Simultaneous delivery of doxorubicin and protease inhibitor derivative to solid tumors via star-shaped polymer nanomedicines overcomes P-gp- and STAT3-mediated chemoresistance

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F22%3A00558142" target="_blank" >RIV/61388971:_____/22:00558142 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61389013:_____/22:00558142 RIV/68378050:_____/22:00558142

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acs.biomac.2c00256" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.biomac.2c00256</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.biomac.2c00256" target="_blank" >10.1021/acs.biomac.2c00256</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Simultaneous delivery of doxorubicin and protease inhibitor derivative to solid tumors via star-shaped polymer nanomedicines overcomes P-gp- and STAT3-mediated chemoresistance

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Simultaneous delivery of doxorubicin and protease inhibitor derivative to solid tumors via star-shaped polymer nanomedicines overcomes P-gp- and STAT3-mediated chemoresistance

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10606 - Microbiology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biomacromolecules

ISSN

1525-7797

e-ISSN

1526-4602

Svazek periodika

23

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

2522-2535

Kód UT WoS článku

000811352100001

EID výsledku v databázi Scopus

2-s2.0-85131813821