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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

  • Libor Kostka
    Libor Kostka
    Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 16206 Prague, Czech Republic
    More by Libor Kostka
  • Ladislav Sivák
    Ladislav Sivák
    Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
  • Vladimír Šubr
    Vladimír Šubr
    Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 16206 Prague, Czech Republic
  • Jiřina Kovářová
    Jiřina Kovářová
    Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
  • Milada Šírová
    Milada Šírová
    Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
  • Blanka Říhová
    Blanka Říhová
    Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
  • Radislav Sedlacek
    Radislav Sedlacek
    Czech Center of Phenogenomics, Institute of Molecular Genetics, Czech Academy of Sciences, Průmyslová 595, 25250 Vestec, Czech Republic
  • Tomáš Etrych*
    Tomáš Etrych
    Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 16206 Prague, Czech Republic
    *Email: [email protected]
  • , and 
  • Marek Kovář*
    Marek Kovář
    Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
    *Email: [email protected]. Phone: +420 296 442 362.
Cite this: Biomacromolecules 2022, 23, 6, 2522–2535
Publication Date (Web):May 18, 2022
https://doi.org/10.1021/acs.biomac.2c00256
Copyright © 2022 American Chemical Society

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    Abstract

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    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.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.biomac.2c00256.

    • SEC chromatogram of starlike conjugates in various stages of the synthesis (Figure S1); cytostatic activity of RD and Star-RD in P388/MDR and CT26 cells in vitro (Figure S2); inhibition of JAK2 phosphorylation in CT26 cells in vitro (Figure S3); and antitumor activity of Star-RD-Dox and Star-Dox conjugates in mice bearing LL2 tumors (Figure S4) (PDF)

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