Bloodstream stability predetermines the antitumor efficacy of micellar polymer-doxorubicin drug conjugates with pH-triggered drug release

0492820 - ÚMCH 2019 RIV US eng J - Článek v odborném periodiku
Chytil, Petr - Šírová, Milada - Kudláčová, Júlia - Říhová, Blanka - Ulbrich, Karel - Etrych, Tomáš
Bloodstream stability predetermines the antitumor efficacy of micellar polymer-doxorubicin drug conjugates with pH-triggered drug release.
Molecular Pharmaceutics. Roč. 15, č. 9 (2018), s. 3654-3663. ISSN 1543-8384. E-ISSN 1543-8392
Grant CEP: GA ČR(CZ) GA17-08084S; GA ČR(CZ) GA17-13283S; GA MŠMT(CZ) LO1507
Institucionální podpora: RVO:61389013 ; RVO:61388971
Klíčová slova: degradation * HPMA copolymer * pH-controlled release
Obor OECD: Polymer science; Microbiology (MBU-M)
Impakt faktor: 4.396, rok: 2018

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.
Trvalý link: http://hdl.handle.net/11104/0286873