Novel norcantharidin-loaded liver targeting chitosan nanoparticles to enhance intestinal absorption

Yong-yan Bei¹, Xiao-yan Chen¹, Yang Liu¹, Jing-yu Xu¹, Wen-juan Wang¹, Zong-lin Gu¹, Kong-lang Xing¹, Ai-jun Zhu¹, Wei-liang Chen¹, Lin-seng Shi¹, Qin Wang¹, Xue-nong Zhang¹, Qiang Zhang^2
1College of Pharmaceutical Science, Soochow University, Suzhou, ²Department of Pharmaceutics, School of Pharmaceutical Science, Peking University, Beijing, People's Republic of China

Abstract: In this paper, two novel liver-targeting nanoparticles, norcantharidin-loaded chitosan nanoparticles (NCTD-CS-NPs) and norcantharidin-associated galactosylated chitosan nanoparticles (NCTD-GC-NPs), were prepared using ionic cross-linkage. The physical properties, particle size, encapsulation efficiency, and drug release characteristics of the nanoparticles were investigated in vitro. To investigate the intestinal absorption mechanisms of the two preparations, a series of experiments was carried out, including in situ circulation method, in vitro everted gut sacs, and Ussing chamber perfusion technique. The absorption rate constants (Ka) of NCTD at different segments were found to be duodenum > jejunum > ileum > colon. The concentration had no distinctive effect on absorption kinetics, suggesting that drug absorption is not dose-dependent. The transport of NCTD was found to be inhibited by P-glycoprotein (P-gp) inhibitor, indicating that NCTD might be the substrate of P-gp. The order of the absorption enhancer effects were as follows: low molecular weight chitosan (CS-8kDa) . high molecular weight chitosan (CS-30kDa) > Poloxamer > sodium dodecyl sulfate (SDS) > sodium deoxycholate (SDCh). The results indicate that the chitosan nanoparticles can improve intestinal absorption of NCTD.

Keywords: P-glycoprotein, absorption enhancers