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Reversion of P‑gp-Mediated Drug Resistance in Ovarian Carcinoma Cells with PHPMA-Zosuquidar Conjugates
journal contribution
posted on 2017-04-14, 00:00 authored by Claudia Battistella, Harm-Anton KlokInhibition
of P-glycoprotein (P-gp) transporter is an attractive
approach for the reversion of cancer-associated multidrug resistance
(MDR). Poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA)-based carriers
that are able to release the anticancer drug doxorubicin in the lysosomes
have shown promise to reduce P-gp mediated resistance. This is attributed
to the release of the drug in close proximity to the nucleus and distant
from the P-gp transporter. This work presents a strategy to maximize
P-gp inhibition and enhance doxorubicin cytotoxicity in cancer cells
by using a dual functional PHPMA conjugate carrying both the anticancer
drug doxorubicin and the P-glycoprotein inhibitor zosuquidar (Zos).
While doxorubicin was connected to the polymer backbone via a lysosomally
cleavable spacer, the P-gp inhibitor Zos was attached by a hydrazone
linker in order to promote release in the early stage of the endocytic
process and maximize its cytosolic concentration in proximity of the
P-gp transporter. Following Zos modification and determination of
its ability to inhibit P-gp, conjugation to the PHPMA polymer backbone
resulted in enhanced doxorubicin cytotoxicity in resistant A2780ADR
ovarian carcinoma cells. Finally, the incorporation of both Dox and
Zos in a single polymer carrier enhanced P-gp inhibition as compared
to a control PHPMA conjugate containing only Dox.
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PHPMA-Zosuquidar Conjugates InhibitionreleaseOvarian Carcinoma CellsPHPMA polymer backbone2780ADRcancer-associated multidrug resistancedoxorubicin cytotoxicityanticancer drug doxorubicinMDRlysosomally cleavable spacercontrol PHPMA conjugateP-gp inhibitor ZosP-gp transporterP-gp inhibitionP-glycoprotein inhibitor zosuquidar
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