Počet záznamů: 1
Bloodstream stability predetermines the antitumor efficacy of micellar polymer-doxorubicin drug conjugates with pH-triggered drug release
- 1.
SYSNO ASEP 0492820 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Bloodstream stability predetermines the antitumor efficacy of micellar polymer-doxorubicin drug conjugates with pH-triggered drug release Tvůrce(i) Chytil, Petr (UMCH-V) RID, ORCID
Šírová, Milada (MBU-M) RID, ORCID
Kudláčová, Júlia (UMCH-V) RID, ORCID
Říhová, Blanka (MBU-M) RID
Ulbrich, Karel (UMCH-V) RID
Etrych, Tomáš (UMCH-V) RID, ORCIDZdroj.dok. Molecular Pharmaceutics. - : American Chemical Society - ISSN 1543-8384
Roč. 15, č. 9 (2018), s. 3654-3663Poč.str. 10 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova degradation ; HPMA copolymer ; pH-controlled release Vědní obor RIV CD - Makromolekulární chemie Obor OECD Polymer science Vědní obor RIV – spolupráce Mikrobiologický ústav - Mikrobiologie, virologie CEP GA17-08084S GA ČR - Grantová agentura ČR GA17-13283S GA ČR - Grantová agentura ČR LO1507 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UMCH-V - RVO:61389013 ; MBU-M - RVO:61388971 UT WOS 000443923800007 EID SCOPUS 85053166275 DOI 10.1021/acs.molpharmaceut.8b00156 Anotace Herein, the biodegradable micelle-forming amphiphilic N-(2-hydroxypropyl) methacrylamide (HPMA)-based polymer conjugates with the anticancer drug doxorubicin (Dox) designed for enhanced tumor accumulation were investigated, and the influence of their stability in the bloodstream on biodistribution, namely, tumor uptake, and in vivo antitumor efficacy were evaluated in detail. Dox was attached to the polymer carrier by a hydrazone bond enabling pH-controlled drug release. While the polymer–drug conjugates were stable in a buffer at pH 7.4 (mimicking bloodstream environment), Dox was released in a buffer under mild acidic conditions modeling the tumor microenvironment or cells. The amphiphilic polymer carriers differed in the structure of hydrophobic cholesterol derivative moieties bound to the HPMA copolymers via a hydrolyzable hydrazone bond, exhibiting different rates of micellar structure disintegration at various pH values. Considerable dependence of the studied polymer–drug conjugate biodistribution on the stability of the micellar structure was observed in neutral, bloodstream-mimicking, environment, showing that a faster rate of the micelle disintegration in pH 7.4 increased the conjugate blood clearance, decreased tumor accumulation, and significantly reduced the tumor:blood and tumor:muscle ratios. Similarly, the final therapeutic outcome was strongly affected by the stability of the micellar structure because the most stable micellar conjugate showed an almost similar therapeutic outcome as the water-soluble, nondegradable, high-molecular-weight starlike HPMA copolymer–Dox conjugate, which was highly efficient in the treatment of solid tumors in mice. Based on the results, we conclude that the bloodstream stability of micellar polymer–anticancer drug conjugates, in addition to their low side toxicity, is a crucial parameter for their efficient solid tumor accumulation and high in vivo antitumor activity. Pracoviště Ústav makromolekulární chemie Kontakt Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358 Rok sběru 2019
Počet záznamů: 1