ORAL ABSORPTION OF SOLIDIFIED POLYMER NANOMICELLES

Oral delivery of poorly soluble drugs represents a significant challenge in drug development. Oral administration is the preferable route of drug delivery, especially in chronic disease, that requires prolonged treatments. However, the gastrointestinal track presents a significant physiological barrier for drugs with its wide range of pH and enzymatic activity. Encapsulation of drugs may increase drug absorption, protecting drugs from the external milieu, and providing a controlled release.

Our previous studies demonstrated that conjugation of lipophilic drugs to short polymer monomethoxy poly lactic acid polyethylene glycol (mPEG-PLA) improved drug solubility, stability and oral availability. Here we present our recent results characterizing mPEG-PLA nanomicelles (~20nm) as a vehicle for oral delivery of encapsulated compounds (without chemical conjugation).

To study the intestinal absorption of solid nanomicelles, we used the Caco-2 permeability assay. Caco-2 are human epithelial colorectal adenocarcinoma cells which are used as a standard cellular model for studying oral availability of drugs. In order to elucidate the molecular mechanism of mPEG-PLA nanomicelle endocytosis in Caco-2 cells, specific inhibitors of clathrin, caveolae and lipid raft mediated endocytosis were used. mPEG-PLA nanomicelles were found to internalize rapidly, in a 30 min initial kinetics, with an Apical to Basolateral apparent permeability coefficient (Papp) of 3.8 x10-6 cm/s (2 hr) and 5x10-6 cm/s (4 hr). Moreover, endocytosis was found to be mediated by clathrin in an energy-dependent manner. Finally, we found that the low-density lipoprotein (LDL) receptor is directly involved in the endocytosis of mPEG-PLA, as indicated by interruption in internalization after blockage of the receptor by anti-LDLR antibody and by siRNA knockdown of LDLR gene. Our results introduce mPEG-PLA nanomicelles as a platform for oral delivery of poorly absorbed drugs.