Cargoing P-gp inhibitors via nanoparticle sensitizes tumor cells against doxorubicin

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TitreCargoing P-gp inhibitors via nanoparticle sensitizes tumor cells against doxorubicin
Type de publicationJournal Article
Year of Publication2015
AuteursSingh MSmriti, Lamprecht A
JournalINTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume478
Pagination745-752
Date PublishedJAN 30
Type of ArticleArticle
ISSN0378-5173
Mots-clésCancer, Inhibitor, Multidrug resistance, Nanoparticle, P-gp
Résumé

Inhibitors against multidrug resistance (MDR) efflux transporters have failed in most clinical settings due to unfavorable pharmacokinetic interactions with co-administered anti-cancer drug and their inherent toxicities. Nanoparticles (NPs) have shown potential to overcome drug efflux by delivering and localizing therapeutic molecules within tumor mass. In this work, we investigated effect of nanocarrier surface charge and formulation parameters for a hydrophilic and lipophilic MDR inhibitor on their ability to reverse drug resistance. Active inhibition of efflux pumps was achieved by encapsulating first and third generation P-gp inhibitors- verapamil and elacridar respectively in non-ionic, anionic and cationic surfactant-based NPs. The ability of NPs to reverse P-glycoprotein (P-gp)-mediated MDR efflux was evaluated in sensitive (A2780) and resistant (A2780Adr) ovarian cancer cell lines by various in vitro accumulation and cytotoxicity assays. Uptake mechanism for NP appears to be caveolae-dependent with 20%-higher internalization in A2780Adr than A2780 cell lines which can be co-related to the biophysical membrane composition. Cationic- CTAB NPs showed highest reversal efficacy followed by PVA and SDS-NP (P + S NP) and PVA-NPs. As compared to doxorubicin treated drug resistant cells lines, blank-, verapamil- and elacridar-CTAB-NPs showed 2.6-, 20- and 193-fold lower IC50 values. This work highlights the importance of inhibitor-loaded charged particles to overcome cancer drug resistance. (C) 2014 Elsevier B.V. All rights reserved.

DOI10.1016/j.ijpharm.2014.11.064