Nanocrystals with different stabilizers overcome the mucus and epithelial barriers for oral delivery of multicomponent Bufadienolides

BU nanocrystals (NCs) with different stabilizers, which codelivery three kinds of crude anti-tumor active ingredients with synergistic effect, were successfully prepared by media grinding method. The BU NCs were studied from the aspects of in vitro dissolution, mucus permeation, cell uptake, endocytosis mechanisms, transmembrane transport and ex vivo rat intestinal absorption. Results revealed that BU NCs can improve the transport efficiency of Bufadienolides to overcome two important barriers in the intestine - mucus layer and intestinal epithelial cells. [Display omitted] Using nanocrystals (NCs) technology may be a promising drug delivery strategy for oral administration of multicomponent anticancer drugs. However, the intestinal epithelium and the mucus layer on the intestine extremely limited drug transport and absorption by orally. In this study, we selected multicomponent inartificial compound Bufadienolides (BU) with broad spectrum antitumor activity as the model drug to prepare BU NCs with different stabilizers by wet grinding, and explored the efficiency of penetrating through the mucus layer and transporting intestinal epithelial cells in vitro and ex vivo. Results revealed that BU NCs can dramatically improve dissolution behavior synergistically and the efficiency of mucus permeation. Besides, we found that BU NCs with different stabilizers enhanced cellular uptake, which was mainly attributed to increasing or changing the endocytosis pathway and plasma membrane/Endoplasmic reticulum (ER) pathway involved in the transmembrane transport of NCs. Furthermore, BU NCs could definitely improve intestinal absorption efficiency and change the absorption site of BU ex vivo. This multi-angle exploration will provide reference for the development of BU oral delivery formulations.