Simultaneous delivery of doxorubicin and protease inhibitor derivative to solid tumors via star-shaped polymer nanomedicines overcomes P-gp- and STAT3-mediated chemoresistance

0558142 - ÚMCH 2023 RIV US eng J - Článek v odborném periodiku
Kostka, Libor - Sivák, Ladislav - Šubr, Vladimír - Kovářová, Jiřina - Šírová, Milada - Říhová, Blanka - Sedláček, Radislav - Etrych, Tomáš - Kovář, Marek
Simultaneous delivery of doxorubicin and protease inhibitor derivative to solid tumors via star-shaped polymer nanomedicines overcomes P-gp- and STAT3-mediated chemoresistance.
Biomacromolecules. Roč. 23, č. 6 (2022), s. 2522-2535. ISSN 1525-7797. E-ISSN 1526-4602
Grant CEP: GA ČR(CZ) GA19-05649S; GA MZd(CZ) NU21-03-00273; GA MŠMT(CZ) LTAUSA18083; GA MŠMT(CZ) LM2018126; GA MŠMT(CZ) ED1.1.00/02.0109
Výzkumná infrastruktura: CCP II - 90126
Institucionální podpora: RVO:61389013 ; RVO:61388971 ; RVO:68378050
Klíčová slova: HPMA * RAFT * star-like
Obor OECD: Polymer science; Microbiology (MBU-M); Genetics and heredity (medical genetics to be 3) (UMG-J)
Impakt faktor: 6.2, rok: 2022
Způsob publikování: Omezený přístup
https://pubs.acs.org/doi/10.1021/acs.biomac.2c00256

The derivative of protease inhibitor ritonavir (5-methyl-4-oxohexanoic acid ritonavir ester, RD) was recently recognized as a potent P-gp inhibitor and cancerostatic drug inhibiting the proteasome and STAT3 signaling. Therefore, we designed high-molecular-weight HPMA copolymer conjugates with a PAMAM dendrimer core bearing both doxorubicin (Dox) and RD (Star-RD + Dox) to increase the circulation half-life to maximize simultaneous delivery of Dox and RD into the tumor. Star-RD inhibited P-gp activity, potently sensitizing both low- and high-P-gp-expressing cancer cells to the cytostatic and proapoptotic activity of Dox in vitro. Star-RD + Dox possessed higher cytostatic and proapoptotic activities compared to Star-Dox and the equivalent mixture of Star-Dox and Star-RD in vitro. Star-RD + Dox efficiently inhibited STAT3 signaling and induced caspase-3 activation and DNA fragmentation in cancer cells in vivo. Importantly, Star-RD + Dox was found to have superior antitumor activity in terms of tumor growth inhibition and increased survival of mice bearing P-gp-expressing tumors.
Trvalý link: https://hdl.handle.net/11104/0332796