Overcoming P-glycoprotein-mediated multidrug resistance in cancer cells through micelle-forming PHPMA-b-PPO diblock copolymers for doxorubicin delivery

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Multidrug resistance (MDR) represents one of the major concerns in cancer therapy as it may cause reduced efficacy of chemotherapeutic drugs due to the overexpression of ABC transporters, particularly P-glycoprotein (P-gp). This study explores the potential of novel amphiphilic diblock (DB) copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide]-based copolymers (PHPMA) and poly(propylene oxide) (PPO) to overcome MDR mechanisms. The DB copolymers and their doxorubicin (Dox) conjugates significantly increased Dox accumulation in P-gp positive cells, markedly sensitizing them to Dox cytotoxic activity. The underlying mechanisms included depletion of intracellular ATP with subsequent inhibition of P-gp mediated drug efflux, an altered mitochondrial membrane potential, and increased ROS production. Moreover, the DB-Dox conjugates inhibited tumor growth in vivo more effectively compared to the corresponding PHPMA-based drug delivery system. Copolymers with additionally loaded PPO in the micelle core demonstrated superior efficacy in terms of P-gp inhibition, ATP depletion, and chemosensitizing effect in vitro, as well as antitumor activity in vivo. DB copolymers effectively depleted ATP levels both in vitro and in vivo using patient-derived xenograft (PDX) models, underscoring their capacity to enhance the effectiveness of standard chemotherapy and translational potential.