, the dynamic bioactivity of ECM is another critical factor that affects cell behavior. In this work, a novel injectable poly(l-glutamic acid)-based hydrogel decorated with RGD was fabricated. The presentation of RGD significantly enhanced the cell-matrix interaction and promoted cell adhesion and proliferation. Moreover, the cell-adhesive RGD was conjugated to the network via a disulfide bond, so that the density of RGD and the bioactivity of hydrogel can be well controlled by tuning the RGD content through treating with glutathione. As a result, the cell behaviors on the hydrogel can be tuned on demand. The injectable hydrogel with controllable bioactivity may provide an interesting strategy to develop a scaffold mimicking ECM that can regulate cell adhesion dynamically.
Co-reporter:
Macromolecular Bioscience 2017 Volume 17(Issue 4) pp:
Publication Date(Web):2017/04/01
DOI:10.1002/mabi.201600347
Biocompatible and antibacterial hydrogels have received increasing attention for preventing local bacterial infections. In this study, a type of polysaccharide hydrogels is prepared via the Schiff-based reaction at physiological conditions. The gelation time and mechanical property of the hydrogels are found to be dependent on the polysaccharide concentration and the polysaccharide weight ratio. 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and live/dead assay indicate that the hydrogels display nontoxicity in vitro. After subcutaneous injection into rats, the hydrogels exhibit an acceptable biocompatibility in vivo. Furthermore, the bacterial inhibition tests by shaking flask method and agar disc-diffusion method demonstrate that the ceftriaxone-sodium-loaded hydrogels have remarkable antibacterial properties in vitro. The in vivo anti-infective tests further display that the antibiotic-loaded hydrogels display excellent anti-infective efficacies in both superficial and deep tissue infection. Consequently, the injectable and biocompatible polysaccharide hydrogels may serve as promising platforms for localized, sustained delivery of antibiotics for preventing local infections.
Co-reporter:Xilong Wu, Yundi Wu, Hongbo Ye, Shuangjiang Yu, Chaoliang He, Xuesi Chen
Journal of Controlled Release 2017 Volume 255(Volume 255) pp:
Publication Date(Web):10 June 2017
DOI:10.1016/j.jconrel.2017.04.011
In situ-forming thermosensitive hydrogels based on poly(ethylene glycol)-poly(γ-ethyl-l-glutamate) diblock copolymers (mPEG-b-PELG) were prepared for the co-delivery of interleukin-15 (IL-15) and cisplatin (CDDP). The polypeptide-based hydrogels as local drug delivery carriers could reduce the systemic toxicity, degrade thoroughly within 3 weeks after subcutaneous injection into rats and display an acceptable biocompatibility. When incubated with mouse melanoma B16 cells, only the CDDP-treated groups had significant effects on the S phase cell-cycle arrest in melanoma cells. After a single peritumoral injection of the hydrogel containing IL-15/CDDP in C57BL/6 mice inoculated with B16F0-RFP melanoma cells, the dual drug-loaded hydrogels displayed synergistic anticancer efficacy, which was resulted from a combination of CDDP-mediated S arrest and IL-15/CDDP-induced recovery of CD8+ T cell and NK cell populations to reduce immunosuppression and enhance antitumor immunity. Hence, the as-prepared thermosensitive polypeptide hydrogels for localized and sustained co-delivery of IL-15 and CDDP may have potential for efficient treatment of melanoma.The mechanism for synergistic antitumor effects of coadministration of IL-15 and CDDP released from the mPEG-b-PELG hydrogels.Download high-res image (267KB)Download full-size image
Co-reporter:Qinghua Xu, Chaoliang He, Zhen Zhang, Kaixuan Ren, and Xuesi Chen
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 45) pp:30692
Publication Date(Web):October 20, 2016
DOI:10.1021/acsami.6b08292
Injectable hydrogels have been widely investigated in biomedical applications, and increasing demand has been proposed to achieve dynamic regulation of physiological properties of hydrogels. Herein, a new type of injectable and biomolecule-responsive hydrogel based on poly(l-glutamic acid) (PLG) grafted with disulfide bond-modified phloretic acid (denoted as PLG-g-CPA) was developed. The hydrogels formed in situ via enzymatic cross-linking under physiological conditions in the presence of horseradish peroxidase and hydrogen peroxide. The physiochemical properties of the hydrogels, including gelation time and the rheological property, were measured. Particularly, the triggered degradation of the hydrogel in response to a reductive biomolecule, glutathione (GSH), was investigated in detail. The mechanical strength and inner porous structure of the hydrogel were influenced by the addition of GSH. The polypeptide hydrogel was used as a three-dimensional (3D) platform for cell encapsulation, which could release the cells through triggered disruption of the hydrogel in response to the addition of GSH. The cells released from the hydrogel were found to maintain high viability. Moreover, after subcutaneous injection into rats, the PLG-g-CPA hydrogels with disulfide-containing cross-links exhibited a markedly faster degradation behavior in vivo compared to that of the PLG hydrogels without disulfide cross-links, implying an interesting accelerated degradation process of the disulfide-containing polypeptide hydrogels in the physiological environment in vivo. Overall, the injectable and biomolecule-responsive polypeptide hydrogels may serve as a potential platform for 3D cell culture and easy cell collection.Keywords: biomolecule-responsive hydrogel; cell recovery; enzymatic cross-linking; polypeptide hydrogel; triggered degradation
Co-reporter:Qinghua Xu;Kaixuan Ren;Chunsheng Xiao;Xuesi Chen
Advanced Healthcare Materials 2016 Volume 5( Issue 15) pp:1979-1990
Publication Date(Web):
DOI:10.1002/adhm.201600292
Reactive oxygen species (ROS) play important roles in cell signaling pathways, while increased production of ROS may disrupt cellular homeostasis, giving rise to a series of diseases. Therefore, materials responding to ROS at physiological levels are of great significance. In this work, a novel ROS-responsive thermogelling hydrogel based on methoxy poly(ethylene glycol)-poly(l-methionine) diblock copolymers is designed and synthesized. The mechanism for solution-to-hydrogel (sol-gel) phase transitions of the copolymer aqueous solutions is studied. Incubation of the hydrogels in the presence of peroxide hydrogen (H2O2 ) displays a H2O2-responsive degradation process. The hydrogels containing Rhodamine 6G exhibit sustained release profiles that are accelerated in response to H2O2. An innate cytoprotective ability of the hydrogels is revealed by incubation of L929 cells with the hydrogels under oxidative stress, which reduces H2O2-mediated cell death. ROS produced by activated macrophages can accelerate the erosion of the hydrogel, suggesting that the hydrogel is also responsive to pathological level of H2O2. Meanwhile, the poly(l-methionine)-based hydrogels degrade within 6 weeks after subcutaneous injection into rats, with a good biocompatibility in vivo. Overall, the injectable, ROS-responsive hydrogels may serve as promising platforms for sustained drug delivery and cell-based therapies in treatment of diseases with local oxidative stress.
Co-reporter:Qinghua Xu;Chunsheng Xiao;Xuesi Chen
Macromolecular Bioscience 2016 Volume 16( Issue 5) pp:635-646
Publication Date(Web):
DOI:10.1002/mabi.201500440
Co-reporter:Xilong Wu, Chaoliang He, Yundi Wu, Xuesi Chen
Biomaterials 2016 Volume 75() pp:148-162
Publication Date(Web):January 2016
DOI:10.1016/j.biomaterials.2015.10.016
In situ formed hydrogels based on Schiff base reaction were formulated for the co-delivery of metformin (ME) and 5-fluorouracil (5FU). The reactive aldehyde-functionalized four-arm polyethylene glycol (PFA) was synthesized by end-capping of 4-arm PEG with 4-formylbenzoic acid (FA) and used as a cross-linking agent. The injectable hydrogels are designed through the quick gelation induced by the formation of covalent bonds via Schiff-base reaction of PFA with 4-arm poly (ethylene glycol)-b-poly (L-lysine) (PPLL). This formulation eliminated the need for metal catalysts and complicated processes in the preparation of in situ-forming hydrogels. In vitro degradation and drug release studies demonstrated that both ME and 5FU were released through PFA/PPLL hydrogels in a controlled and pH-dependent manner. When incubated with mouse colon adenocarcinoma cells (C26), the ME/5FU-incorporated PFA/PPLL hydrogels had synergistic inhibitory effects on the cell cycle progression and cell proliferation in colon cancer cells. After a single subcutaneous injection of the hydrogel containing ME/5FU beside the tumors of BALB/c mice inoculated with C26 cells, the dual-drug-loaded hydrogels displayed superior therapeutic activity resulted from a combination of p53-mediated G1 arrest and apoptosis in C26 cells. Hence, the Schiff's base cross-linked hydrogels containing ME and 5FU may have potential therapeutic applications in the treatments of colon cancer.
Co-reporter:Zhe Zhang, Qiang Lv, Xiaoye Gao, Li Chen, Yue Cao, Shuangjiang Yu, Chaoliang He, and Xuesi Chen
ACS Applied Materials & Interfaces 2015 Volume 7(Issue 16) pp:8404
Publication Date(Web):April 9, 2015
DOI:10.1021/acsami.5b01213
pH-responsive supramolecular amphiphilic micelles based on benzimidazole-terminated poly(ethylene glycol) (PEG-BM) and β-cyclodextrin-modified poly(l-lactide) (CD-PLLA) were developed by exploiting the host–guest interaction between benzimidazole (BM) and β-cyclodextrin (β-CD). The dissociation of the supramolecular micelles was triggered in acidic environments. An antineoplastic drug, doxorubicin (DOX), was loaded into the supramolecular micelles as a model drug. The release of DOX from the supramolecular micelles was clearly accelerated as the pH was reduced from 7.4 to 5.5. The DOX-loaded PEG-BM/CD-PLLA supramolecular micelles displayed an enhanced intracellular drug-release rate in HepG2 cells compared to the pH-insensitive DOX-loaded PEG-b-PLLA counterpart. After intravenous injection into nude mice bearing HepG2 xenografts by the tail vein, the DOX-loaded supramolecular micelles exhibited significantly higher tumor inhibition efficacy and reduced systemic toxicity compared to free DOX. Furthermore, the DOX-loaded supramolecular micelles showed a blood clearance rate markedly lower than that of free DOX and comparable to that of the DOX-loaded PEG-b-PLLA micelles after intravenous injection into rats. Therefore, the pH-responsive PEG-BM/CD-PLLA supramolecular micelles hold potential as a smart nanocarrier for anticancer drug delivery.Keywords: drug delivery; host−guest interaction; pH-responsive; supramolecular amphiphiles;
Co-reporter:Hecheng Ma, Chaoliang He, Yilong Cheng, Zhiming Yang, Junting Zang, Jianguo Liu, and Xuesi Chen
ACS Applied Materials & Interfaces 2015 Volume 7(Issue 49) pp:27040
Publication Date(Web):November 17, 2015
DOI:10.1021/acsami.5b09112
Localized cancer treatments with combination drugs have recently emerged as crucial approaches for effective inhibition of tumor growth and reoccurrence. In this study, we present a new strategy for the osteosarcoma treatment by localized co-delivery of multiple drugs, including doxorubicin (DOX), cisplatin (CDDP) and methotraxate (MTX), using thermosensitive PLGA–PEG–PLGA hydrogels. The release profiles of the drugs from the hydrogels were investigated in vitro. It was found that the multidrug coloaded hydrogels exhibited synergistic effects on cytotoxicity against osteosarcoma Saos-2 and MG-63 cells in vitro. After a single peritumoral injection of the drug-loaded hydrogels into nude mice bearing human osteosarcoma Saos-2 xenografts, the hydrogels coloaded with DOX, CDDP, and MTX displayed the highest tumor suppression efficacy in vivo for up to 16 days, as well as led to enhanced tumor apoptosis and increased regulation of the expressions of apoptosis-related genes. Moreover, the monitoring on the mice body change and the ex vivo histological analysis of the key organs indicated that the localized treatments caused less systemic toxicity and no obvious damage to the normal organs. Therefore, the approach of localized co-delivery of DOX, CDDP, and MTX by the thermosensitive hydrogels may be a promising approach for enhanced osteosarcoma treatment.Keywords: combination therapy; injectable hydrogels; localized delivery; multidrug co-delivery; osteosarcoma treatment; synergistic therapy
Co-reporter:Chaoliang He, Hecheng Ma, Yilong Cheng, Dongsong Li, Yubao Gong, Jianguo Liu, Huayu Tian, Xuesi Chen
Journal of Controlled Release 2015 Volume 213() pp:e18
Publication Date(Web):10 September 2015
DOI:10.1016/j.jconrel.2015.05.026
Co-reporter:Qinghua Xu, Chaoliang He, Chunsheng Xiao, Shuangjiang Yu and Xuesi Chen
Polymer Chemistry 2015 vol. 6(Issue 10) pp:1758-1767
Publication Date(Web):18 Dec 2014
DOI:10.1039/C4PY01523A
Facile synthesis of biopolymers that facilitate versatile post-polymerization modification is of great interest for biotechnological and biomedical applications. In this study, a methacryloyl-substituted L-lysine N-carboxyanhydride (LysMA-NCA) monomer was designed and synthesized, and methacryloyl-functionalized polypeptides were prepared through the ring opening polymerization (ROP) of the L-lysine-based monomer. The post-polymerization functionalization of the methacryloyl-containing polypeptides with various thiol-containing molecules was achieved with high efficiency through facile radical-mediated thiol–ene chemistry. Moreover, a block copolypeptide bearing both methacryloyl and alkynyl pendants was developed through successive ROP of LysMA-NCA and γ-propargyl-L-glutamate (PPLG-NCA). The sequential modification of the block copolypeptide with hydrophilic and hydrophobic molecules, respectively, was achieved by the successive alkyne–azido and thiol–ene “click” reactions. Overall, the facile synthesis of polypeptides bearing functional substituents and their versatile post-polymerization modification may serve as a useful platform for the development of various functional polymers.
Co-reporter:Ziyi Li, Baoming Yuan, Xiaoming Dong, Lijie Duan, Huayu Tian, Chaoliang He and Xuesi Chen
RSC Advances 2015 vol. 5(Issue 114) pp:94248-94256
Publication Date(Web):29 Oct 2015
DOI:10.1039/C5RA16912G
In this study, a type of injectable polysaccharide-based hydrogels were prepared via the Schiff-base crosslinking reaction between the amino groups of carboxymethyl chitosan (CMC) and the aldehyde groups of oxidized dextran (Odex). The gelation time of the CMC/Odex hybrid hydrogels was 25–50 s, depending on the CMC/Odex weight ratio. The hydrogel displayed a storage modulus of ∼1 kPa, and the freeze-dried hydrogel showed an interconnected porous structure. The in vitro degradation test of the hydrogel in PBS showed a fast mass loss in the first 2 days, and then a gradual degradation profile over 4 weeks. The in vitro cytotoxicity and the ability to support cell attachment of the hydrogels were tested by incubation with L929 cells. The results indicated that the hydrogels displayed good cytocompatibility, and the hydrogels with relatively higher CMC content supported the attachment of L929 cells. Moreover, the potential application of the hydrogels in burn wound healing was tested on SD rats with a deep second-degree burn wound. It was found that the group treated with the CMC/Odex hydrogel showed nearly complete wound closure at 21 days after the treatment compared to unsatisfactory wound healing efficiency of the untreated group. Additionally, the histological analysis by H&E and Masson's trichrome staining indicated clearly the regeneration of skin appendages, including hair follicles, sebaceous glands and dermal papillary, suggesting that the treatment with the hydrogel promoted the wound healing and skin regeneration. Overall, the injectable polysaccharide hybrid hydrogels may serve as suitable scaffolds for promoting burn wound healing and skin regeneration.
Co-reporter:Baoming Yuan, Chaoliang He, Xiaoming Dong, Jincheng Wang, Zhongli Gao, Qian Wang, Huayu Tian and Xuesi Chen
RSC Advances 2015 vol. 5(Issue 32) pp:25295-25303
Publication Date(Web):24 Feb 2015
DOI:10.1039/C5RA01307K
Prevention of adhesion after tendon repair surgery is of considerable importance during tendon healing; however, current clinical outcomes are still not fully satisfactory. In this study, thermosensitive 5-fluorouracil (5-Fu) loaded PLGA–PEG–PLGA hydrogels were used as injectable physical barriers for the prevention of tissue adhesion during tendon healing and inhibition of fibroblast proliferation. The 5-Fu-loaded hydrogels showed a sol–gel–precipitation phase transition with increasing temperature, and the hydrogels displayed the maximum storage moduli at around physiological temperature. The sustained release of 5-Fu from the hydrogels lasted over 7 days. The PLGA–PEG–PLGA hydrogels degraded within 4 weeks after subcutaneous injection into rats, and showed acceptable biocompatibility in vivo. The anti-adhesion efficacy of the hydrogels, with or without 5-Fu, during the Achilles tendon healing of rats was evaluated by macroscopic and histological analysis. It was found that the group treated with 5-Fu-loaded hydrogels showed a significant inhibition of adhesion formation when compared to the untreated group or the group treated with the hydrogels only. Therefore, the 5-Fu-loaded injectable hydrogels hold potential as efficient physical barriers for the prevention of adhesion formation during Achilles tendon healing.
Co-reporter:Kaixuan Ren, Chaoliang He, Chunsheng Xiao, Gao Li, Xuesi Chen
Biomaterials 2015 51() pp: 238-249
Publication Date(Web):
DOI:10.1016/j.biomaterials.2015.02.026
Co-reporter:Xuemei Yao, Li Chen, Xiaofei Chen, Zhe Zhang, Hui Zheng, Chaoliang He, Jingping Zhang, and Xuesi Chen
ACS Applied Materials & Interfaces 2014 Volume 6(Issue 10) pp:7816
Publication Date(Web):April 23, 2014
DOI:10.1021/am501093a
For drug delivery systems, the most important factors are biocompatibility and stability. To achieve excellent biocompatibility, learning from naturally occurring systems may be the best choice. Herein, a series of pH-sensitive metallo-supramolecular nanogels (MSNs) were prepared by the metallo-supramolecular coordinated interaction between histidine and iron-meso-tetraphenylporphin, which mimicks the way that hemoglobin carries oxygen. With the excellent biocompatibility and special supramolecular pH sensitivity, MSNs had been exploited to load and release anticancer drug doxorubicin (DOX). In vitro drug release profiles showed that only a small amount of the loaded DOX was released in PBS solution at pH 7.4, while up to about 80% of the loaded DOX could be quickly released at pH 5.3 due to the pH-dependent disassembly of MSNs. Confocal laser scanning microscopy (CLSM) and flow cytometry were used to verify the cellular uptake and intracellular drug release behaviors of DOX-loaded MSNs toward MCF-7. Efficient cellular proliferation inhibition against MCF-7 and HeLa cells was also observed by a 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. These features suggested that MSNs could be of great potential as intelligent drug delivery systems.Keywords: dextran; drug delivery; histidine; intracellular pH-sensitive; iron-meso-tetraphenylporphin; metallo-supramolecular nanogels;
Co-reporter:Kaixuan Ren, Chaoliang He, Yilong Cheng, Gao Li and Xuesi Chen
Polymer Chemistry 2014 vol. 5(Issue 17) pp:5069-5076
Publication Date(Web):07 May 2014
DOI:10.1039/C4PY00420E
Enzymatically crosslinked injectable hydrogels based on poly(L-glutamic acid) grafted with tyramine and poly(ethylene glycol) (denoted as PLG-g-TA/PEG) were developed under physiological conditions in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). Their gelation time, mechanical properties, swelling behaviors and porous structure were evaluated. The hydrogels were rapidly formed in the presence of low concentrations of HRP and H2O2. The storage modulus of the hydrogels could be well controlled and increased by increasing the concentrations of HRP and H2O2. The average pore-size of the hydrogels varied from 20 to 120 μm, depending on the H2O2 concentration. In addition, the encapsulated L929 fibroblast cells in the PLG-g-TA/PEG hydrogels exhibited high viability. After subcutaneous injection of the PLG-g-TA/PEG solutions containing HRP and H2O2 into the back of rats, the hydrogels were rapidly formed in situ. The hydrogels were found to persist for up to 10 weeks in vivo, and histological analysis indicated that the hydrogels exhibited acceptable biocompatibility. These results suggested that the biocompatible, injectable enzyme-mediated PLG-g-TA/PEG hydrogels are promising for biomedical applications including tissue engineering scaffolds and drug delivery carriers.
Co-reporter:Shuangjiang Yu;Jianxun Ding;Yue Cao;Weiguo Xu ;Xuesi Chen
Advanced Healthcare Materials 2014 Volume 3( Issue 5) pp:752-760
Publication Date(Web):
DOI:10.1002/adhm.201300308
Nanoscale carriers that stably load drugs in blood circulation and release the payloads in desirable sites in response to a specific trigger are of great interest for smart drug delivery systems. For this purpose, a novel type of disulfide core cross-linked micelles, which are facilely fabricated by cross-linking of poly(ethylene glycol)/polyurethane block copolymers containing cyclic disulfide moieties via a thiol-disulfide exchange reaction, are developed. A broad-spectrum anti-cancer drug, doxorubicin (DOX), is loaded into the micelles as a model drug. The drug release from the core cross-linked polyurethane micelles (CCL-PUMs) loaded with DOX is suppressed in normal phosphate buffer saline (PBS), whereas it is markedly accelerated with addition of an intracellular reducing agent, glutathione (GSH). Notably, although DOX-loaded CCL-PUMs display lower cytotoxicity in vitro compared to either free DOX or DOX-loaded uncross-linked polyurethane micelles, the drug-loaded CCL-PUMs show the highest anti-tumor efficacy with reduced toxicity in vivo. Since enhanced anti-tumor efficacy and reduced toxic side effects are key aspects of efficient cancer therapy, the novel reduction-responsive CCL-PUMs may hold great potential as a bio-triggered drug delivery system for cancer therapy.
Co-reporter:Xiaoye Gao;Yue Cao;Xiangfu Song;Zhe Zhang;Xiuli Zhuang;Xuesi Chen
Macromolecular Bioscience 2014 Volume 14( Issue 4) pp:565-575
Publication Date(Web):
DOI:10.1002/mabi.201300384
Biodegradable and pH-responsive carboxymethyl cellulose/poly(acrylic acid) hybrid hydrogels are synthesized. The hydrogels deswell in acidic artificial gastric fluid (AGF) but rapidly swell in neutral artificial intestinal fluid (AIF), rendering selective enzymatic degradation of the gels as well as accelerated drug release from insulin-loaded hydrogels in AIF. Oral administration of insulin-loaded hydrogels to streptozotocin-induced diabetic rats leads to a continuous decline in the fasting blood glucose level within 6 h post-administration, and the relative pharmacological availability increases more than 10 times compared to oral administration of free insulin solution. The relative bioavailability of hydrogel-encapsulated insulin after oral administration to healthy rabbits is 6.6%.
Co-reporter:Shuangjiang Yu, Chaoliang He, Qiang Lv, Hai Sun and Xuesi Chen
RSC Advances 2014 vol. 4(Issue 108) pp:63070-63078
Publication Date(Web):14 Nov 2014
DOI:10.1039/C4RA14221G
Nano-vehicles that exhibit enhanced stability in blood circulation while spontaneously releasing therapeutic cargos at pathological sites in response to specific biological triggers are of interest for on-demand drug delivery. In this work, disulfide cross-linked polyurethane micelles (CL-PUMs) that respond to pH change and an intracellular reducing agent were developed. The micelles were prepared by cross-linking of poly(ethylene glycol)–polyurethane multiblock copolymers containing tertiary amino and cyclic disulfide moieties via a thiol–disulfide exchange reaction. The CL-PUMs tended to swell or decompose under a weakly acidic environment or in the presence of an intracellular reducing agent, glutathione (GSH), likely owing to the protonation of the tertiary amino groups and cleavage of the disulfide cross-linking bonds. The doxorubicin (DOX)-loaded CL-PUMs suppressed the initial burst release at pH 7.4 without GSH, while they displayed a triggered drug release manner in response to an acidic environment and GSH. It was found that the intracellular DOX release of the DOX-loaded CL-PUMs in HepG2 cells was accelerated by an acidic environment or enhanced intracellular GSH concentration. Moreover, the time-dependent cytotoxicity against HepG2 and HeLa cells of the DOX-loaded CL-PUMs was confirmed by an MTT assay. Overall, due to the enhanced stability, selective swelling and decomposition properties in response to intracellular micro-environments, the pH- and reduction-sensitive polyurethane cross-linked nano-carriers can serve as a potential system for intracellular drug delivery.
Co-reporter:Hecheng Ma, Chaoliang He, Yilong Cheng, Dongsong Li, Yubao Gong, Jianguo Liu, Huayu Tian, Xuesi Chen
Biomaterials 2014 35(30) pp: 8723-8734
Publication Date(Web):
DOI:10.1016/j.biomaterials.2014.06.045
Co-reporter:Xiaoye Gao, Yue Cao, Xiangfu Song, Zhe Zhang, Chunsheng Xiao, Chaoliang He and Xuesi Chen
Journal of Materials Chemistry A 2013 vol. 1(Issue 41) pp:5578-5587
Publication Date(Web):19 Aug 2013
DOI:10.1039/C3TB20901F
A series of pH- and temperature-responsive poly(N-isopropylacrylamide-co-acrylic acid derivative) (P(NIPAM-co-AAD)) copolymers and hydrogels were prepared. The lower critical solution temperatures (LCSTs) of the copolymers exhibited a dependence on both pH and the hydrophobicity of the AAD unit. The influence of pH and temperature on the equilibrium swelling ratio of the hydrogels was investigated. The hydrogels displayed a unique thermo-induced swelling–deswelling transition that can be self-regulated to occur at above or below the physiological temperature in response to the environmental pH. Scanning electron microscopic (SEM) analysis revealed porous sponge-like microstructures of the hydrogels. Insulin was loaded into the hydrogels as a model protein, and the in vitro release profiles indicated that the loaded protein could be protected within the hydrogels in an acidic environment and selectively released in neutral medium. MTT assay proved that both the copolymers and hydrogels are nontoxic. After oral administration of the insulin-loaded hydrogels to streptozotocin-induced diabetic rats at 60 IU per kg, the fasting plasma glucose level was reduced continuously to 72.1% within 6 h. The bioavailability of hydrogel-encapsulated insulin via the oral administration to healthy rabbits reached 5.24%, which is much higher than that of pure insulin solution given orally. These results showed that the smart copolymers and hydrogels may hold great promise for pH-triggered drug delivery systems.
Co-reporter:Zhe Zhang, Xiaofei Chen, Li Chen, Shuangjiang Yu, Yue Cao, Chaoliang He, and Xuesi Chen
ACS Applied Materials & Interfaces 2013 Volume 5(Issue 21) pp:10760
Publication Date(Web):October 3, 2013
DOI:10.1021/am402840f
Intracellular pH-sensitive micelles of PEG-block-acetalated-dextran (PEG-b-AC-Dex) were prepared and used for acid-triggered intracellular release of anticancer drug. The hydrodynamic radii (Rh) of PEG-b-AC-Dex micelles could increase after incubation in PBS solution at pH 5.5. Based on the pH-responsive Rh variation behavior, it was expected that the PEG-b-AC-Dex micelles should be interesting for intracellular drug delivery. Thus, doxorubicin (DOX), a wide-spectrum anticancer drug, was loaded into the micelles and the pH-dependent release of the payload DOX was tested in vitro. The in vitro drug release profiles showed that only a small amount of the loaded DOX was released in PBS solution at pH 7.4, while up to about 90% of the loaded DOX could be quickly released in PBS solution at pH 5.5. Compared to pH-insensitive PEG-PLA micelles, the PEG-b-AC-Dex micelles displayed a faster drug release behavior in tumor cells. Moreover, higher cellular proliferation inhibition efficacy was achieved toward tumor cells. These features suggested that DOX could be efficiently loaded and delivered into tumor cells in vitro by the intracelluar pH-sensitive micelles, leading to enhanced inhibition of tumor cell proliferation. Therefore, the pH-sensitive micelles may provide a promising carrier for acid-triggered drug release for cancer therapy.Keywords: acetalated-dextran; doxorubicin; intracellular pH-sensitive; tumor therapy;
Co-reporter:Ziwei Zhao, Zhe Zhang, Li Chen, Yue Cao, Chaoliang He, and Xuesi Chen
Langmuir 2013 Volume 29(Issue 42) pp:13072-13080
Publication Date(Web):September 26, 2013
DOI:10.1021/la402890k
Biodegradable stereocomplex micelles (SCMs) based on amphiphilic dextran-block-polylactide (Dex-b-PLA) were designed and used for efficient intracellular drug deliveries. The Dex-b-PLA copolymers were successfully synthesized by click reaction. The structures of the resultant copolymers were verified by 1H NMR and FT-IR spectra. The formation of stable micelles through self-assembly driven by the stereocomplexation between enantiomeric l- and d-PLA blocks was characterized by transmission electron microscopy (TEM), dynamic laser scattering (DLS), and fluorescence techniques. It was interesting to observe that the SCMs showed lower critical micelle concentration values (CMCs) because of the stereocomplex interaction between PLLA and PDLA. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis provided information on the thermal and crystal properties of the copolymers and SCMs. The improved stability of SCMs should be attractive for intracellular drug delivery. Thus, a model anticancer drug doxorubicin (DOX) was loaded into micelles, and the in vitro drug release in was also studied. The release kinetics of DOX showed DOX-loaded SCMs exhibited slower DOX release. Confocal laser scanning microscopy (CLSM) and flow cytometry studies also showed that the DOX-loaded SCMs exhibited a slower drug release behavior. Meanwhile, the MTT assay demonstrated that DOX-loaded SCMs show lower cellular proliferation inhibition against HepG2. In sum, the micelles through self-assembly driven by stereocomplex interaction would have great potential to be used as stable delivery vehicles for pharmaceutical and biomedical applications.
Co-reporter:Xiaoye Gao, Yue Cao, Xiangfu Song, Zhe Zhang, Chunsheng Xiao, Chaoliang He and Xuesi Chen
Journal of Materials Chemistry A 2013 - vol. 1(Issue 41) pp:NaN5587-5587
Publication Date(Web):2013/08/19
DOI:10.1039/C3TB20901F
A series of pH- and temperature-responsive poly(N-isopropylacrylamide-co-acrylic acid derivative) (P(NIPAM-co-AAD)) copolymers and hydrogels were prepared. The lower critical solution temperatures (LCSTs) of the copolymers exhibited a dependence on both pH and the hydrophobicity of the AAD unit. The influence of pH and temperature on the equilibrium swelling ratio of the hydrogels was investigated. The hydrogels displayed a unique thermo-induced swelling–deswelling transition that can be self-regulated to occur at above or below the physiological temperature in response to the environmental pH. Scanning electron microscopic (SEM) analysis revealed porous sponge-like microstructures of the hydrogels. Insulin was loaded into the hydrogels as a model protein, and the in vitro release profiles indicated that the loaded protein could be protected within the hydrogels in an acidic environment and selectively released in neutral medium. MTT assay proved that both the copolymers and hydrogels are nontoxic. After oral administration of the insulin-loaded hydrogels to streptozotocin-induced diabetic rats at 60 IU per kg, the fasting plasma glucose level was reduced continuously to 72.1% within 6 h. The bioavailability of hydrogel-encapsulated insulin via the oral administration to healthy rabbits reached 5.24%, which is much higher than that of pure insulin solution given orally. These results showed that the smart copolymers and hydrogels may hold great promise for pH-triggered drug delivery systems.
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