Polyethylene glycol encapsulation enhances phytol-induced oxidative stress, mitochondrial dysfunction and apoptotic...

Oral carcinoma is an aggressive cancer characterized by significant morbidity and limited treatment alternatives due to drug resistance and systemic toxicity. The study investigates phytol (PYT), for its unexplored anticancer efficacy against oral epidermal carcinoma (KB) cells. The objective was to enhance the limitations associated with the inadequate solubility and bioavailability of PYT via polyethylene glycol (PEG) encapsulation (PYT @PEG), and to establish its molecular mechanism through in vitro and in silico methodologies. In vitro assays showed that PEG encapsulation improves the therapeutic efficacy of PYT by enhancing its bioavailability and cellular uptake, leading to increased cytotoxic activity, generate higher levels of reactive oxygen species (ROS), depolarize the mitochondria, trigger apoptosis, and interrupt the cell cycle at the G₀/G₁ stage. Molecular docking showed that PYT binds effectively to CDK4 (-9.8 kcal/mol) because of hydrophobic and polar interactions with Val 96, Glu 144, and Asp 99. Molecular dynamics simulations validated complex stability, exhibiting RMSD values between 2.0 and 2.6 Å and RMSF ≤1.4 Å, thereby indicating a stable interaction. The study demonstrated that encapsulating PYT with PEG mitigates its poor solubility and low bioavailability, thus establishing PYT@PEG as a promising natural therapeutic candidate, with computational analyses suggesting CDK4 as a potential molecular target associated with its antiproliferative activity in oral carcinoma.