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

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 Cmax 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.

New cycloartane triterpenoids from Dysoxylum malabaricum and their cytotoxic evaluation.

The cytotoxic dichloromethane-methanol bark extract of Dysoxylum malabaricum was subjected to bioassay-guided fractionation, followed by systematic dereplication to focus on the identification of new compounds. From the bark of Dysoxylum malabaricum, two new cycloartane-type triterpenoids were isolated in addition to two previously known triterpenoids. The structures and absolute configurations of the isolated compounds were elucidated unambiguously via NMR, HRESIMS data, and electronic circular dichroism calculations. The isolated compounds were tested for their cytotoxic potential against the panel of breast, lung, and hypopharynx cancer cell lines and displayed notable cytotoxicity against breast cancer cell lines. Compound 3 exhibited the most potent cytotoxic effect with an IC50 14 µM against MCF-7 cell lines and induced cell cycle arrest. Through western blot and cell cycle analysis, it was revealed that compound 3 halts the G0/G1 phase of the cell cycle by inhibiting CDC20 and CDC25 enzymes.