Tumor-Triggered Drug Release with Tumor-Targeted Accumulation and Elevated Drug Retention To Overcome Multidrug Resistance

Abstract

Multidrug resistance (MDR) is one of the main causes of the failure in cancer chemotherapy. To address this challenge, this work develops a tumor-triggered nanomedicine (HA-MSDOX-KLA; comprised of a tumor active targeting segment (hyaluronic acid, HA) and two programmed therapeutic agents, MMP-substrate peptide (CPLGLAGG) conjugated doxorubicin (designated as MSDOX) and proapoptotic peptide (KLAKLAK)2 (designated as KLA)) with switchable morphology transformation that significantly enhances tumor-specific accumulation and retention for overcoming MDR. Morphology changes could be triggered by tumor overexpressed matrix metalloproteinases (MMPs), achieving elevated drug accumulation and prolonged intracellular drug retention. Additionally, the adjunctive release of proapoptotic peptide KLA would targetedly induce the dysfunction of mitochondria with decreased adenosine 5′-triphosphate (ATP) generation to further inhibit the drug efflux. In vitro and in vivo studies demonstrate that, compared with free doxor...