Enhanced cellular accumulation of a P-glycoprotein substrate, rhodamine-123, by Caco-2 cells using low molecular weight methoxypolyethylene glycol-block-polycaprolactone diblock copolymers.

A series of diblock copolymers based on methoxypolyethylene glycol-block-poly(caprolactone) (MePEG-b-PCL) was synthesized and evaluated for enhancing the cellular accumulation of a P-glycoprotein (P-gp) substrate, rhodamine-123 (R-123), into caco-2 cells. Altering MePEG:caprolactone feed weight ratio allowed diblocks with varying PCL lengths to be synthesized onto MePEG of molecular weight 750 or 2000. The critical micelle concentration (CMC) and the hydrophilic-lipophilic balance all decreased with increasing degree of polymerization of PCL. R-123 accumulation by caco-2 cells increased to a maximum in the presence of increasing concentrations of MePEG-b-PCL diblock copolymers (compared to R-123 alone) beginning at concentrations at or above the CMC, with little or no R-123 accumulation enhancement observed below the CMC. Further increases in MePEG-b-PCL concentration resulted in a decrease in R-123 uptake back to baseline levels. It is suggested that the higher concentrations of diblock above the CMC were required to serve as a 'depot' for free unimer partitioning into the cell membrane in order to obtain a critical concentration of diblock in the membrane for P-gp modulation. Alternatively, MePEG-b-PCL micelles may increase R-123 accumulation via endocytosis of micellized R-123.