Dasatinib loaded mucoadhesive lecithin-chitosan hybrid nanoparticles for its augmented oral delivery, in-vitro efficacy and safety

Abstract

Dasatinib (DAS) is an oral tyrosine kinase inhibitor; however, its efficacy is significantly subsided by its low oral bioavailability. The present research aimed to improve DAS's oral delivery and efficacy in triple-negative breast cancer by fabricating its mucoadhesive lecithin-chitosan hybrid nanoparticles (DAS-L/CS-NPs). DAS-L/CS-NPs were optimized using Box-Behnken design which showed mean particle size and percent entrapment efficiency of 179.7 ± 5.42 nm and 64.65 ± 0.06 %, respectively. DAS-L/CS-NPs demonstrated sustained release profile in different release media up to 48 h and showed 10 times higher apparent permeability coefficient and flux than free DAS suspension. The binding of DAS-L/CS-NPs to the mucus layer was demonstrated via ex-vivo mucoadhesion study and change in absorbance using turbidimetry. In cell culture studies, DAS-L/CS-NPs revealed a 4.14-fold decrease in IC₅₀, significantly higher cellular uptake and mitochondrial membrane depolarization, 3.82-fold increased reactive oxygen species generation and 2.10-fold enhanced apoptosis in MDA-MB-231 cells than free DAS. In in-vivo pharmacokinetic assessment, DAS-L/CS-NPs showed a 5.08-fold and 3.74-fold rise in AUC _(0-t) and C_max than free DAS suspension, respectively. An acute toxicity study revealed a good safety profile of DAS-L/CS-NPs. In a nutshell, proposed hybrid nanoparticles are promising carriers for improved oral delivery of poorly water-soluble drugs.

Keywords: Bioavailability; Breast cancer; Chitosan; Dasatinib; Hybrid-nanocarrier; Mucoadhesion.