程茹教授与钟志远教授合作在 Biomacromolecules 上发表研究论文

A6 Peptide-Tagged Core-Disulfide-Cross-Linked Micelles for Targeted Delivery of Proteasome Inhibitor Carfilzomib to Multiple Myeloma In Vivo

Changjiang Zhang, Xiuxiu Wang, Ru Cheng*(程茹), and Zhiyuan Zhong*(钟志远)


Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, People’s Republic of China


Biomacromolecules 2020, 21, 2049--2059


Carfilzomib (CFZ) is a second-generation proteasome inhibitor approved for treating relapsed/refractory multiple myeloma (MM). The clinical formulation utilizing sulfobutylether-β-cyclodextrin to solubilize CFZ (Captisol, CFZ-CD) shows, however, short circulation time, lack of cell selectivity, and unmet antitumor efficacy. Here, we designed and prepared A6 peptide (sequence: KPSSPPEE)-tagged core-disulfide-cross-linked biodegradable micelles (A6-PMs) for targeted CFZ therapy of CD44-overexpressing LP-1 human MM in vivo. A6-PMs had a small size of about 40 nm and stable CFZ encapsulation. CFZ-loaded micelles (CFZ-A6-PMs) showed a glutathione-triggered drug release profile with negligible drug leakage under physiological conditions. CFZ-A6-PMs displayed good proteasome activity inhibition and more potent apoptotic activity than CFZ-CD and nontargeted CFZ-PMs toward LP-1 MM cells in vitro. The in vivo fluorescence images revealed that Cy5-labeled A6-PMs induced much higher tumor accumulation than the nontargeted Cy5-labeled PMs control. The systemic administration of CFZ-A6-PMs to subcutaneous LP-1 xenografts in mice brought about notably more potent tumor suppression, higher survival rate and lower systemic toxicities than clinically used CFZ-CD formulation. These A6-tagged core-disulfide-cross-linked micelles appear interesting for targeted delivery of proteasome inhibitors to CD44+ MM.




链接:https://pubs.acs.org/doi/10.1021/acs.biomac.9b01790