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Nanomedicine (London, England)

Inhibition of P-glycoprotein pumps by PEO-PPO amphiphiles: branched versus linear derivatives.


PMID 21128720

Abstract

Inhibition of the activity of efflux transporters may relevantly improve the chemotherapy of cancer and infectious diseases. To explore the ability of poloxamines (Tetronic(®), X-shaped structure with a central ethylendiamine group and four branches of poly[ethylene oxide]-poly[propylene oxide] [PEO-PPO]) to inhibit the activity of P-glycoprotein (P-gp) on Caco-2 cell monolayers and to elucidate the incidence of the molecular architecture of PEO-PPO block copolymers on the intracellular accumulation of a relevant substrate, doxorubicin, by comparison with poloxamers (Pluronic(®), linear triblock copolymers), well-known inhibitors of this efflux transporter. Both pristine and N-methylated poloxamines displaying a wide range of molecular weights and EO/PO ratios were tested regarding cytocompatibility and accumulation of doxorubicin in Caco-2 monolayers. Verapamil was used as a control. The most active anti-P-gp poloxamines (which enhanced two- to three-fold doxorubicin accumulation compared with verapamil) resulted to be pristine medium-to-high hydrophobic T304, T904, T1301, T901 and T150R1. A notable dependence of the anti-P-gp activity on the copolymer concentration was found. A joint diagram of the inhibitory activity of poloxamers and poloxamines as a function of the effective length of the PPO block is proposed. The anti-P-gp activity is maxima for block copolymers possessing a low-to-medium hydrophilic-lipophilic balance and an 'effective number' of PO units ranging from 30 to 50.