Poly(Ethylene Glycol) Hydrogels as Possible Multidrug Resistance Associated Protein (MRP) Inhibitors

Multidrug resistance (MDR) has been recognized by the scientific community as one of the major hurdles in the bioavailability of broad spectrum of drugs. This work focuses on the examination of the effects of the variables involved in hydrogel design on the multidrug resistance phenomenon. Hydrogels were synthesized using monomer lengths of 200, 400 and 1000 g/mol and a crosslinker length of 1000 and 600 g/mol. Hydrogels were characterized by the determination of release of model substrate Fluorescein sodium salt (FLUO), a multidrug resistance-associated protein (MRP) substrate, from the networks, and its transport trough Caco-2 cells. The effect of the hydrogels on the cytotoxicity of the chemotherapeutic agent 5-Fluoracil, an MRP substrate, was also assessed. The release profile of the model substrate FLUO indicated an anomalous release for all the morphologies with both Fickian and relaxation effects playing a role in the release of the substrate, making these hydrogels excellent candidates for controlled drug delivery applications. Preliminary results on the fluorescein sodium salt transport across Caco-2 cell monolayer in contact with 10 mg/mL PEG hydrogels suspensions showed a transport enhancement of up to 152%. Finally, cytotoxicity of Caco-2 cells with chemotherapeutic agent 5-Fluoracil was enhanced in the presence of the hydrogels. This data suggests that PEG hydrogels are acting as MRP inhibitors.