Examination of the effect of PEG-rich matrices in multi drug resistance-associated protein (MRP) and multi drug resistance (MDR) substrates transport utilizing the CaCo-2 cell model.

摘要

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 resistance (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, crosslinker length, and particle size. Results demonstrated that the length of the tethered chain has an important role on the properties of the hydrogel, specifically swelling ratio, correlation length, and diffusion mechanism. As the length of the tethered chain increased, the diffusion mechanism changed from almost Fickian to relaxation controlled. The hydrogels were considere not cytotoxic after appropriate wash protocol was established, thus cytotoxic effect can be dismissed. Also, 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 (crosslinker and tethered chain length). 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 4°C. 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 linear PEG-300 morphology. Contrary to the expected results a reduction in particle size did not produce an increase in transport enhancement, possibly due to direct interaction effects. Finally, no correlation was observed between membrane fluidity and transport enhancement, suggesting other mechanisms are present. Therefore, we can conclude that PEG based hydrogels are potential candidates for controlled drug delivery devices that could be used in conjuntio with the inhibition of MRP and MDR1 proteins.