Bioactive fucoidan-coated polylactic acid-based nanoparticles for co-delivery of vincristine and thymoquinone: Enhanced antitumor efficacy with reduced vincristine-associated toxicity.
Abstract
The clinical efficacy of vincristine (VIN) is often restricted by dose-limiting toxicity, poor tumor selectivity, and rapid systemic distribution. Another biomolecule, thymoquinone (TQ), has negligible toxicity, but poor aqueous solubility and limited bioavailability hamper its use in cancer therapy. In this study, a fucoidan (Fu)-based methoxy-poly (ethylene glycol)-block-poly (lactic acid) (mPEG-PLA) nanoformulation has been optimized for the co-delivery of VIN & TQ to synergistically enhance cancer therapy. Besides acting as a surface stabilizer, Fu provides anticancer therapeutic responses owing to its intrinsic anti-cancer, anti-inflammatory, and tumor-targeting properties, thereby enhancing the overall therapeutic efficacy of the nanoformulation. Molecular docking was first performed to investigate the drug and the polymer interactions, which revealed several favourable bindings of both the biomolecules with the hydrophobic domain of the mPEG-PLA polymer. Formed Fu-based co-loaded nanoparticles (VIN-TQ-PLA-CN-Fu-NPs) exhibited narrow size distribution, high drug entrapment efficiency, slow and sustained pH-responsive drug release. In-vitro studies using the triple negative breast cancer (TNBC) cell line showed excellent cellular uptake, cytotoxicity, apoptosis, and inhibition of tumor proliferation using the Calcein-AM/PI live/dead assay, JC-1 assay, and DCFDH-DA reactive oxygen species (ROS) generation assay compared to free drugs. In-vivo experiments further confirmed remarkable tumor growth inhibition, achieving 90.2% tumor regression, prolonged survival periods, while exhibiting excellent biocompatibility without obvious changes to vital organs, probably due to toxicity-alleviating properties of TQ. Collectively, the combination of VIN, TQ, and Fu in a single nanoformulation produced a multitargeted synergistic therapeutic system for combination cancer chemotherapy and offers significant potential for use in clinical settings.