Self-assembling amphiphilic copolymers as inhibitors of ATP-binding cassette pumps

ALEJANDRO SOSNIK; VERÓNICA L MATHET; MARÍA L CUESTAS

Cancún

Congreso; XXI International Materials Research Congress.; 2012

Poloxamers and poloxamines are thermo-sensitive poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) amphiphiles. As opposed to poloxamers that display a linear structure, poloxamines have a branched architecture and the presence of two central tertiary amine groups confers the molecule pH-responsiveness. Above the critical micellar concentration, these copolymers self-assemble generating a kind of nano-aggregate, polymeric micelle, that has been extensively capitalized to encapsulate and stabilize poorly-water soluble drugs. In addition, these copolymers inhibit the functional activity of pumps of the ATP-binding cassette (ABCs) superfamily. ABCs are transmembrane proteins that transport drug molecules against a concentration gradient. The over-expression of these pumps has been associated with a multidrug resistance (MDR) phenotype, which is considered a crucial cause of treatment refractoriness in patients with cancer. ABCs have been also related to the generation of HIV reservoirs, a phenomenon that prevents the eradication of the virus from the host in specific body sites such as the central nervous system. Our research group dedicates efforts to study of the inhibitory activity of the branched derivatives for the improvement of the therapy in HIV and liver diseases. In this study, we report on the inhibitory effect of different concentrations of poloxamines showing a wide range of molecular weights and EO/PO ratios on the functional activity of three different ABC proteins, namely P-glycoprotein (P-gp or MDR1), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein MRP1, in two human hepatocarcinoma cell lines, HepG2 and Huh7. Moderate to highly hydrophobic poloxamines T304, T904 and T1301 showed inhibitory activity against P-gp and BCRP but not against MRP1 in both hepatic cell lines. A remarkable dependence of this effect on the copolymer concentration and hydrophobicity was found. No inhibitory effect against these ABC pumps was observed with the hydrophilic T1107. Finally, we assessed for the first time the effect of these copolymers on the expression of mRNA encoding for the main ABCs in a human hepatoma cell line. These findings support the potential usefulness of these Trojan horses as both drug nanocarriers and ABC inhibitors in hepatic MDR tumors and infections that involve the activity of these efflux transporters.   References 1. Alvarez-Lorenzo C, Rey-Rico A, Brea J, Loza MI, Concheiro A, Sosnik A, Nanomedicine-UK 5, 1371-1383 (2010). 2. Cuestas ML, Sosnik A, Mathet VL, Mol Pharmaceutics 8, 1152-1164 (2011).