Co–Assembly of Polymeric Conjugates Sensitizes Neoadjuvant Chemotherapy of Tnbc with Reduced Systemic Toxicity

Abstract

Rational design of polymeric conjugates could greatly potentiate the combination therapy of solid tumors. In this study, we designed and prepared two polymeric conjugates (HT-DTX and PEG-YC-1), whereas the drugs were attached to the PEG via a linker sensitive to cathepsin B, over-expressed in TNBC. Stable nanostructures (PPCC) were obtained by assembling two polymeric conjugates as a co-delivery system. The stimuli-responsiveness of PPCC was confirmed, and the size shrinkage under tumor microenvironment would facilitate the penetration of PPCC into tumor tissue. In vitro experiments revealed the molecular mechanism for the synergistic effect of the combination of DTX and YC-1. Moreover, the systemic side effects were significantly diminished since the biodistribution of PPCC was improved after i.v. administration in vivo. In this context, the co-assembled nano-structural approach could be employed for delivering therapeutic drugs with different mechanisms of action to exert a synergistic anti-tumor effect against advanced cancers, including TNBC.

Note:

Funding Information: This work was supported by National Natural Science Foundation of China (32271445, 52073193, 32101085), 1‧3‧5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYJC21013), Post-Doctor Research Project, West China Hospital, Sichuan University (21HXBH056).

Declaration of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethics Approval Statement: All animal procedures were reviewed and approved by the Animal Ethics Committee of West China Hospital, Sichuan University in accordance with the Guidelines for Care and Use of Laboratory Animals of China.

Keywords: Polymeric conjugates, Co-assembly, drug delivery system, Combination therapy, Triple-negative breast cancer