Počet záznamů: 1
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 ASEP 0542896 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Polymer-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, ORCIDZdroj.dok. Journal of Controlled Release. - : Elsevier - ISSN 0168-3659
Roč. 332, APR 10 2021 (2021), s. 563-580Poč.str. 18 s. Jazyk dok. eng - angličtina Země vyd. NL - Nizozemsko Klíč. slova Ritonavir derivate ; Polymer carrier ; pH-controlled release ; Antitumor activity ; Proteasome inhibition ; STAT3 signaling inhibition Vědní obor RIV EE - Mikrobiologie, virologie Obor OECD Microbiology Vědní obor RIV – spolupráce Ústav makromolekulární chemie - Makromolekulární chemie
Ústav molekulární genetikyCEP GA19-05649S GA ČR - Grantová agentura ČR LM2015040 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy ED1.1.00/02.0109 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Výzkumná infrastruktura CCP - 90040 - Ústav molekulární genetiky AV ČR, v. v. i. Způsob publikování Omezený přístup Institucionální podpora 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 Anotace 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. Pracoviště Mikrobiologický ústav Kontakt Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Rok sběru 2022 Elektronická adresa https://www.sciencedirect.com/science/article/pii/S0168365921001267
Počet záznamů: 1