Impact of droplet size and surface charge on oral bioavailability of Norcantharidin-loaded SEDDS: Mechanistic insights into lymphatic transport and intestinal permeability.

Norcantharidin (NCTD), a promising anti-tumor agent, is limited by poor water solubility and low oral bioavailability. This study aimed to formulate NCTD into a self-emulsifying drug delivery system (SEDDS) to enhance its oral bioavailability and elucidate the underlying mechanisms. Six NCTD-loaded SEDDS formulations with droplet sizes ranging from 50 nm to 200 nm and different surface charges were prepared. These formulations were characterized, and the impact of digestion on drug solubility was evaluated through in vitro lipolysis. The effects of droplet size and surface charge on cellular uptake were investigated using in vitro cell experiments. Intestinal permeability was evaluated using a Caco-2 cell monolayer model, with apparent permeability coefficients and trans-epithelial electrical resistance (TEER) changes monitored. The oral bioavailability of different SEDDS formulations was clarified by in vivo pharmacokinetics and the influence of surface charge on lymphatic absorption was examined through in vivo distribution studies. Results showed that reducing droplet size and modifying droplets to carry a positive charge significantly enhanced NCTD's oral bioavailability by improving cellular uptake, intestinal permeability, and modulating lymphatic absorption. These findings provide valuable insights for the design of effective oral nanoformulations of NCTD.