Highly hydrophilic methacrylamide-based copolymers as precursors for polymeric nanomedicines containing anthracyclines

Abstract

The crucial limitation of most low molecular weight cytostatic drugs, including anthracyclines, is their nonspecific biodistribution causing severe adverse effects during cancer treatment. Recently, nanomedicines such as polymer-based systems have been developed as advanced drug delivery systems. Herein, we report the design, synthesis, and characterization of highly water-soluble polymer-carriers based on N‑(1,3‑dihydroxyprop-2-yl)methacrylamide (DHPMA). Polymers differing in molecular weight, hydrodynamic size, and dispersity were synthesized via free or controlled radical polymerization and conjugated to an anthracycline drug pirarubicin (THP) via a pH-sensitive hydrazone bond achieving up to 21 wt% of THP. The DHPMA copolymers were extensively compared to the well-known drug delivery vectors, N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymers. Importantly, DHPMA-based conjugates showed excellent hydrophilicity exceeding that of HPMA-based copolymers and did not aggregate even after loading with THP reaching 21 wt%. The DHPMA-based polymer nanomedicines exhibited excellent cytotoxicity, body biodistribution, tumor accumulation, and antitumor efficacy, significantly reducing the side effects and toxicity comparable to HPMA-based systems, thus demonstrating their applicability and suitability as efficient drug carriers.