Here, we present the synthesis, physicochemical, and preliminary biological characterization of micellar polymer-betulinic acid (BA) conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers, enabling the controlled release of cytotoxic BA derivatives in solid tumors or tumor cells. Various HPMA copolymer conjugates differing in the structure of the spacer between the drug and the carrier were synthesized, all designed for pH-triggered drug release in tumor tissue or tumor cells. The high molecular weight of the micellar conjugates should improve the uptake of the drug in solid tumors due to the Enhanced permeability and retention (EPR) effect. Nevertheless, only the conjugate containing BA with methylated carboxyl groups enabled pH-dependent controlled release in vitro. Moreover, drug release led to the disassembly of the micellar structure, which facilitated elimination of the water-soluble HPMA copolymer carrier from the body by renal filtration. The methylated BA derivative and its polymer conjugate exhibited high cytostatic activity against DLD-1, HT-29, and HeLa carcinoma cell lines and enhanced tumor accumulation in HT-29 xenograft in mice.

Institute of Macromolecular Chemistry The Czech Academy of Sciences Heyrovsky Sq 2 Prague 6 162 06 Czech Republic

Institute of Macromolecular Compounds Russian Academy of Sciences 31 Bolshoy pr VO St Petersburg 199004 Russian Federation

Martin Luther University Halle Wittenberg Department of Internal Medicine 4 Oncology and Haematology Ernst Grube Str 40 06120 Halle Germany

Martin Luther University Halle Wittenberg Institute of Pharmacy AG Pharmaceutical Technology Wolfgang Langenbeck Str 4 06120 Halle Germany

St Petersburg State Chemical Pharmaceutical Academy 14 Prof Popov St St Petersburg 197022 Russian Federation

St Petersburg State Technological Institute 26 Moskovsky Pr St Petersburg 190013 Russian Federation

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HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery