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Polymer-ritonavir derivate nanomedicine with pH-sensitive activation possesses potent anti-tumor activity in vivo via inhibition of proteasome and STAT3 signaling
- 1.0542896 - MBÚ 2022 RIV NL eng J - Journal Article
Sivák, Ladislav - Šubr, Vladimír - Kovářová, Jiřina - Dvořáková, Barbora - Šírová, Milada - Říhová, Blanka - Randárová, Eva - Kraus, Michal - Tomala, Jakub - Studenovský, Martin - Vondráčková, Michaela - Sedláček, Radislav - Makovický, Peter - Fučíková, J. - Vošahlíková, Š. - Spíšek, R. - Kostka, Libor - Etrych, Tomáš - Kovář, Marek
Polymer-ritonavir derivate nanomedicine with pH-sensitive activation possesses potent anti-tumor activity in vivo via inhibition of proteasome and STAT3 signaling.
Journal of Controlled Release. Roč. 332, APR 10 2021 (2021), s. 563-580. ISSN 0168-3659. E-ISSN 1873-4995
R&D Projects: GA ČR(CZ) GA19-05649S; GA MŠk(CZ) LM2015040; GA MŠk(CZ) ED1.1.00/02.0109
Research Infrastructure: CCP - 90040
Institutional support: RVO:61388971 ; RVO:61389013 ; RVO:68378050
Keywords : Ritonavir derivate * Polymer carrier * pH-controlled release * Antitumor activity * Proteasome inhibition * STAT3 signaling inhibition
OECD category: Microbiology; Polymer science (UMCH-V)
Impact factor: 9.776, year: 2020
Method of publishing: Limited access
Drug repurposing is a promising strategy for identifying new applications for approved drugs. Here, we describe a polymer biomaterial composed of the antiretroviral drug ritonavir derivative (5-methyl-4-oxohexanoic acid ritonavir ester, 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 (IC50 2.3?17.4 ?M) and six human (IC50 4.3?8.7 ?M) cancer cell lines, and that RD inhibits the migration and invasiveness of cancer cells in vitro. Importantly, RD inhibits STAT3 phosphorylation in CT26 cells in vitro and in vivo, and expression of the NF-?B p65 subunit, Bcl-2 and Mcl-1 in vitro. RD also dampens chymotrypsin-like and trypsin-like proteasome activity and induces ER stress as documented by induction of PERK phosphorylation and expression of ATF4 and CHOP. P-RD nanomedicine showed powerful antitumor activity in CT26 and B16F10 tumor-bearing mice, which, moreover, synergized with IL-2based immunotherapy. P-RD proved very promising therapeutic activity also in human FaDu xenografts and negligible toxicity predetermining these nanomedicines as side-effect free nanosystem. The therapeutic potential could be highly increased using the fine-tuned combination with other drugs, i.e. doxorubicin, attached to the same polymer system. Finally, we summarize that described polymer nanomedicines fulfilled all the requirements as potential candidates for deep preclinical investigation.
Permanent Link: http://hdl.handle.net/11104/0320232
Number of the records: 1