Co-assembly of polymeric conjugates sensitizes neoadjuvant chemotherapy of triple-negative breast cancer with re duce d systemic toxicity

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 were formed by these two polymer prodrug conjugates co -assembly (PPCC). The stimuliresponsiveness 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 solid tumors, including triple -negative breast cancer. center dot Co -assembly of polymeric prodrug conjugates could form stable and homogeneous nanostructures, improving cellular uptake by cancer cells and in vivo tumor penetration and retention. center dot Co -delivery of neoadjuvant therapeutic drug (DTX) and HIF-1 alpha inhibitor (YC-1) synergizes the antitumor effect by affecting HIF-1 alpha expression and G2/M phase arrest. center dot Polymer prodrug conjugates co -assembly (PPCC) could reverse tumor resistance to neoadjuvant therapy, retard tumor progression, and prevent lung metastasis with reduced systemic toxicity in a murine triple -negative breast cancer model. (c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.