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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
    Document TypeJ - Journal Article
    R&D Document TypeJournal Article
    Subsidiary JČlánek ve WOS
    TitlePolymer-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 TitleJournal of Controlled Release. - : Elsevier - ISSN 0168-3659
    Roč. 332, APR 10 2021 (2021), s. 563-580
    Number of pages18 s.
    Languageeng - English
    CountryNL - Netherlands
    KeywordsRitonavir derivate ; Polymer carrier ; pH-controlled release ; Antitumor activity ; Proteasome inhibition ; STAT3 signaling inhibition
    Subject RIVEE - Microbiology, Virology
    OECD categoryMicrobiology
    Subject RIV - cooperationInstitute of Macromolecular Chemistry - Macromolecular Chemistry
    Institute of Molecular Genetics
    R&D ProjectsGA19-05649S 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 InfrastructureCCP - 90040 - Ústav molekulární genetiky AV ČR, v. v. i.
    Method of publishingLimited access
    Institutional supportMBU-M - RVO:61388971 ; UMCH-V - RVO:61389013 ; UMG-J - RVO:68378050
    UT WOS000646224400003
    EID SCOPUS85102813848
    DOI10.1016/j.jconrel.2021.03.015
    AnnotationDrug 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.
    WorkplaceInstitute of Microbiology
    ContactEliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231
    Year of Publishing2022
    Electronic addresshttps://www.sciencedirect.com/science/article/pii/S0168365921001267
Number of the records: 1