Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China; Department of Polymer Chemistry and Biomaterials, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. Box 217, 7500, AE, Enschede, The Netherlands.
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
J Control Release. 2016 Jul 10;233:29-38. doi: 10.1016/j.jconrel.2016.05.014. Epub 2016 May 10.
Biodegradable micelles are one of the most studied systems for the delivery of hydrophobic anticancer drugs. Their therapeutic efficacy in vivo is, however, suboptimal, partly due to poor tumor cell uptake as well as slow intracellular drug release. Here, we show that cRGD-functionalized intracellularly shell-sheddable biodegradable PEG-SS-PCL micelles mediate enhanced doxorubicin (DOX) delivery to U87MG glioma xenografts in vivo, resulting in significantly improved tumor growth inhibition as compared to reduction-insensitive cRGD/PEG-PCL controls. cRGD/PEG-SS-PCL micelles revealed a small size of ca. 61nm, a decent DOX loading of 14.9wt%, and triggered drug release in a reductive environment (10mM glutathione). Flow cytometry, confocal microscopy, and MTT assays demonstrated that cRGD/PEG-SS-PCL micelles with a cRGD ligand density of 20% efficiently delivered and released DOX into αvβ3 integrin overexpressing U87MG cells. The in vivo pharmacokinetics studies displayed that DOX-loaded cRGD20/PEG-SS-PCL micelles had a prolonged elimination half-life time of 3.51h, which was comparable to that of cRGD20/PEG-PCL counterparts, indicating that disulfide bonds in the PEG-SS-PCL micelles are stable in the circulation. Notably, in vivo imaging and biodistribution studies in U87MG glioma xenografts showed that cRGD20/PEG-SS-PCL micelles led to efficient accumulation as well as fast drug release in the tumor. The therapeutic outcomes demonstrated that DOX-loaded cRGD20/PEG-SS-PCL micelles exhibited little side effects and superior tumor growth inhibition as compared to non-targeting PEG-SS-PCL and reduction-insensitive cRGD20/PEG-PCL counterparts. The reduction-sensitive shell-sheddable biodegradable micelles have appeared as a fascinating platform for targeted tumor chemotherapy.
可生物降解的胶束是用于递送疏水性抗癌药物的最有研究价值的体系之一。然而，其在体内的治疗效果并不理想，部分原因是肿瘤细胞摄取效果差以及细胞内药物释放缓慢。在这里，我们展示了细胞内壳层可降解的可生物降解的 PEG-SS-PCL 胶束通过 cRGD 功能化，介导阿霉素（DOX）在体内向 U87MG 神经胶质瘤异种移植物的传递增强，与还原不敏感的 cRGD/PEG-PCL 对照相比，显著改善了肿瘤生长抑制。cRGD/PEG-SS-PCL 胶束表现出约 61nm 的小尺寸、14.9wt%的良好 DOX 负载能力，并在还原环境（10mM 谷胱甘肽）中触发药物释放。流式细胞术、共聚焦显微镜和 MTT 测定表明，具有 20%cRGD 配体密度的 cRGD/PEG-SS-PCL 胶束能够有效地将 DOX 递送至和释放到过表达 αvβ3 整合素的 U87MG 细胞中。体内药代动力学研究显示，载 DOX 的 cRGD20/PEG-SS-PCL 胶束的消除半衰期延长至 3.51h，与 cRGD20/PEG-PCL 对应物相当，表明 PEG-SS-PCL 胶束中的二硫键在循环中稳定。值得注意的是，在 U87MG 神经胶质瘤异种移植瘤的体内成像和生物分布研究中，cRGD20/PEG-SS-PCL 胶束导致肿瘤内的有效积累和快速药物释放。治疗结果表明，与非靶向 PEG-SS-PCL 和还原不敏感的 cRGD20/PEG-PCL 对应物相比，载 DOX 的 cRGD20/PEG-SS-PCL 胶束具有较小的副作用和优异的肿瘤生长抑制作用。这种具有还原敏感性的壳层可降解的可生物降解的胶束已经成为靶向肿瘤化疗的一个有吸引力的平台。
