Journal of Biomedical Nanotechnology
·
2014
·Vol. 10
·期 2
·324-335
·
IF 7.578
Lv Li,Shen Yuanyuan,Li Min,Xu Xiaofen,Li Mingna,Guo Shengrong,Huang Shengtang
Novel poly(anhydride-ester)-b-poly(ethylene glycol) copolymers (PAE-b-PEGs) were synthesized by esterization of methyl poly(ethylene glycol) and poly(anhydride-ester), which were obtained by the melt polycondensation of α, ω- acetic anhydride-terminated poly(L-lactic
acid), and characterized by 1H-NMR and gel permeation chromatography. The two poly(anhydride-ester)-b-poly(ethylene glycols) (denoted as PAE-b-PEG2k and PAE-b-PEG5k) thus obtained can selfassemble in water to form micelles with hydrodynamic
diameters of 92.5 and 97.5 nm above their critical micelle concentrations of 3.78 and 2.36 μg/mL, respectively. The curcumin-loaded PAE-b-PEG2k and PAE-b-PEG5k micelles were prepared by the solid dispersion method, and they could encapsulate approximately
7% (w/w) curcumin. The diameters of the micelles were stable for 5 days. Curcumin is released faster from the micelles at pH 5.0 than at pH 7.4. Curcumin is released from the micelles at a fast rate during the initial 12 h, followed by a zero-order release during the subsequent 200 h, both
at pH 5.0 and 7.4. The IC50 values of the curcumin-loaded PAE-b-PEG2k and PAE-b-PEG5k micelles against HeLa cells are 12.41 and 15.31 μg/mL, respectively, which is lower than that of free curcumin (25.90 μg/mL). The PAE-bPEG2k
micelles are taken up faster than the PAE-b-PEG5k micelles by HeLa cells. Curcumin-loaded micelles can induce G2/M phase cell cycle arrest and apoptosis of HeLa cells.
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Nanomedicine
·
2016
·
IF 4.889
Yanjun Chen,Qiaoxin Yue,Gejing De,Jie Wang,Zhenzhen Li,Shuiming Xiao,Huatao Yu,Hai Ma,Feng Sui,Qinghe Zhao
Aim: Tumor metastasis is one of the leading causes of insufficient chemotherapy during cancer treatment. In this study, a poly(β-amino ester) derivate was developed to fabricate paclitaxel (PTX) entrapped pH-responsive copolymer micelles for inhibition of breast cancer metastasis. Materials & methods: PTX-loaded micelles were fabricated by thin film hydration method. The inhibition efficacy of the as-prepared micelles was evaluated on MDA-MB-231 cells and tumor bearing mice. Results: PTX-loaded micelles were successfully prepared. Such micelles could promote drug uptake and MDA-MB-231 cell deaths, and suppress tumor metastasis. Conclusion: The pH-responsive PTX-loaded micelles are promising candidates in developing stimuli triggered drug delivery systems in acidic tumor microenvironments with improved inhibitory effects on tumor metastasis.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2013
·
IF 3.554
Jinfeng Dou,Haiqun Zhang,Xiuju Liu,Mengyu Zhang,Guangxi Zhai
A mixed micelle that comprised of monomethylol poly(ethylene glycol)-poly( d , l -lactic acid) (MPP), d -α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and stearic acid grafted chitosan oligosaccharide(CSO-SA) copolymers was developed to enhance the oral absorption of docetaxel (DTX). DTX-loaded MPP/TPGS/CSO-SA mixed polymeric micelles (MPMs) were prepared with thin film hydration method and characterized in terms of morphology, size, zeta potential, encapsulation efficiency, critical micellization concentration, and in vitro stability in media modeling physiological conditions. The in vitro release of docetaxel from the mixed micelles was studied with dialysis method. The oral bioavailability studies were conducted in rats and the pharmacokinetic parameters were evaluated. The results showed that DTX-loaded MPP/TPGS/CSO-SA MPMs had a mean diameter of 34.96 nm and exhibited spherical shape under transmission electron microscopy. The drug loading of DTX in the mixed micelles was 19.15%. The critical micellization concentration of MPP/TPGS/CSO-SA copolymer was 2.11 × 10 −5 M, and the size of mixed micelles in gastric fluid (pH 1.6) for 2 h and simulated intestinal fluid (pH 6.5) for 6 h showed no significant change. The in vitro release study showed that DTX-loaded MPP/TPGS/CSO-SA MPMs exhibited slower release characteristics compared to DTX solution. The oral bioavailability of the DTX-loaded MPP/TPGS/CSO-SA MPMs was increased by 2.52 times compared to that of DTX solution. The current results encourage further development of DTX mixed polymeric micelles as the oral drug delivery system.
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POLYMERS FOR ADVANCED TECHNOLOGIES
·
2022
·Vol. 33
·期 9
·2835-2844
·
IF 3.348
Xiaoqiang Li,Yongli Shi,Shuxin Xu
Increasing the accumulation of therapeutics in tumor site and improving the bioavailability of delivered drug are vital strategies to enhance chemotherapy efficiency as well as reduce side effects. Herein, we report an injectable hydrogel system to locally deliver tumor-targeting nano-micelles with GSH-responsive drug release to improve antitumor efficiency. Amphiphilic polymers with different functions were designed and successfully synthesized. Then, the prepared polymers self-assembled into nano-micelles (PPR-NP), which exhibited tumor cell targeting and GSH-responsive drug release behavior. Furthermore, we constructed an injectable hydrogel system composed of the nano-micelles (PPR-NP@α-CD gel ). Peritumorally administrated to tumor site, PPR-NP@α-CD gel sustainedly released PPR-NP around tumor site in situ, which were specifically taken up by tumor cells and rapidly released loaded paclitaxel in responsible to the high concentration of GSH in tumor cell, thus effectively inhibiting tumor growth. Synergized by the multitargeting effect, the present system could effectively improve the bioavailability of antineoplastic drug and enhance the antitumor efficiency, holding potential for solid tumor therapy.
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Polymer Chemistry
·
2016
·Vol. 7
·期 9
·1719-1729
·
IF 5.687
Xiao-Qing Yi,Quan Zhang,Dan Zhao,Jia-Qi Xu,Zhen-Lin Zhong,Ren-Xi Zhuo,Feng Li
In this paper, we first synthesized an amphiphilic block copolymer poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate-co-5-methyl-5-propargyl-1,3-dioxan-2-one), i.e., PEG-P(TMBPEC-co-MPMC), with pendant reactive alkynyl groups as well as pH-sensitive acetal groups. Next, core crosslinked (CCL) micelles were prepared by the introduction of 1,6-diazidohexane and bis(azidoethyl)disulfide into micelles via azide–alkyne click chemistry, which were denoted as CCL/CC and CCL/SS, respectively. The CCL micelles had superior stability and drug loading efficiency to the uncrosslinked (UCL) micelles. In comparison with free DOX, drug-loaded CCL micelles exhibited lower cell viability in MCF-7/ADR cells due to their “stealth” endocytosis effect that might be beneficial for overcoming delivery barriers of drug resistance. More interestingly, as compared with CCL/CC micelles, CCL/SS micelles were found to further enhance cytotoxicity in MCF-7/ADR cells because of their better on-demand drug release capability of pH and redox dual-sensitive CCL/SS micelles. These results suggest that the self-assembled pH and redox dual-sensitive CCL/SS micelles have promising applications to overcome multi-drug resistance in tumor treatments.
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JOURNAL OF BIOMATERIALS APPLICATIONS
·
2016
·
IF 1.988
Gongyan Liu,Kaijun Li,Haibo Wang
To develop a drug delivery system with long circulation and controlled drug release in cancer cells, polymeric micelles based on PEGylated chitosan-g-lipoic acid were prepared to use as a drug delivery platform. These micelles possessed good stability and were stable in physiological environment and high salt concentrations. The in vitro drug release results implied that the drug carrier could maintain their stability and minimize the payload leakage in systemic circulation, but release drugs faster under intracellular redox condition. Furthermore, the cellular uptake and therapeutic efficacy of the drug carrier were evaluated in vitro, and the results demonstrated that the drug carrier could escape from the endo/lysosomes of tumor cells effectively and present high cytotoxicity to tumor cells. Therefore, this drug delivery system has the potential to serve as a drug carrier for cancer therapy.
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Biomaterials Science
·
2023
·Vol. 11
·期 12
·4335-4345
·
IF 6.6
Penghui Wang,Yuling Wang,Xuelin Xia,Wei Huang,Deyue Yan
Multidrug resistance (MDR) is a major cause of chemotherapy failure in cancer treatment. P-glycoprotein (P-gp) inhibitors are helpful for chemotherapy drugs to overcome tumor MDR effectively. With the traditional physical mixing of chemotherapy drugs and inhibitors, it is difficult to achieve satisfactory results due to the different pharmacokinetics and physicochemical properties between the two of them. Herein, we prepared a novel drug-inhibitor conjugate prodrug (PTX-ss-Zos) from a cytotoxin (PTX) and a third-generation P-gp inhibitor (Zos) linked with a redox-responsive disulfide. Then, PTX-ss-Zos was encapsulated in DSPE-PEG2k micelles to form stable and uniform nanoparticles (PTX-ss-Zos@DSPE-PEG2k NPs). PTX-ss-Zos@DSPE-PEG2k NPs could be cleaved by the high-concentration GSH in cancer cells and release PTX and Zos simultaneously to inhibit MDR tumor growth synergistically without apparent systemic toxicity. The in vivo evaluation experiments exhibited that the tumor inhibition rates (TIR) of PTX-ss-Zos@DSPE-PEG2k NPs were high up to 66.5% for HeLa/PTX tumor-bearing mice. This smart nanoplatform would bring new hope for cancer treatment in clinical trials.
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JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE
·
2015
·Vol. 26
·期 9
·1-12
·
IF 2.587
Zeng Xiaolong,Zhou Xiaoyan,Li Mengyi,Wang Changyong,Xu Jiake,Ma Dong,Xue Wei
Bioreducible polymers have appeared as the ideal drug carriers for tumor therapy due to their properties of high stability in extracellular circulation and rapid drug release in intracellular reducing environment. Recently, the diselenide bond has emerged as a new reduction-sensitive linkage. In this work, the amphiphilic poly(ethylene glycol)- b -poly( l -lactide) containing diselenide bond has been synthesized and used to load anti-tumor drug, docetaxel (DTX), to form the redox micelles. It was found that the redox micelles showed a rapid response to glutataione (GSH), which resulted in a fast release of DTX in the presence of GSH. In contrast, <40 % of DTX was released from the micelles within 72 h under the normal condition (absence of GSH). The DTX-loaded redox micelles showed the significant inhibition effect to MCF-7 cells, and the cytotoxicity was dependent on the intracellular GSH concentrations. Moreover, considering the potentially clinical applications of the micelles through intravenous injection, the blood compatibility was also studied by the hemolysis analysis, activated partial thromboplastin time, prothrombin time and thromboelastography assays. These results confirmed that the redox micelles showed good blood safety, suggesting a potential application in tumor therapy.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Min Li,Ling'e Zhang,Yang Xuan,Defu Zhi,Wei Wang,Wenjun Zhang,Yinan Zhao,Shufen Zhang,Shubiao Zhang
Although many chemotherapy prodrugs have been developed for tumor therapy, non-targeted delivery, uncontrolled release and tedious construction procedure of prodrugs still limit their clinical application in tumor treatment. In this work, hyaluronic acid (HA) which has tumor-targeting ability was used to conjugate to antitumor drug podophyllotoxin (PPT) to construct a pH-sensitive prodrug named HA-CO-O-PPT just via a one-step esterification reaction. The HA-CO-O-PPT spontaneously assembled into nano spherical micelles in aqueous medium, which had outstanding serum stability and blood compatibility. The obtained prodrug micelles (named HP micelles) exhibited a pH-responsive drug release mode with cumulative release reaching 81.2% due to their dissociation in response to acid stimulus, and had a high cellular uptake efficiency beyond 97% owing to HA receptor-mediated targeting. Furthermore, it was found that the prodrug micelles showed excellent antitumor activities in vivo with the tumor inhibition ratio up to 85% and negligible systemic toxicity. Accordingly, the pH-responsive HP micelles constructed by a simple one-step reaction, could be a promising candidate as a chemotherapeutic agent for cancer therapy.
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MACROMOLECULAR BIOSCIENCE
·
2015
·Vol. 16
·期 3
·420-431
·
IF 3.851
Yuanyuan Guo,Pei Zhang,Qingyun Zhao,Kaiming Wang,Yuxia Luan
In this article, the low-molecular weight biodegradable methoxy poly (ethylene glycol)-poly ( d , l -lactide-co-glycolide) (PP) is chosen as polymeric skeleton to be conjugated with docetaxel (DTX) by disulfide bond (PP-SS-DTX) to construct the reduction-sensitive drug delivery system. The conjugates are synthesized via three steps and are further employed to physically load free DTX to develop the PP-SS-DTX/DTX micelles which exhibit many merits including high drug loading content, good stability, and stimuli-sensitive release of drugs. The hydrodynamic diameter of PP-SS-DTX/DTX micelles determined by DLS is 112.3 nm. The hemolysis assay reveals the good blood compatibility of PP-SS-DTX/DTX micelles. In order to investigate the reductive sensitivity of PP-SS-DTX/DTX micelles, dithiothreitol (DTT) is added into the release medium and a programmed drug release mode is observed in the conjugated micelles. In vitro cytotoxity assay shows that the PP-SS-DTX/DTX micelles are more cytotoxic than that of free DTX solution for both MCF-7 and B16F10 cancer cells. In addition, the PP-SS-DTX/DTX micelles also show a higher cellular uptake rate than that of free DTX. Hence, the prepared reduction-sensitive PP-SS-DTX/DTX micelles are effective on inhibiting cancer cells compared with the free DTX which would be a promising carrier in cancer therapy.
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MOLECULAR PHARMACEUTICS
·
2014
·
IF 4.787
Chaoyu Liu,Jiang Yuan,Xiaoming Luo,Maohua Chen,Zhoujiang Chen,Yuancong Zhao,Xiaohong Li
It is one of the challenges for a wide clinical application of polymer micelles to address the structure disintegration and premature drug release before reaching a pathological site. In the current study, folic acid (FA)-decorated polymer–drug conjugates (FSC) were synthesized with disulfide linkages between camptothecin (CPT) and amphiphilic poly(ethylene glycol)-b-poly(ε-caprolactone) (PECL) copolymers. FSC conjugates were proposed to assemble into micelles with a hydrophobic core of PCL segments and CPT and a hydrophilic corona of PEG segments. The addition of hexadecanol during micelle formation (FSC-16) was proposed to modulate the interactions of hydrophobic segments in micelles and enhance the reductive sensitivity. FSC-16 micelles were obtained with critical micelle concentration of around 2 μg/mL and an average size of around 200 nm, and the conjugated CPT was rapidly released out in response to glutathione. The reductive sensitivity was also demonstrated with respect to the changes of micelle size and morphologies as well as the fluorescent intensity of pyrene loaded in micelles. Benefiting from the FA receptor-mediated uptake and the reduction-sensitive release of CPT, significant cytotoxicity and cell apoptosis were identified for FSC-16 micelles against SKOV-3 cells with strong expressions of FA receptors. Flow cytometry and confocal laser scanning microscopy analyses demonstrated that CPT was distributed into nuclei after cellular uptake and intracellular release from FSC-16 micelles. Thus, the FA-decorated and reduction-sensitive micelles assembled from polymer–drug conjugates show advantages in inhibiting premature release during circulation, enhancing cellular uptake at the tumor tissues, and promoting intracellular release and nuclei location of the active moieties.
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Journal of Biomedical Nanotechnology
·
2015
·Vol. 11
·期 10
·1764-1775
·
IF 5.338
Yin Qi,Shen Jianan,Yu Haijun,Huang Yongzhuo,Zhang Zhiwen,Li Yaping
The clinical success of anthracyclines-containing chemotherapy for breast cancer is mainly restricted by cardiac damage and the development of multidrug resistance (MDR). For efficient reversal of drug resistance, doxorubicin (DOX) loaded multifunctional bioreducible micelles were constructed
from a new amphiphilic copolymer consisting of polyethylene glycol and poly[bis(2-hydroxylethyl)-disulfide-diacrylate-β-histamine] and characterized. The introduction of imidazole group endowed the micelles with endosomal buffering capacity and improved the endosomal escape. The
reductionresponsiveness of the micelles promoted DOX release. The activity of P-glycoprotein, one of the most well-described drug-efflux pumps, and glutathione S-transferase, an important detoxification enzyme, were also inhibited by the micelles. The accumulation of DOX in tumor after intravenous
administration of the drug-loading micelles was increased in drug resistant tumor-bearing mice. These results indicated that the micelle was a promising drug delivery system for MDR cancer therapy.
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