Fucoidan-mediated targeted delivery of dasatinib-loaded nanoparticles amplifies apoptosis and endows cytotoxic potential in triple-negative breast cancer

Dasatinib (DST) is a tyrosine kinase inhibitor with established antiproliferative activity in Triple-negative breast cancer. Conventional treatment strategies with DST have several pitfalls related to the development of resistance, lower cellular uptake and unwanted adverse effects. To address these issues, we have prepared P-selectin-targeted nanoparticles of DST with fucoidan (FUC) as a ligand. Poly lactide-co-glycolide nanoparticles of DST were coated with chitosan (CH) and FUC via electrostatic interaction (DST-CH-FUC-NPs). The mean particle size of 210.36 +/- 0.66 nm and a polydispersity index of 0.234 +/- 0.013 was observed for DST-CH-FUC-NPs. TEM and FTIR analysis proved CH coating followed by an FUC layer on nanoparticles. DST-CH-FUC-NPs showed a sustained release profile up to 120 h and 2.9 times less hemolytic potential than free DST suspension. DST-CH-FUC-NPs demonstrated 8-fold higher cytotoxicity compared to free DST in MDA-MB-231 cells. Rhodamine-CH-FUC-NPs showed 19 times and 3 times higher cellular uptake than free Rhodamine and Rhodamine-CH-NPs, respectively. DST-CH-FUC-NPs also displayed increased ROS production and mitochondrial membrane potential damage. Apoptosis study revealed a 7.5-fold higher apoptosis index for DST-CH-FUC-NPs than free DST. Subsequently, the DST-CH-FUC-NPs showed increased inhibition of cell migration, where approximately 5 % wound closure was noted. Further, DST-CH-FUC-NPs confirmed higher disruption of lysosomal membrane integrity, which is well correlated with apoptosis results. In addition, developed NPs were nontoxic on MCF 10 A normal cells. All these findings suggest that fabricated DST-CH-FUC-NPs are promising biocompatible carriers for tumor-targeted delivery and enhanced efficacy of dasatinib.

Automated summary

This study developed P-selectin-targeted dasatinib nanoparticles coated with chitosan and fucoidan (DST-CH-FUC-NPs), which showed sustained release, reduced hemolytic potential, increased cytotoxicity and cellular uptake compared to free dasatinib. These nanoparticles also demonstrated enhanced ROS production, mitochondrial membrane potential damage, apoptosis induction, cell migration inhibition, and disruption of lysosomal membrane integrity.