Development of Sesamol Loaded-Polymer-Lipid Blend Nanoparticles: Statistical Optimization, In-Vitro, and Preclinical Assessment

Background: The oral route is the most preferred drug delivery method for treating both chronic and acute diseases due to its ease of administration and high patient compliance. However, sesamol (SM), a natural bioactive compound, exhibits promising antioxidant and anticancer activity but suffers from poor water solubility, inconsistent absorption, and low bioavailability, limiting its therapeutic potential. This study aimed to develop SM-loaded hybrid nanoparticles (HNP) composed of a polymer-lipid matrix to enhance bioavailability and therapeutic efficacy for its antioxidant potential and anticancer activity. Method: SMHNP were formulated using homogenization and ionotropic gelation techniques and optimized by Box-Behnken design using design expert software. The SMHNP were evaluated through in-vitro and in vivo studies using the albino Wistar rat model. Results: The optimized SMHNP formulation (SMHNP13) exhibits a particle size of 177.6 ± 4.7 nm, a polydispersity index of 0.179, and a zeta potential of 27.2 mV. Scanning electron microscopy (SEM) confirmed that the particles were spherical and non-aggregated. FTIR and X-ray diffraction (XRD) analyses indicated successful drug encapsulation within the HNP matrix. The SMHNP13 formulation exhibited a sustained drug release profile, with 92.81 ± 3.76% release over 24 h, attributed to its nanosize and encapsulation. It displayed 2.45-fold higher ex-vivo intestinal permeation and significantly higher in-vitro antioxidant activity (P < 0.05) at all tested concentrations than pure SM. It also increased cytotoxicity against SK-LU-1 cells (IC50 = 590.23 µM) compared to pure SM (IC50 = 1510.12 µM) and demonstrated a 3.33-fold higher relative bioavailability than pure SM. Conclusion: The results indicate that HNP are a promising strategy for enhancing the oral bioavailability and therapeutic potential of sesamol. Further preclinical investigations are needed to confirm their clinical applicability.