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
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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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
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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