School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Acta Biomater. 2018 Mar 1;68:137-153. doi: 10.1016/j.actbio.2017.12.028. Epub 2017 Dec 26.
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.
The 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 anti-tumor 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 PAAs, such as doxorubicin, methotrexate and other drugs with carboxy groups in their structure.
通过酰胺键将藤黄酸（GA）与聚（酰胺-胺）（PAAs）偶联，开发了一种新型的用于共递送疏水性药物和亲水性 siRNA 或 shRNA 的氧化还原敏感系统，称为 GA 偶联的 PAAs（PAG）。PAG 可以自组装成具有可调剂量比的胶束作为两亲性嵌段共聚物，具有出色的共递送多西他赛（DTX）和 MMP-9 shRNA 的负载能力。此外，共聚焦显微镜、流式细胞术和体外转染分析表明，与游离药物相比，在用 PAG/DTX-MMP-9 shRNA 胶束（PAG/DTX-shRNA）孵育后，DTX 和 MMP-9 shRNA 的细胞内摄取效率更高。与传统的两亲性共聚物胶束不同，GA 共轭在 PAG 中具有内在的抗癌功效。PAAs 中的二硫键能够响应还原剂快速解组装 PAG 胶束，从而释放负载的药物（DTX、GA 和 MMP-9 shRNA）。体外细胞实验表明，与单一药物或单一药物负载的胶束相比，PAG/DTX-shRNA 胶束更有效地抑制 MCF-7 细胞增殖。使用 MCF-7 乳腺癌异种移植小鼠模型进行的体内分布和抗肿瘤效果研究表明，与游离药物相比，PAG/DTX-shRNA 胶束可以增强药物积累，从而维持对肿瘤的治疗效果。此外，PAG/DTX-shRNA 胶束显示出比 Taxotere®和 PAG-shRNA 胶束更高的抗肿瘤功效。这些结果表明，氧化还原敏感的 PAG 平台是一种有前途的联合药物和基因治疗的共递药系统，可用于治疗癌症。
通过将藤黄酸（GA）与聚（酰胺-胺）（PAAs）偶联，设计了 PAG 胶束，它将兼具基因和药物共递药载体以及抗肿瘤前药的双重功能。与传统的两亲性胶束不同，GA 共轭在 PAG 中可以发挥其内在的功效，并与 MCF-7 细胞中的多西他赛（DTX）产生协同的抗增殖作用。PAG 中的二硫键能够响应还原剂快速解组装 PAG 胶束，并在肿瘤部位释放所有负载的药物（DTX、GA 和 MMP-9 shRNA）。PAG/DTX-shRNA 胶束显示出比 Taxotere®更高的抗肿瘤功效，表明 PAG 的设计理念效果良好。并且，通过将其他结构中带有羧基的小分子药物与 PAAs 偶联，如阿霉素、甲氨蝶呤等，PAG 策略可以用于开发一系列类似的共递药系统。
