Emulsion-based Colloidal Nanosystems for Oral Delivery of Doxorubicin: Improved Intestinal Paracellular Absorption and Alleviated Cardiotoxicity

We have previously reported that the limited intestinal absorption via the paracellular pathway may be the primary cause of the low oral bioavailability of doxorubicin (DOX). In this study, we have formulated medium chain glycerides-based colloidal nanosystems to enhance the intestinal paracellular absorption of DOX and reduce its cardiotoxicity. The DOX formulations prepared by the construction of pseudo-ternary phase diagram were characterized in terms of their droplet size distribution, viscosity, drug loading, and drug release. Further evaluation was conducted by an in vitro Caco-2 transport study as well as in situ/in vivo intestinal absorption, bioavailability and toxicity studies. Compared with DOX solution, these formulations enhanced the absorptive transport of DOX across Caco-2 cell monolayers at least partly due to the paracellular-enhancing effects of their lipidic components. Moreover, the in situ intestinal absorption and in vivo oral bioavailability of DOX in rats were markedly enhanced. In addition, no discernible damage was observed in the rat jejunum after oral administration of these DOX formulations while the cardiac toxicity was significantly reduced when compared with intravenous DOX solution. Taken together, the medium chain glycerides-based colloidal nanosystems prepared in this study represent a potentially effective oral delivery system for DOX.