Journal of Materials Chemistry B
·
2018
·Vol. 6
·期 20
·3372-3386
·
IF 4.776
Longbao Feng,Shina Yan,Qiyu Zhu,Jie Chen,Lian Deng,Yanfang Zheng,Wei Xue,Rui Guo
Drug/gene co-delivery carriers are a promising strategy for cancer treatment. Thus, herein, T7-conjugated redox-sensitive amphiphilic polyethylene glycol–polyethyleneimine–poly(caprolactone)-SS-poly(caprolactone)–polyethyleneimine–polyethylene glycol (PEG–PEI–PCL-SS-PCL–PEG) (PPPT) is designed to realize the co-delivery of pORF-hTRAIL and DOX efficiently into tumor cells. PPPT is synthesized via the ring opening polymerization (ROP) of ε-caprolactone followed by Michael addition polymerization and atom transfer radical polymerization (ATRP) of the maleic imide group of MAL-PEG-NHS. The PPPT micelles present a spherical or ellipsoidal geometry with a mean diameter of approximately 100–120 nm. Meanwhile, they also exhibit a redox-responsive drug release profile in vitro. The blood compatibility and complement activation tests reveal that the PPPT micelles do not induce blood hemolysis, blood clotting, or complement activation. The T7-modified co-delivery system shows a higher cellular uptake efficiency than the unmodified co-delivery system in human breast cancer MCF-7 cells and is accumulated in tumor more efficiently in vivo. These results suggest that the T7-targeted codelivery system of DOX and pORF-hTRAIL is a combined delivery platform that can significantly improve the treatment of breast cancer.
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Polymer Chemistry
·
2013
·Vol. 4
·期 10
·3012-3019
·
IF 5.231
Haibo Wang,Fangming Xu,Yin Wang,Xiangsheng Liu,Qiao Jin,Jian Ji
The pH-triggered biodegradable micelles based on poly(β-amino ester)-graft-12-acryloyloxy dodecyl phosphorylcholine (PAE-graft-ADPC) were explored as an efficient acid-triggered anticancer drug delivery system. A pH-responsive biodegradable polymer was synthesized by using hydrophilic 12-acryloyloxy dodecyl phosphorylcholine (ADPC) and poly(β-amino ester) (PAE) via Michael addition reaction. Micelles with phosphorylcholine shells were prepared in aqueous solution and doxorubicin (DOX) was loaded into the core of the micelles with high efficiency (73%). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) demonstrated that the size of the drug-loaded micelles was about 230 nm. DOX-loaded micelles were stable in the physiological environment, whereas they disassembled at pH 6.5 which is similar to the extracellular pH of most tumors. In vitro drug release showed that DOX release from micelles was faster at pH 6.5 than at 7.4. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles at pH 6.5. Moreover, an in vitro cytotoxicity study indicated that the growth of HepG2 cells was inhibited remarkably when the cells were preincubated with DOX-loaded micelles at pH 6.5. The results indicated that the pH-triggered biodegradable micelles could serve as promising drug carriers for cancer therapy.
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ADVANCED FUNCTIONAL MATERIALS
·
2014
·Vol. 25
·期 8
·1193-1204
·
IF 10.439
He Zhang,Jinbo Fei,Xuehai Yan,Anhe Wang,Junbai Li
Small aldehyde molecule are demonstrated to induce cationic diphenylalanine to assemble into monodisperse enzyme-responsive nanocarriers with high biocompatibility and excellent biodegradability. The formation of Schiff base covalent bond and accompanying π–π interaction of aromatic rings are found to be the mainly driving forces for the assembly of the nanocarriers. Interestingly, the nanocarriers show autofluorescence due to the n–π* transitions of C = N bonds, which lends them visually traceable property in living cells. Importantly, the nanocarriers can be taken in by cells and biodegraded in the cells. In addition, doxorubicin is easily loaded into the nanocarriers with high encapsulation amount, and its release can be triggered by tyrisin under physiological conditions. Noticeably, even at a very low drug concentration, the doxorubicin-loaded nanocarriers still exhibit a much higher killing capacity of HeLa cells in vitro, compared to the equivalent-dose free doxorubicin, indicating they have a great potential biomedical application.
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EUROPEAN POLYMER JOURNAL
·
2015
·
IF 3.005
Yan Zhang,Chenhong Wang,Yunxiao Huang,Husheng Yan,Keliang Liu
Polymeric micelles containing a poly(ethylene glycol) shell and a disulfide-crosslinked core with a hydrophobic moiety and carboxylic acid groups were prepared. The loading of doxorubicin into the core was achieved with a combination of ionic bonding and hydrophobic effects. The cooperativity of these effects enabled doxorubicin to bind tightly to the core, thereby endowing the system with a high loading capacity and a low rate of premature release in the bloodstream. Disulfide crosslinkages prevented the dissociation of the micelles into unimers upon extensive dilution. Under intracellular-like conditions (e.g., pH 5 with the presence of glutathione), the payload was released at a high rate from the micelles. The release was attributed to cleavage of the disulfide crosslinkages by glutathione and disruption of the ionic bonds at a lower pH due to protonation of the carboxylate anions in the core. Intracellular doxorubicin release was found to positively correlate with intracellular glutathione levels.
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BIOMATERIALS
·
2014
·
IF 8.312
Qiao-ling Zhu,Yi Zhou,Min Guan,Xiao-feng Zhou,Shu-di Yang,Yang Liu,Wei-liang Chen,Chun-ge Zhang,Zhi-qiang Yuan,Chun Liu,Ai-jun Zhu,Xue-nong Zhang
Developing safe and effective carriers of small interference RNA (siRNA) is a significant demand for the systemic delivery of siRNA. In this study, low-density lipoprotein (LDL) was isolated from human plasma and loaded with cholesterol-conjugated siRNA to silence the multidrug resistant gene of tumors. Chol-siRNA/LDL-coupled N-succinyl chitosan nanoparticles loaded with doxorubicin (Dox-siRNA/LDL-SCS-NPs) were then prepared and characterised. The Dox-siRNA/LDL-SCS-NPs had average particle size of 206.4 ± 9.2 nm, entrapment efficiency of 71.06% ± 1.42%, and drug-loading amount of 12.35% ± 0.87%. In vitro antitumor activity revealed that cell growth was significantly inhibited. The accumulation of Dox by fluorescence microscopy and flow cytometry showed that LDL-coupled nanoparticles were more easily taken up than Dox-SCS-NPs. Results of confocal microscopy and reverse transcription-PCR revealed the highly efficient uptake of siRNA and the decrease in mdr1 mRNA expression. LDL-coupled nanoparticles protected siRNA from macrophage phagocytosis by dynamic observation using live cell station. In vivo tumor-targeting suggested that Cy7-labelled Dox-LDL-SCS-NPs were markedly accumulated in an analyzed in situ liver tumor model. Results indicated that LDL-SCS-NPs were effective tumor-targeting vectors and that the preparation form may provide a new strategy for co-delivering siRNA and antitumor drugs.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2013
·
IF 3.458
Hejian Guo,Dianrui Zhang,Caiyun Li,Lejiao Jia,Guangpu Liu,Leilei Hao,Dandan Zheng,Jingyi Shen,Tingting Li,Yuanyuan Guo,Qiang Zhang
A novel polymer, i.e. galactosylated O-carboxymethyl chitosan-graft-stearic acid (Gal-OCMC-g-SA) was synthesized for liver targeting delivery of doxorubicin . The chemical structure was characterized by FT-IR, 1 H NMR and elemental analysis. Gal-OCMC-g-SA could self-assemble into nanoparticles with diameter of 160 nm by probe sonication in aqueous medium and exhibited a low critical aggregation concentration of 0.047 mg/mL. The DOX-loaded Gal-OCMC-g-SA (Gal-OCMC-g-SA/DOX) self-assembled nanoparticles were almost spherical in shape with an average diameter of less than 200 nm and zeta potential of around −10 mV. In vitro release revealed that the Gal-OCMC-g-SA/DOX nanoparticles exhibited a sustained and pH-dependent drug release manner. Furthermore, the hemolysis test demonstrated the good safety of Gal-OCMC-g-SA in blood-contacting applications. These results indicated that Gal-OCMC-g-SA/DOX nanoparticles were highly potential to be applied in cancer therapy.
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RSC Advances
·
2015
·Vol. 5
·期 36
·28060-28069
·
IF 3.84
Yan Cao,Junqiang Zhao,Yumin Zhang,Jianfeng Liu,Jinjian Liu,Anjie Dong,Liandong Deng
pH/redox dual-sensitive nanoparticles (NPs) based on a poly(ε-caprolactone) (PCL) and polyethylene glycol (PEG) triblock copolymer were developed and investigated aiming at improving the drug release property of PCL in cancer chemotherapy. A redox-sensitive disulfide bond and pH-sensitive benzoic-imine linkers were introduced to the backbone of the amphiphilic block copolymer termed SCHE, which could self-assemble into stable spherical NPs in aqueous solutions with an average size of about 100 nm. Doxorubicin (DOX) as a hydrophobic anticancer drug was loaded into the NPs by a dialysis method. The in vitro drug release results showed that the accumulative release amount of DOX at pH 5.0 with 10 mM glutathione (GSH) was accelerated apparently by more than twice compared to that at pH 7.4 without GSH. After a pre-treatment with GSH, the intracellular fluorescence intensity of Hela cells was enhanced compared to those without the pretreatment, which indicated faster DOX release in cells with higher GSH concentration. In an MTT assay, no obvious toxicity of blank NPs was found. In conclusion, SCHE NPs could serve as a novel colloidal drug delivery system in cancer chemotherapy and the introduced unstable linkers could enhance the drug release rate at tumor sites.
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Materials Science & Engineering C-Materials for Biological Applications
·
2015
·
IF 3.088
Luyan Wu,Liping Zhang,Gang Shi,Caihua Ni
Zwitterionic nanoparticles have excellent serum stability. In this study, pH/redox responsive polymer was synthesized through a modification of dextran using succinic acid, followed by crosslinking with cystamine. The polymer could self-assemble into stable nanoparticles (NPs) in aqueous solution. The NPs carried certain amount of free carboxyl and amino groups on the surface, which endowed the NPs excellent anti-protein adsorption ability. The surface charge was negative at pH 7.4 and was converted to positive at pH 5.0. It was revealed that the NPs showed little non-specific protein adsorption and had excellent serum stability, and the NPs could be internalized in Hela cells rapidly. This result was ascribed to the charge reversible feature of the NPs. Doxorubicin (DOX) was loaded in the NPs for release studies in vitro. The DOX-loaded NPs exhibited obvious pH and reduction sensitivities in response to the environment in tumor cells due to the introduction of carboxyl groups, amino groups and disulfide bonds in the NPs. The NPs were biocompatible, biodegradable, and could be potentially applied as anticancer drug carriers for enhancement of tumor intercellular uptake of doxorubicin.
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DRUG DELIVERY
·
2016
·
IF 4.843
Yawei Wang,Haiyan Zhang,Jing Hao,Bei Li,Ming Li,Wang Xiuwen
Context: Paclitaxel (PTX) and doxorubicin (DOX) are widely used for the combined chemotherapy of solid tumors. However, free drug combination has lower antitumor efficiency. It is necessary to design a drug delivery system to carry both of them.Objective: This study aimed to engineer a nano-drug delivery system for co-encapsulating PTX and DOX. This system was expected to resolve the multidrug resistance caused by single drug, and the dual–drug-loaded nanostructured lipid carriers were also planned to specifically target the cancer cells without obvious influence on normal cells and tissues.Methods: In this paper, nanostructured lipid carriers for combination delivery of PTX and DOX were prepared by the melt-emulsification technique. In vitro cytotoxicity against NCL-H460 human non-small cell lung carcinoma (NSCLS) cell line was investigated, and in vivo anti-tumor of NLC was evaluated on mice models grafting NCL-H460 cells.Results: PTX-DOX NLC achieved the highest cytotoxic effect among all formulations in vitro, as compared to single drug delivery NLC. In vivo investigation on NSCLC animal models showed that co-delivery of PTX and DOX possessed high tumor-targeting capacity and strong anti-tumor activity.Conclusion: The PTX-DOX NLC constructed in this research offers an effective strategy for targeted combinational lung cancer therapy.
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Acta Biomaterialia
·
2016
·
IF 6.008
Wen Hu,Lipeng Qiu,Liang Cheng,Qing Hu,Yang Liu,Ziyang Hu,Dawei Chen,Lifang Cheng
To solve the contradiction between long circulation time and effective intracellular drug release, redox and pH-responsive drug delivery system was developed by incorporated redox-sensitive disulfide linkage between poly(amidoamine) dendrimers (PAMAM) and poly(ethylene glycol) (PEG). Doxorubicin (DOX) was loaded into the hydrophobic core of the conjugates to prepare PAMAM-SS-PEG/DOX complexes (PSSP/DOX). In vitro release studies suggested that DOX release from PSSP/DOX complexes followed an redox and acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PSSP/DOX complexes against B16 tumor cells increased with, while cellular uptake decreased with increasing PEGylation degree. Further, intracellular DOX release observation and measurement indicate that the intracellular DOX release played a critical role for the cytotoxicity of DOX-loaded PSSP conjugates. In addition, cellular entry mechanism of the PSSP/DOX study demonstrated that both clathrin- and caveolae-mediated endocytosis were the primary pathways for cellular entry of PSSP/DOX. Finally, in vivo study of PSSP/DOX complexes in B16 tumor-bearing mice indicate that PSSP/DOX could significantly improve antitumor efficiency and present a good safety. The redox and pH-responsive drug delivery system has been demonstrated to be a promising candidate for solid tumor therapy. Statement of Significance In previous research, pH-sensitive diblock polymer of poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate) (PEG-PTMBPEC) was synthesized to facilitate the intracellular anticancer drug release. However, the nanoparticles based on PEG-PTMBPEC get into the tumor cells just relying on the EPR-mediated passive targeting resulting in the low drug accumulation. Therefore, cRGD peptide modified PEG-PTMBPEC polymeric micelles were developed for specific targeted delivery of doxorubicin (DOX) to neovascular cells and tumor cells simultaneously. The precise intracellular target site and effective drug concentration will contribute to enhancing the antitumor toxicity and reducing the systematic toxicity of DOX. The cRGD modified pH-sensitive micellar system is a promising vehicle for intracellular drug delivery to αvβ3 integrin receptor overexpressed tumor cells and neovascular cells.
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JOURNAL OF CONTROLLED RELEASE
·
2016
·
IF 7.441
Yuling Bao,Mingxing Yin,Xiaomeng Hu,Xiangting Zhuang,Yu Sun,Yuanyuan Guo,Songwei Tan,Zhiping Zhang
A pH-sensitive prodrug , TPGS-CH N -DOX, was introduced by conjugating anticancer drug , doxorubicin (DOX), onto d -α-tocopherol polyethylene glycol 1000 succinate (TPGS) via a cleavable Schiff base linkage. The prodrug was mixed with a PEGylated lipid to form a simple but multifunctional hybrid micelle system, which can realize high drug loading capability and biocompatibility , extended blood circulation time, inhibited drug resistance in cancer cells, improved therapeutic response, reduced side effects, and easy functionalities for targeting delivery. The hybrid micelles exhibited in vitro pH-sensitive drug release, enhanced cellular uptake and strengthened cytotoxicity on both drug-sensitive human breast cancer MCF-7 and resistant MCF-7/ADR cells. P-glycoprotein functional inhibition and mitochondria-associated cell apoptosis induced by TPGS were thought to play an important role in overcoming the multidrug resistance . As a result, the hybrid micelles demonstrated good anticancer efficacy in MCF-7/ADR xenograft model. Additionally, after modifying with a tumor-specific targeting peptic ligand, cRGD, the tumor growth/metastasis inhibition was further evidenced in integrin receptor overexpressed melanoma cancer B16F10 and even murine hepatocarcinoma H22 models. This TPGS-based pH-sensitive prodrug provides a safe and “Molecular economical” way in the rational design of prodrugs for overcoming multidrug resistance and targeting delivery, which can improve the potency for clinical use.
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Journal of Materials Chemistry B
·
2017
·Vol. 5
·期 12
·2337-2346
·
IF 4.543
Cheng Gao,Fan Tang,Jianxiang Zhang,Simon M. Y. Lee,Ruibing Wang
To enhance selective drug release and overcome undesired side effects, novel disulfide crosslinked sodium alginate nanoparticles were designed for achieving glutahione triggered drug release in tumor cells. The doxorubicin loaded crosslinked nanoparticles (DOX-NPs) demonstrated selective drug release in 10 mM glutathione and the further study of their cellular uptake and intracellular release confirmed that the crosslinked nanoparticles could be easily taken up and they only released the encapsulated therapeutic payload in cancer cells. The in vitro cytotoxicity of crosslinked DOX-NPs showed a selective and remarkable cytotoxic effect on Hep-G2 and HeLa cells, instead of on healthy human liver L-O2 cells. More interestingly, the otherwise cardiotoxic DOX showed no cardiotoxicity when formulated as crosslinked DOX-NPs, in an in vivo zebrafish model. This study has demonstrated that the disulfide crosslinked nanoparticle system may provide a promising drug delivery platform for selective drug release in cancer cells with a much improved safety profile.
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