SOLIDIFIED POLYMER MICELLES FOR ORAL DRUG DELIVERY

polymeric nanoparticles are an attractive vehicle for drug delivery, that are mostly studied as injectable formulation. However, oral administration remained the preferable route of drug delivery for chronic diseases. Oral absorption of poorly soluble drugs present significant challenges. The gastrointestinal track, with its wide range of pH and enzymatic activity, is a significant physiological barrier. However, encapsulating drugs may increase their absorption and provide protection from the external milieu.

We demonstrated that by stabilizing poly-ethylene glycol-poly lactic acid (PEG-PLA) nanomicelles we can successfully increase absorption of conjugated small molecule drugs. In our current study, we investigate how the same polymeric system can be used to encapsulate a small molecule surrogate drug without chemical conjugation.

The mPEG-PLA di-block copolymer self-assembled into ~20 nm nanomicelles in aqueous solution. To investigate the intestinal absorption of solid nanomicelles, we employed the caco-2 permeability assay. Caco-2 is a line of human epithelial colorectal adenocarcinoma cells used as a standard model for studying the oral availability of drugs. In order to elucidate the molecular mechanism of mPEG-PLA nanomicelle endocytosis in these caco-2 cells, specific inhibitors of clathrin, caveolae and lipid raft mediated endocytosis were used.

The results showed that fluorescent labeled mPEG-PLA nanomicelles can internalize rapidly into caco-2 cells as early as 15 min post incubation, indicating good intestinal absorption. Biochemical inhibition of endocytosis, along with the detection of intracellular vesicles entrapping nanomicelles, suggest that endocytosis is mediated by clathrin in an energy-dependent manner.

Our results indicate that mPEG-PLA nanomicelles permeate intestinal epithelial cells in a clathrin-mediated manner. Their penetration potential across the caco-2 monolayer supports their use as a platform technology for the oral delivery of poorly absorbed drugs.