Hepatoma-targeted chitosan-based polymeric micelles for oral delivery of celastrol for liver cancer treatment.

Chitosan-based polymeric micelles have great potential for oral delivery of poorly soluble antitumor drugs. Celastrol (Cela) exhibits excellent anti-hepatoma activity with several challenges for oral administration, including gastrointestinal irritation, short plasma half-life, low bioavailability, and limited biosecurity. In our previous study, glycyrrhetinic acid-carboxymethyl chitosan-thioketal-rhein polymeric micelles (GCTR PMs) were developed to address the limitations of Cela for intravenous injection. In this study, GCTR PMs loaded with Cela (Cela/GCTR PMs) remained stable in gastrointestinal fluids and physiological pH environments and demonstrated sustained-release behavior. Cela/GCTR PMs enhanced Cela absorption in the intestine by bypassing P-gp and improved its oral bioavailability. The micelles exhibited hepatoma-targeting properties and accumulated in liver tumors through both active and passive targeting mechanisms in intact PM form following oral administration, thereby enhancing the antitumor effect of Cela and reducing systemic toxicity. Therefore, Cela/GCTR PMs offer a promising oral nano-delivery system for liver cancer treatment.