Redox-responsive polymeric micelles formed by conjugating gambogic acid with bioreducible poly(amido amine)s for the co-delivery of docetaxel and MMP-9 shRNA
Redox-responsive polymeric micelles formed by conjugating gambogic acid with bioreducible poly(amido amine)s for the co-delivery of docetaxel and MMP-9 shRNA
复制标题
DOI：
10.1016/j.actbio.2017.12.028
复制
发表时间：
2018-03-01
影响因子：
9.7
通讯作者：
Ho, Rodney J. Y.
中科院分区：
文献类型：
--
作者：
Kang, Yanan;Lu, Lu;Ho, Rodney J. Y.
将伽玛酸(GA)与聚氨基胺S(PAAS)通过酰胺键连接，形成了一种新型的氧化还原敏感的疏水药物和亲水性siRNA或shRNA共传递体系，称为GA-PAAS(PAG)。PAG能以两亲嵌段共聚物的形式自组装成胶束，具有良好的负载多西紫杉醇(DTX)和可调节剂量比的基质金属蛋白酶-9 shRNA的能力。此外，共聚焦显微镜、流式细胞仪和体外转染分析表明，与PAG/DTX-MMP-9 shRNA胶束(PAG/DTX-shRNA)孵育后，DTX和MMP-9 shRNA的细胞内化效率高于游离药物。与传统的两亲性共聚胶束不同，GA偶联在PAG中具有内在的抗癌效果。PAAS中二硫键的存在使PAG胶束能够在还原剂的响应下快速解体，导致负载药物(DTX、GA和MMP-9 shRNA)的释放。体外细胞实验表明，PAG/DTX-shRNA胶束对MCF-7细胞增殖的抑制作用强于单一药物胶束或单一载药胶束。利用MCF-7乳腺癌移植瘤小鼠模型进行的体内生物分布和抗肿瘤效应研究表明，与游离药物相比，PAG/DTX-shRNA胶束可以促进药物蓄积，从而维持对肿瘤的治疗效果。此外，PAG/DTX-shRNA胶束比泰素帝和PAG-shRNA胶束显示出更强的抗肿瘤效果。这些结果表明，氧化还原敏感的PAG平台是一种很有前途的联合药物和基因治疗癌症治疗的共给药系统。意义陈述PAG胶束是通过将伽马酸(GA)和聚氨基胺S(PAAS)偶联而设计的，它既可以作为基因和药物的联合载体，又可以作为抗肿瘤的前药。与传统的两亲性胶束不同，GA偶联PAG能发挥其内在效应，并与多西紫杉醇(DTX)协同抗MCF-7细胞增殖作用。PAG中的二硫键使PAG胶束能够在还原剂的响应下快速分解，并在肿瘤部位释放所有负载的药物(DTX、GA和MMP-9 shRNA)。PAG/DTX-shRNA胶束比泰素帝具有更强的抗肿瘤作用，说明PAG的设计理念是可行的。而PAG策略也可用于通过其他小分子药物与PAM的偶联来开发一系列类似的共给药系统，如阿霉素、甲氨蝶呤等结构上带有羧基的药物。(C)2017 Acta Materialia Inc.由Elsevier Ltd.出版。保留所有权利。
A novel redox-sensitive system for co-delivering hydrophobic drugs and hydrophilic siRNA or shRNA was developed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs) through amide bonds, which is called GA-conjugated PAAs (PAG). PAG can self-assemble into micelles as amphiphilic block copolymers, which exhibits an excellent loading ability for the co-delivery of docetaxel (DTX) and MMP-9 shRNA with adjustable dosing ratios. In addition, confocal microscopy, flow cytometry and in vitro transfection analyses demonstrated more efficient cellular internalization of DTX and MMP-9 shRNA after incubation with PAG/DTX-MMP-9 shRNA micelles (PAG/DTX-shRNA) than with free drugs. Unlike traditional amphiphilic copolymer micelles, GA conjugated in PAG possesses an intrinsic anticancer efficacy. The presence of disulfide bonds in PAAs enables rapid disassembly of PAG micelles in response to reducing agents, inducing the release of loaded drugs (DTX, GA and MMP-9 shRNA). In vitro cellular assays revealed that PAG/DTX-shRNA micelles inhibited MCF-7 cell proliferation more efficiently than the single drug or single drug-loaded micelles. In vivo biodistribution and anti-tumor effect studies using an MCF-7 breast cancer xenograft mouse model have indicated that PAG/DTX-shRNA micelles can enhance drug accumulation compared with the free drug, thereby sustaining the therapeutic effect on tumors. Additionally, PAG/DTX-shRNA micelles displayed a greater anti-tumor efficacy than Taxotere and PAG-shRNA micelles. These results suggest that the redox-sensitive PAG platform is a promising co-delivery system for combining drugs and gene therapy for the treatment of cancer.Statement of SignificanceThe PAG micelles were designed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs), which would serve dual purposes as both gene and drugs co-delivery carrier and an anti-tumor prodrug. Unlike traditional amphiphilic micelles, GA conjugated in PAG could exert its intrinsic efficacy and provide synergistic antiproliferative effects with docetaxel (DTX) on MCF-7 cells. Disulfide bonds in PAG enables a rapid disassembly of PAG micelles in response to reducing agents and to release all loaded drugs (DTX, GA and MMP-9 shRNA) at tumor sites. PAG/DTX-shRNA micelles displayed greater antitumor efficacy than that of Taxotere, indicating the design concept for PAG works well. And the strategy for PAG could be used to develop a series of similar co-delivery systems through conjugations of other small-molecule drugs with PAM, such as doxorubicin, methotrexate and other drugs with carboxy groups in their structure. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.