Novel Silybin-Conjugated Chitosan Polymeric Micelles for Improving the Oral Absorption of Doxorubicin Based on the Inhibition of P-gp and CYP3A4.

A drug delivery system based on silybin-conjugated chitosan (CS-SB) polymeric micelles was developed to improve the oral absorption of doxorubicin (DOX). SB was grafted to CS via succinic acid, and CS-SB was identified by ¹H NMR and FT-IR. The DOX-loaded micelles were prepared by self-assembly, and the characteristics of micelles, including a small particle size of 167.8 ± 2.3 nm, a high drug loading capacity of 8.59%, and a low critical micelle concentration of 1.3 × 10^-5 g/mL, were demonstrated. The micelles showed oral bioavailability of up to 193% versus DOX·HCl. The cytotoxicity test showed the biosafety of CS-SB and the potential of reductive DOX-induced cardiotoxicity. The inhibition of P-gp efflux and CYP3A4 enzyme in CS-SB micelles was confirmed by cellular uptake and enzyme activity inhibition tests. The endocytosis process of micelles was revealed by an endocytosis inhibition test. The findings exhibited the potential of CS-SB micelles in drug delivery.