Yaqin Zhu^{a, b}, Jian Zhang^{a, *}（张建）, Fenghua Meng^a, Chao Deng^a, Ru Cheng^a, Jan Feijen^{a, b, *} , Zhiyuan Zhong^{a, *} （钟志远）

^a 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

^b 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

Journal of Controlled Release，Volume 233, 10 July 2016, Pages 29–38

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. 61 nm, a decent DOX loading of 14.9 wt%, and triggered drug release in a reductive environment (10 mM 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 α_vβ₃ 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 3.51 h, 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.

链接：http://www.sciencedirect.com/science/article/pii/S0168365916302814