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Simultaneous delivery of doxorubicin and protease inhibitor derivative to solid tumors via star-shaped polymer nanomedicines overcomes P-gp- and STAT3-mediated chemoresistance
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SYSNO ASEP 0558142 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Simultaneous delivery of doxorubicin and protease inhibitor derivative to solid tumors via star-shaped polymer nanomedicines overcomes P-gp- and STAT3-mediated chemoresistance Author(s) Kostka, Libor (UMCH-V) RID, ORCID
Sivák, Ladislav (MBU-M) RID
Šubr, Vladimír (UMCH-V) RID, ORCID
Kovářová, Jiřina (MBU-M)
Šírová, Milada (MBU-M) RID, ORCID
Říhová, Blanka (MBU-M) RID
Sedláček, Radislav (UMG-J) RID
Etrych, Tomáš (UMCH-V) RID, ORCID
Kovář, Marek (MBU-M) RID, ORCIDSource Title Biomacromolecules. - : American Chemical Society - ISSN 1525-7797
Roč. 23, č. 6 (2022), s. 2522-2535Number of pages 14 s. Language eng - English Country US - United States Keywords HPMA ; RAFT ; star-like OECD category Polymer science Subject RIV - cooperation Institute of Macromolecular Chemistry - Macromolecular Chemistry
Institute of Microbiology - Microbiology, Virology
Institute of Molecular Genetics - Genetics ; Molecular BiologyR&D Projects GA19-05649S GA ČR - Czech Science Foundation (CSF) NU21-03-00273 GA MZd - Ministry of Health (MZ) LTAUSA18083 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure CCP II - 90126 - Ústav molekulární genetiky AV ČR, v. v. i. Method of publishing Limited access Institutional support UMCH-V - RVO:61389013 ; MBU-M - RVO:61388971 ; UMG-J - RVO:68378050 UT WOS 000811352100001 EID SCOPUS 85131813821 DOI 10.1021/acs.biomac.2c00256 Annotation The derivative of protease inhibitor ritonavir (5-methyl-4-oxohexanoic acid ritonavir ester, RD) was recently recognized as a potent P-gp inhibitor and cancerostatic drug inhibiting the proteasome and STAT3 signaling. Therefore, we designed high-molecular-weight HPMA copolymer conjugates with a PAMAM dendrimer core bearing both doxorubicin (Dox) and RD (Star-RD + Dox) to increase the circulation half-life to maximize simultaneous delivery of Dox and RD into the tumor. Star-RD inhibited P-gp activity, potently sensitizing both low- and high-P-gp-expressing cancer cells to the cytostatic and proapoptotic activity of Dox in vitro. Star-RD + Dox possessed higher cytostatic and proapoptotic activities compared to Star-Dox and the equivalent mixture of Star-Dox and Star-RD in vitro. Star-RD + Dox efficiently inhibited STAT3 signaling and induced caspase-3 activation and DNA fragmentation in cancer cells in vivo. Importantly, Star-RD + Dox was found to have superior antitumor activity in terms of tumor growth inhibition and increased survival of mice bearing P-gp-expressing tumors. Workplace Institute of Macromolecular Chemistry Contact Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358 Year of Publishing 2023 Electronic address https://pubs.acs.org/doi/10.1021/acs.biomac.2c00256
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