Polymeric Antitumor Systems with Dual Mechanism of Action

Use of chemotherapeutics is the main therapeutic approach for the treatment of cancer, although they suffer from various limitations, such as limited water solubility, lack of selectivity or multidrug resistance.¹ A promising strategy to improve performance of various chemotherapeutics is employment of a drug delivery system (DDS), such as polymer drug conjugates, liposomes or self-assembled micelles.^1-4 DDSs bearing anticancer drugs ensure their increased accumulation in solid tumors via the enhanced permeability and retention (EPR) effect^5-7 and provide more favorable pharmacokinetics, prolonged half-life in circulation, solubilization of water-insoluble drugs and reduction of side toxicity via controlled drug release. One of the most promising DDS is water-soluble biocompatible polymer carrier based on <i>N</i>-(2-hydroxypropyl)methacrylamide (HPMA). HPMA copolymers bearing different cytostatic drugs (e.g. Doxorubicin) have been extensively tested for several decades and proved to have excellent antitumor activity in numerous mouse and human tumors, both in vitro and in vivo.^2,8,9 HPMA copolymers prepared by reversible addition−fragmentation chain transfer (RAFT) copolymerization with well-defined molar mass and with narrow dispersity (Mw/Mn &lt; 1.1) conjugated with doxorubicin (Dox) have high tumor accumulation and promising antitumor activity in animal models. This synthetic way allows to prepare advance polymeric structures like star-like carriers which shows even better delivery abilities compared to linear carriers.^10,11<br/>Polymeric drug carriers are able to deliver a combination of two different cytostatic agents with different mechanism of action and with this feature hit the targeted tumor cells at one moment.<br/>Here, we described a polymer biomaterial composed of the antiretroviral drug ritonavir derivative (RD), covalently bound to HPMA copolymer carrier via a pH-sensitive hydrazone bond (P-RD). Apart from being more potent inhibitor of P-glycoprotein in comparison to ritonavir, we found RD to have considerable cytostatic activity in six mice and six human cancer cell lines per se. We studied deeply molecular mechanism of action of RD and antitumor activity in CT26 and B16F10 tumor-bearing mice.¹² We combined this repurposed drug with another cytostatic drug doxorubicin on the same carrier with linear and star-like structure. HPMA conjugates containing Dox and RD both attached via hydrazone bond showed powerful antitumor activity in CT26 and B16F10 tumor-bearing mice and showed very promising therapeutic activity also in human FaDu xenografts. Negligible toxicity predetermining these nanomedicines as side-effect free nanosystems. We are convinced that these conjugates are worth of investigation for future clinical application.<br/>This project is financially supported by the Czech health research council (project no. NU 21-03-00273).<br/><br/>References :<br/>E. Perez-Herrero et al., Eur. J. of Pharm. and Biopharm., 93 (2015) 52-79.<br/>K. Ulbrich et al., Chem. Rev., 116 (2016) 5338-5431.<br/>J. Kopeček, Adv. Drug Deliv. Rev, 65 (2013) 49-59.<br/>J. Kopeček, Adv. Drug Deliv. Rev, (2020).<br/>Y. Matsumura et al, Cancer Research, 46 (1986) 6387-6392.<br/>H. Maeda et al, Microcirculation, 23 (2016) 173-182.<br/>J. Fang et al, Adv. Drug Deliv. Rev, (2020).<br/>K. Ulbrich et al, Adv. Drug Deliv. Rev., 62 (2010) 150-166.<br/>K. Ulbrich et al, Adv. Drug Deliv. Rev, 56 (2004) 1023-1050.<br/>L.W. Seymour et al., Eur. J. Cancer, 31A (1995) 766-770.<br/>T. Etrych et al., J. Control. Release, 164 (2012) 346-354.<br/>L. Sivák et al., J. Control. Release, (2021).