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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

SYSNO ASEP	0542896
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Polymer-ritonavir derivate nanomedicine with pH-sensitive activation possesses potent anti-tumor activity in vivo via inhibition of proteasome and STAT3 signaling
Author(s)	Sivák, Ladislav (MBU-M)_RID Šubr, Vladimír (UMCH-V)_{RID, ORCID} Kovářová, Jiřina (MBU-M) Dvořáková, Barbora (MBU-M)_RID Šírová, Milada (MBU-M)_{RID, ORCID} Říhová, Blanka (MBU-M)_RID Randárová, Eva (UMCH-V)_RID Kraus, Michal (MBU-M) Tomala, Jakub (MBU-M)_{RID, ORCID} Studenovský, Martin (UMCH-V)_{RID, ORCID} Vondráčková, Michaela (MBU-M) Sedláček, Radislav (UMG-J)_RID Makovický, Peter (UMG-J) Fučíková, J. (CZ) Vošahlíková, Š. (CZ) Spíšek, R. (CZ) Kostka, Libor (UMCH-V)_{RID, ORCID} Etrych, Tomáš (UMCH-V)_{RID, ORCID} Kovář, Marek (MBU-M)_{RID, ORCID}
Source Title	Journal of Controlled Release. - : Elsevier - ISSN 0168-3659 Roč. 332, APR 10 2021 (2021), s. 563-580
Number of pages	18 s.
Language	eng - English
Country	NL - Netherlands
Keywords	Ritonavir derivate ; Polymer carrier ; pH-controlled release ; Antitumor activity ; Proteasome inhibition ; STAT3 signaling inhibition
Subject RIV	EE - Microbiology, Virology
OECD category	Microbiology
Subject RIV - cooperation	Institute of Macromolecular Chemistry - Macromolecular Chemistry Institute of Molecular Genetics
R&D Projects	GA19-05649S GA ČR - Czech Science Foundation (CSF)
	LM2015040 GA MŠk - Ministry of Education, Youth and Sports (MEYS)
	ED1.1.00/02.0109 GA MŠk - Ministry of Education, Youth and Sports (MEYS)
Research Infrastructure	CCP - 90040 - Ústav molekulární genetiky AV ČR, v. v. i.
Method of publishing	Limited access
Institutional support	MBU-M - RVO:61388971 ; UMCH-V - RVO:61389013 ; UMG-J - RVO:68378050
UT WOS	000646224400003
EID SCOPUS	85102813848
DOI	10.1016/j.jconrel.2021.03.015
Annotation	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.
Workplace	Institute of Microbiology
Contact	Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231
Year of Publishing	2022
Electronic address	https://www.sciencedirect.com/science/article/pii/S0168365921001267

Number of the records: 1