Inhibition of P-glycoprotein pumps by PEO–PPO amphiphiles: branched versus linear derivatives. (November 2010)

• Record Type: Journal Article
• Authors: Alvarez-Lorenzo, Carmen; Rey-Rico, Ana; Brea, Jose; Loza, Maria Isabel; Concheiro, Angel; Sosnik, Alejandro
• Is Part Of: Nanomedicine. Volume 5:Number 9(2010)
• Page Start: 1371
• Page End: 1383
• Publication Date: 2010-11
• Subjects: cancer -- doxorubicin -- drug efflux -- HIV/AIDS -- P-glycoprotein inhibition -- poloxamer -- poloxamine -- polymeric micelle -- transport; Nanotechnology -- Periodicals; Medical technology -- Periodicals; Nanotechnology -- Therapeutic use -- Periodicals; 610.28
• DOI: 10.2217/nnm.10.53
• Languages: English
• ISSNs: 1743-5889

Abstract

Inhibition of the activity of efflux transporters may relevantly improve the chemotherapy of cancer and infectious diseases.Aim: 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.Methods: 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.Results: 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.Conclusion: 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.