P-glycoprotein inhibition of drug resistant cell lines by nanoparticles

Abstract

Several pharmaceutical excipients are known for their ability to interact with cell membrane lipids and reverse the phenomenon of multidrug resistance (MDR) in cancer. Interestingly, many excipients act as stabilizers and are key ingredients in a variety of nano-formulations. In this study, representatives of ionic and non-ionic excipients were used as surface active agents in nanoparticle (NP) formulations to utilize their MDR reversing potential. In-vitro assays were performed to elucidate particle–cell interaction and accumulation of P-glycoprotein (P-gp) substrates-rhodamine-123 and calcein AM, in highly drug resistant glioma cell lines. Chemosensitization achieved using NPs and their equivalent dose of free excipients was assessed with the co-administered anti-cancer drug doxorubicin. Among the excipients used, non-ionic surfactant, Cremophor® EL, and cationic surfactant, cetyltrimethylammonuium bromide (CTAB), demonstrated highest P-gp modulatory activity in both free solution form (up to 7-fold lower IC₅₀) and as a formulation (up to 4.7-fold lower IC₅₀) as compared to doxorubicin treatment alone. Solutol® HS15 and Tween® 80 exhibited considerable chemosensitization as free solution but not when incorporated into a formulation. Sodium dodecyl sulphate (SDS)-based nanocarriers resulted in slightly improved cytotoxicity. Overall, the results highlight and envisage the usage of excipient in nano-formulations in a bid to improve chemosensitization of drug resistant cancer cells towards anti-cancer drugs.

• Cancer
• glioblastoma
• MDR
• nanoparticle
• surfactants

Declaration of interest

Manu Smriti Singh is grateful to NRW International Graduate School of BIOTECH-PHARMA for financial assistance. Alf Lamprecht is thankful for the financial support from the Institut de France. This work was partially supported by a French Government grant managed by the French National Research Agency under the program “Investissements d’Avenir” with referenceANR-11-LABX-0021. The authors report no declarations of interest.