Polyethylene Oxide-Polystyrene Oxide Triblock Copolymers as Biological-Responsive Nanocarriers.
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Polyethylene Oxide-Polystyrene Oxide Triblock Copolymers as BiologicalResponsive Nanocarriers. Adriana Cambón,1, Ana Rey-Rico,2 Silvia Barbosa,1* Jose Brea,3 M. I. Loza,3 Stephen G. Yeates,4 Carmen Alvarez-Lorenzo,2 Angel Concheiro,2 Pablo Taboada,1 and Victor Mosquera1 1
Grupo de Física de Coloides y Polímeros, Facultad de Física, Universidad de Santiago de Compostela, Spain. 2Departamento de Farmacia y Tecnología Farmacéutica and 3 Departamento de Farmacología, Universidad de Santiago de Compostela, Spain. 4Organic Materials Innovation Center, School of Chemistry, University of Manchester, UK.
ABSTRACT The present work presents the synthesis, characterization and evaluation of the biocompatibility and ability to dissolve and chemically protect the anticancer drug doxorubicin (DOXO) of two polyethylene oxide-polystyrene oxide triblock copolymers, EO33SO13EO33 and EO38SO10EO38, where EO and SO denote the ethylene oxide and styrene oxide blocks, respectively. Block copolymer length and SO/EO ratio were selected with the objective of ensuring an optimal compromise between chain solubility, micelle formation ability and core size for enhanced drug solubilization. The temporal stability of the drug-loaded micelles and drug release profile were also analyzed as well as their efficacy as an antitumoral polymeric formulation in vitro by using a multidrug resistant ovarian tumor cell line (NCI-ADR-RES), with the special aim of analyzing the possible capability of both copolymers as potential P-glycoprotein efflux (P-gp) pump inhibitors to enhance DOXO accumulation in this cell line. INTRODUCTION In the last few years, many important advances in the development of efficient chemotherapeutic drug delivery systems have been reached (1-6). Among all the systems suitable as nanocarriers, micelles formed by amphiphilic copolymers, where the core presents a hydrophobic character while the shell is hydrophilic, occupy relevant position (7-9). This core-shell structure allows, among others, to encapsulate and carry poorly water-soluble drugs in the micelles core, to decrease the biofouling of the nanocarrier, to decrease the cytotoxicity of the cargo and to release drugs in a sustained rate (7-9). Probably, the most widely studied amphiphilic copolymers are those composed of ethylene oxide (EO) and propylene oxide (PO) blocks (as for example Pluronics® and Tetronics®). However, to achieve more effective aggregation and more stable micelles, polyethylene oxide-polystyrene oxide triblock copolymers have been tried as nanocarriers due to the higher hydrophobicity of the SO block as compared to PO block (10).Thus, the present work shows the ability of copolymers EO33SO13EO33 and EO38SO10EO38 to dissolve and chemically protect DOXO, evaluating the colloidal stability of the drug-loaded polymer micelles, their drug release profile, the safety of the polymeric nanocarrier and their in vivo efficacy as an antitumoral formulation. EXPERIMENTAL DETAILS Materials. Block copolymer synthesis and experimental characterization were described in
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