Chitosan-based nanoparticles for perillyl alcohol delivery: development, cytotoxicity and mucoadhesion

Perillyl alcohol (POH) is a monoterpene found in the essential oils of several plants and citrus fruits, with well-documented anticancer potential. However, its poor aqueous solubility and low oral bioavailability significantly limit its therapeutic efficacy. This study describes the development of mucoadhesive chitosan/tripolyphosphate (CS/TPP) nanoparticles for the encapsulation and controlled delivery of POH. The nanoparticles, prepared by ionic gelation, exhibited a mean diameter of ~300 nm, a positive zeta potential (+9 ± 3 mV), low polydispersity (0.09 ± 0.04), spherical morphology, and an encapsulation efficiency of 35 ± 3%. XRD and DSC analyses indicated partial amorphization and enhanced thermal stability of the encapsulated compound, whereas FTIR confirmed nanoparticle formation and suggested physical entrapment of POH within the chitosan matrix. The formulation provided sustained POH release for up to 144 h, with approximately 38% released over the first 72 h. Cytotoxicity assays in HT-29 and LNCaP cells demonstrated concentration-dependent reductions in viability for both free and encapsulated POH, with higher IC50 values for the nanoparticle formulation, consistent with its prolonged release profile. Mucoadhesion studies revealed significant mucin adsorption, physicochemical alterations upon contact with mucin, and clear evidence of surface interactions by SEM, supporting strong mucoadhesive properties. Collectively, these findings highlight CS/TPP/POH nanoparticles as a promising platform to improve the oral delivery, absorption, and therapeutic potential of POH for cancer treatment.