Uptake and transport of a novel anticancer drug-delivery system: lactosyl-norcantharidin-associated N-trimethyl chitosan nanoparticles across intestinal Caco-2 cell monolayers

In this paper, novel liver-targeting nanoparticles (NPs), lactosyl-norcantharidin (Lac-NCTD)-associated N-trimethyl chitosan (TMC) NPs (Lac-NCTD-TMC-NPs), were prepared using ionic cross-linkage. The physical properties, particle size, and encapsulation efficiency of the nanoparticles were then investigated. The continuous line of heterogeneous human epithelial colorectal adenocarcinoma cells (Caco-2) cell monolayer model was used to study the transport mechanism of Lac-NCTD, and the effects of factors such as time, temperature, pH level, drug concentration, enhancers, and inhibitors. This model was also used to indicate the differences among Lac-NCTD, Lac-NCTD-associated chitosan NPs (Lac-NCTD-CS-NPs), and Lac-NCTD- TMC-NPs in the absorption and transportation of membranes. Drug concentration levels were measured using high-performance liquid chromatography. Active transport and paracellular transport were suggested to be both the primary and secondary mechanisms for Lac-NCTD absorption, respectively. Lac-NCTD uptake and absorption were not controlled by pH levels, but were positively correlated to uptake time, and negatively correlated to temperature. The basolat- eral to apical apparent permeability coefficients (Papps) were higher than those of the apical to basolateral values. The inhibitor of P-glycoprotein and the multidrug resistance-associated protein 2 significantly enhanced the uptake amount of Lac-NCTD. Compared with Lac-NCTD, Lac- NCTD-CS-NPs and Lac-NCTD-TMC-NPs significantly enhanced drug absorption. Additionally, the latter exhibited stronger action. Lac-NCTD-NPs could penetrate the plasma membrane of Caco-2 cells and translocate into the cytoplasm and even into the nucleus. Nanoparticles were uptaken into Caco-2 cells through the endocytosis pathway.