Nanotherapeutics with suitable properties for advanced anticancer therapy based on HPMA copolymer-bound ritonavir via pH-sensitive spacers

0492736 - ÚMCH 2019 RIV NL eng J - Článek v odborném periodiku
Machová, Daniela - Koziolová, Eva - Chytil, Petr - Venclíková, Kristýna - Etrych, Tomáš - Janoušková, Olga
Nanotherapeutics with suitable properties for advanced anticancer therapy based on HPMA copolymer-bound ritonavir via pH-sensitive spacers.
European Journal of Pharmaceutics and Biopharmaceutics. Roč. 131, October (2018), s. 141-150. ISSN 0939-6411. E-ISSN 1873-3441
Grant CEP: GA ČR(CZ) GA17-13283S; GA MZd(CZ) NV16-28600A; GA MŠMT(CZ) LO1507
Grant ostatní: AV ČR(CZ) MSM200501604
Program: Program na podporu mezinárodní spolupráce začínajících výzkumných pracovníků
Institucionální podpora: RVO:61389013
Klíčová slova: drug delivery * cell penetration compound * anticancer therapy
Obor OECD: Polymer science
Impakt faktor: 4.708, rok: 2018

Ritonavir (RIT) is a widely used antiviral drug that acts as an HIV protease inhibitor with emerging potential in anticancer therapies. RIT causes inhibition of P-glycoprotein, which plays an important role in multidrug resistance (MDR) in cancer cells when overexpressed. Moreover, RIT causes mitochondrial dysfunction, leading to decreased ATP production and reduction of caveolin I expression, which can affect cell migration and tumor progression. To increase its direct antitumor activity, decrease severe side effects induced by the use of free RIT and improve its pharmacokinetics, ritonavir 5-methyl-4-oxohexanoate (RTV) was synthesized and conjugated to a tumor-targeted polymer carrier based on a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. Here we demonstrated that polymer-bound RTV enhanced the internalization of polymer-RTV conjugates, differing in RTV content from 4 to 15 wt%, in HeLa cancer cells compared with polymer without RTV. The most efficient influx and internalization properties were determined for the polymer conjugate bearing 11 wt% of RTV. This conjugate was internalized by cells using both caveolin- and clathrin-dependent endocytic pathways in contrast to the RTV-free polymer, which was preferentially internalized only by clathrin-mediated endocytosis. Moreover, we found the co-localization of the RTV-conjugate with mitochondria and a significant decrease of ATP production in treated cells. Thus, the impact on mitochondrial mechanism can influence the function of ATP-dependent P-glycoprotein and also the cell viability of MDR cancer cells. Overall, this study demonstrated that the polymer-RTV conjugate is a promising polymer-based nanotherapeutic, suitable for antitumor combination therapy with other anticancer drugs and a potential mitochondrial drug delivery system.
Trvalý link: http://hdl.handle.net/11104/0286154