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Journal of Controlled Release
Article . 2025 . Peer-reviewed
License: CC BY
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Overcoming P-glycoprotein-mediated multidrug resistance in cancer cells through micelle-forming PHPMA-b-PPO diblock copolymers for doxorubicin delivery

Authors: Kaňa, M. (Martin); Braunová, A. (Alena); Starenko, D. (Daniil); Frejková, M. (Markéta); Bouček, J. (Jan); Říhová, B. (Blanka); Kovář, M. (Marek); +2 Authors

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

Abstract

Multidrug resistance (MDR) represents one of the major concerns in cancer therapy as it may cause reduced efficacy of chemotherapeutic drugs. The study explores the potential of novel amphiphilic diblock (DB) micelle forming copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide]-based copolymers and poly(propylene oxide) to overcome MDR mechanisms. The DB copolymers and their doxorubicin (Dox) conjugates significantly inhibited drug efflux in chemoresistant cancer cells by depletion of intracellular ATP, resulting in increased Dox accumulation. Mechanisms involved in MDR inhibition are shown. Copolymers with additionally loaded PPO in the micelle core demonstrated superior efficacy in vitro and in vivo in treatment of experimental murine tumor CT26. The ATP depletion capacity was also demonstrátor in patient-derived xenograft (PDX) model.

Country
Czech Republic
Keywords

PPO, Drug delivery system, Intracellular ATP depletion, Multidrug resistance, Sensitization to chemotherapy, HPMA copolymer, Diblock copolymers, P-glycoprotein inhibition

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Cancer Research