Examination of the Effects of PEG-Rich Matrices In Multi Drug Resistance-Associated Protein (MRP) and Multi Drug Resistance (MDR) Substrates Transport Utilizing the Caco-2 Cell Model

Nilmarie Santos-Roman, Janet Mendez-Vega, and Dr. Madeline Torres-Lugo. Chemical Engineering, University of Puerto Rico - Mayaguez, P.O. Box 5289, Mayaguez, PR 00681

Multidrug resistance (MDR) is responsible for the low absorption of a very wide range of drugs and has been recognized as one of the major hurdles in drug absorption. Crosslinked poly(ethylene glycol) based morphologies are being proposed as multidrug resticance1 (MDR1) and multidrug resistance associated protein (MRP) inhibitors with the added advantage that these can be tailored for controlled drug delivery applications. For this purpose, three design variables were studied; the PEG tethered chain length and crosslinker length, and the particle size. The hydrogels demonstrated that they have MRP inhibitory effects by successfully enhancing the transport of fluorescein sodium salt (FLUO) up to 250%. The transport enhancement appears to be dependent on the hydrogel morphology as well. Temperature effect experiments seem to confirm that this transport enhancement is due to an active interaction with the MRP proteins, since no effect was observed at 4C. Polymers also demonstrated to have transport enhancement of the MDR1 substrate, Rhodamine 123 (RHO) of up to 350%. This effect was found to be dependent on the length of the tethered chain as well as the concentration of the suspension. These observations suggest a possible competitive action. The potency of the hydrogel inhibition appears to be greater than the known inhibitors verapamil, genistein and probenecid, but similar to the lineal PEG-300 morphology. Therefore, we can conclude that PEG based hydrogels are potential candidates for controlled drug delivery devices aimed at the inhibition of MRP and MDR1 proteins.