BIOCONJUGATE CHEMISTRY
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2017
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IF 4.818
Luping Zheng,Yunfei Wang,Xianshuo Zhang,Liwei Ma,Baoyan Wang,Xiangling Ji,Hua Wei
Dendrimer with hyperbranched structure and multivalent surface is regarded as one of the most promising candidates close to the ideal drug delivery systems, but the clinical translation and scale-up production of dendrimer has been hampered significantly by the synthetic difficulties. Therefore, there is considerable scope for the development of novel hyperbranched polymer that can not only address the drawbacks of dendrimer but maintain its advantages. The reversible addition–fragmentation chain transfer self-condensing vinyl polymerization (RAFT-SCVP) technique has enabled facile preparation of segmented hyperbranched polymer (SHP) by using chain transfer monomer (CTM)-based double-head agent during the past decade. Meanwhile, the design and development of block-statistical copolymers has been proven in our recent studies to be a simple yet effective way to address the extracellular stability vs intracellular high delivery efficacy dilemma. To integrate the advantages of both hyperbranched and block-statistical structures, we herein reported the fabrication of hyperbranched block-statistical copolymer-based prodrug with pH and reduction dual sensitivities using RAFT-SCVP and post-polymerization click coupling. The external homo oligo(ethylene glycol methyl ether methacrylate) (OEGMA) block provides sufficient extracellularly colloidal stability for the nanocarriers by steric hindrance, and the interior OEGMA units incorporated by the statistical copolymerization promote intracellular drug release by facilitating the permeation of GSH and H+ for the cleavage of the reduction-responsive disulfide bond and pH-liable carbonate link as well as weakening the hydrophobic encapsulation of drug molecules. The delivery efficacy of the target hyperbranched block-statistical copolymer-based prodrug was evaluated in terms of in vitro drug release and cytotoxicity studies, which confirms both acidic pH and reduction-triggered drug release for inhibiting proliferation of HeLa cells. Interestingly, the simultaneous application of both acidic pH and GSH triggers promoted significantly the cleavage and release of CPT compared to the exertion of single trigger. This study thus developed a facile approach toward hyperbranched polymer-based prodrugs with high therapeutic efficacy for anticancer drug delivery.
研究领域:
聚合物化学
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药学
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材料科学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Polymer Chemistry
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2013
·Vol. 5
·期 8
·2801-2808
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IF 5.231
Yu Zhang,Chunsheng Xiao,Mingqiang Li,Jianxun Ding,Chaoliang He,Xiuli Zhuang,Xuesi Chen
The linear-dendritic prodrug MPEG–b-PAMAM–LA/DOX was synthesized through modifying the linear methoxy poly(ethylene glycol)–block-dendritic poly(amidoamine) (MPEG–b-PAMAM) with lipoic acid (LA) and then conjugating doxorubicin (DOX) by an acid-labile hydrazone bond. The obtained amphiphilic prodrug self-assembled into nanosized spherically shaped micelles in deionized water, as characterized by transmission electron microscopy (TEM) and dynamic laser scattering (DLS). The micelles could be cross-linked using a catalytic amount of dithiothreitol (DTT). Compared with the non-cross-linked micellar nanoparticles (NPs) (NCL-NPs), the cross-linked NPs (CL-NPs) were more stable against dilution and high salt concentration. However, in the presence of 10 mM glutathione (GSH), the reducible CL-NPs swelled in a short time, as determined by DLS. In in vitro drug release experiments, the CL-NPs exhibited pH and reduction dual responsive DOX release behaviour. DOX was released slowly under physiological pH (7.4) and/or in the absence of reduced GSH, but was released quickly at endosomal pH (5.5) and in the presence of GSH (5 mM or 10 mM). Both the confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) studies indicated that CL-NPs could be effectively taken up by the HeLa cells, and the conjugated DOX was efficiently released in response to the intracellular environment (low pH and high GSH concentration). In the MTT assay, CL-NPs could effectively inhibit the proliferation of HeLa cells and A549 cells. Thus, CL-NPs with superior stability, pH and reduction dual responsive drug release behaviour and good anti-cancer capability showed promise for anti-cancer treatment in the future.
研究领域:
药学
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纳米技术
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药物递送系统
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癌症治疗
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产品关联
DOI
高影响因子
Acta Pharmaceutica Sinica B
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2019
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IF 5.808
Yan Chen,Chen Chen,Xiaojuan Zhang,Chuanchuan He,Pengxuan Zhao,Minsi Li,Ting Fan,Ruicong Yan,Yao Lu,Robert J. Lee,Muhammad Waseem Khan,Muhammad Sarfraz,Xiang Ma,Tan Yang,Guangya Xiang
Platinum-based chemotherapy is used for non-small cell lung cancer (NSCLC). However, it has side effects and minimum efficacy against lung cancer metastasis. In this study, platinum–curcumin complexes were loaded into pH and redox dual-responsive nanoparticles (denoted as Pt– [email protected] ) to facilitate intracellular release and synergistic anti-cancer effects. Pt– [email protected] was prepared by a nano-precipitation method and had a diameter of ∼100 nm. The nanoparticles showed increased anti-cancer effects both in vivo and in vitro . In addition, Pt– [email protected] blocked PI3K/AKT signal transduction pathway and inhibited MMP2 and VEGFR2, resulting in enhanced anti-metastatic activity. Furthermore, reduced side effects were also observed. In conclusion, Pt– [email protected] provided a novel and attractive therapeutic strategy for NSCLC.
研究领域:
药理学
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肿瘤学
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纳米技术
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化疗
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产品关联
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
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2017
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IF 4.164
Shudi Yang,Ying Wang,Zhaoxiang Ren,Mengtian Chen,Weiliang Chen,Xuenong Zhang
In this research, a charge-conversional polymer, poly- l -lysine-lipoic acid (PLL-LA), was prepared by dimethylmaleic anhydride (DA) modification and applied as a carrier with enhanced cell internalization and intracellular pH- and reduction-triggered doxorubicin (Dox) release. The surface charge of dimethylmaleic anhydride-poly- l -lysine-lipoic acid micelles (DA-PLL-LA) was negative at physiological pH and reversed to positive at the extracellular and intracellular pH of cancer cells. At tumor extracellular pH of 6.8, the conjugates underwent a rapid charge-reversible process with almost 80% DA cleavage within 2 h, and then endocytosed into the endo/lysosomes more rapidly than at physiological pH of 7.4. The Dox/DA-PLL-LA micelles (Dox-micelles) demonstrated a sustained drug release in vitro under physiological condition, and rapid Dox release was triggered by both extracellular pH and high-concentration reducing glutathione. The Dox-micelles also exhibited enhanced internalization at extracellular pH, rapid intracellular drug release, and improved cytotoxicity against A549 cells in vitro . Excellent tumor-penetrating efficacy was also found in A549 tumor spheroids and solid tumor slices. Moreover, the DA-PLL-LA micelles exhibited excellent tumor-targeting ability in tumor tissues and excellent antitumor efficacy and low systemic toxicity in breast tumor-bearing mice. Therefore, the DA-PLL-LA micelles demonstrated great potential for targeted and efficient drug delivery in cancer treatments.
研究领域:
药学
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生物医学工程
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癌症研究
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
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2022
·
IF 3.682
Limin Zhu,Shuangyan Wang
Mesoporous silica nanoparticle (MSN), sodium hyaluronate (SH), silk fibroin (SS), and oxidized sodium carboxymethyl cellulose (O-CMC) hybrids were used to develop an intelligent drug delivery platform that may be employed for pH and redox-responsive bi-drug administration. The first drug, cytarabine (Cyt), was loaded with amino-functionalized mesoporous silica (MSN-NH2) encased by the hydrogel of cystamine (Cys) and SH cross-linked by amide bonds. Hydrophobic doxorubicin (DOX) was co-loaded with Cyt/MSN-NH2/SA in the hydrogel of SS and O-CMC in the Cyt- loaded hydrogel. Dual-responsive drug delivery may be achieved by encapsulating SS and O-CMC in a hydrogel, including Cyt/MSN-NH2/SA/DOX/SS/O-CMC, which has acyl hydrazone bonds (-HC = N) and disulfide bond (-S-S-) exchange reaction with glutathione (GSH). Compared to hydrogels encapsulating only one drug (Cyt or DOX), cell survival analysis revealed that the newly fabricated hydrogels have significantly greater chemotherapeutic efficacy. The cell proliferation of the fabricated nanoparticles was examined in MCF-7 and MDA-MB-231 cells, which indicates that the nanoparticles effectively kill the cancer cells without affecting non-cancerous cells. Further, we effectively investigated the morphological changes, and various biochemical staining methods examined nuclear fragmentation/condensation. Furthermore, the biosafety of the nanoparticles was investigated by the in vivo animal model, which reveals that they remarkably enhanced the safety profile in various organs. These outcomes demonstrated that this nanoparticle platform was a promising beneficial agent for improving breast cancer treatment.
研究领域:
纳米技术
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药学
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癌症研究
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材料科学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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