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

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389013%3A_____%2F18%3A00492820" target="_blank" >RIV/61389013:_____/18:00492820 - isvavai.cz</a>

  • Alternative codes found

    RIV/61388971:_____/18:00492820

  • Result on the web

    <a href="http://dx.doi.org/10.1021/acs.molpharmaceut.8b00156" target="_blank" >http://dx.doi.org/10.1021/acs.molpharmaceut.8b00156</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1021/acs.molpharmaceut.8b00156" target="_blank" >10.1021/acs.molpharmaceut.8b00156</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

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

  • Original language description

    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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10404 - Polymer science

Result continuities

  • Project

    Result was created during the realization of more than one project. More information in the Projects tab.

  • Continuities

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Others

  • Publication year

    2018

  • Confidentiality

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

Data specific for result type

  • Name of the periodical

    MOLECULAR PHARMACEUTICS

  • ISSN

    1543-8384

  • e-ISSN

  • Volume of the periodical

    15

  • Issue of the periodical within the volume

    9

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    10

  • Pages from-to

    3654-3663

  • UT code for WoS article

    000443923800007

  • EID of the result in the Scopus database

    2-s2.0-85053166275