Nanocarrier platforms encapsulating plant-based natural extracts have emerged as an attractive tool to increase the safety and stability of phytomedicines and nutraceuticals. In this study, phenolic fractions were extracted from grape seed waste, spray dried, and characterized. Grape seed extracts (GSE) of Marselan, a red international variety, and Obeidi, a Lebanese autochthonous white variety, had a total phenolic content (TPC) of 301 and 206 mg gallic acid equivalents (GAE)/g of dry matter, respectively, along with a high content of catechins, gallic acid, epicatechins, caffeic acid, syringic acid, and protocatechuic acid. A nanocarrier formulation was developed using poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA), yielding GSE-loaded nanoparticles (NPs) with an average of 230 nm particle size and −35 mV zeta potential, 50% encapsulation efficiency, and sustained release over 96 h. GSE NPs exhibited high colloidal stability in terms of size and high chemical stability in terms of TPC and antioxidant activity for both Marselan and Obeidi when stored at 4 °C for 3 months. GSE NPs showed excellent biocompatibility in human dermal fibroblasts. Both NPs and crude extracts significantly suppressed the proliferation of B16–F10 melanoma cells, particularly Obeidi NPs. This study emphasizes the important role nanotechnology can play in the valorization of bioactive nutraceuticals by presenting GSE NPs as a promising nanoformulation against skin cancer.
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