Clinical Pharmacology & Biopharmaceutics
Open Access

Abstract

Oral administration is the preferable route of drug delivery, especially for chronic administration. However, poorly soluble drugs present a significant challenge in oral drug delivery development as the gastrointestinal track, with its wide range of pH and enzymatic activity, acts as a significant physiological barrier. Our studies demonstrate that the conjugation of lipophilic drugs to the short polymer monomethoxy poly lactic acid polyethylene glycol (mPEG-PLA) improved drug solubility, stability and oral availability. The specific mPEG-PLA di-block copolymer forms nanomicelles through self-assembly in aqueous solution. We investigated the intestinal absorption of solidified nanomicelles, using the cellular model of caco-2 permeability assay. 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 nanomicelles crossed caco-2 monolayer with an apical to basolateral apparent permeability coefficient (Papp) of 5x10-6cm/s after 4 hours, indicating good intestinal absorption. Biochemical inhibition of endocytosis, along with transmission electron microscopy images of nanomicelles packaged inside intracellular vesicles, suggested that endocytosis is mediated by clathrin. Upon conjugation of TNP-470, an anti-cancer drug with low bioavailability, a significant increase of drugs� bioavailabilty, stability and anti-cancer activity were obtained. Importantly the high tumor accumulation of the nanomicelle suggests their absorption as intact particle. Taken together, we propose the use of di-block nanomicelles as a platform for the oral delivery of poorly absorbed drugs. Our findings broaden the possibilities of oral drug delivery and carry significant clinical relevance, particularly for therapy of chronic diseases.

Biography

Email: OfraB@ekmd.huji.ac.il