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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

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    SYSNO ASEP0542896
    Druh ASEPJ - Článek v odborném periodiku
    Zařazení RIVJ - Článek v odborném periodiku
    Poddruh JČlánek ve WOS
    NázevPolymer-ritonavir derivate nanomedicine with pH-sensitive activation possesses potent anti-tumor activity in vivo via inhibition of proteasome and STAT3 signaling
    Tvůrce(i) 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
    Zdroj.dok.Journal of Controlled Release. - : Elsevier - ISSN 0168-3659
    Roč. 332, APR 10 2021 (2021), s. 563-580
    Poč.str.18 s.
    Jazyk dok.eng - angličtina
    Země vyd.NL - Nizozemsko
    Klíč. slovaRitonavir derivate ; Polymer carrier ; pH-controlled release ; Antitumor activity ; Proteasome inhibition ; STAT3 signaling inhibition
    Vědní obor RIVEE - Mikrobiologie, virologie
    Obor OECDMicrobiology
    Vědní obor RIV – spolupráceÚstav makromolekulární chemie - Makromolekulární chemie
    Ústav molekulární genetiky
    CEPGA19-05649S GA ČR - Grantová agentura ČR
    LM2015040 GA MŠk - Ministerstvo školství, mládeže a tělovýchovy
    ED1.1.00/02.0109 GA MŠk - Ministerstvo školství, mládeže a tělovýchovy
    Výzkumná infrastrukturaCCP - 90040 - Ústav molekulární genetiky AV ČR, v. v. i.
    Způsob publikováníOmezený přístup
    Institucionální podporaMBU-M - RVO:61388971 ; UMCH-V - RVO:61389013 ; UMG-J - RVO:68378050
    UT WOS000646224400003
    EID SCOPUS85102813848
    DOI10.1016/j.jconrel.2021.03.015
    AnotaceDrug 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.
    PracovištěMikrobiologický ústav
    KontaktEliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231
    Rok sběru2022
    Elektronická adresahttps://www.sciencedirect.com/science/article/pii/S0168365921001267
Počet záznamů: 1