Electrohydrodynamic Jetting of Mucoadhesive Protein Nanoparticles as a Chemopreventive Strategy for Oral Squamous Cell Carcinoma.

Intraepithelial delivery of cancer preventive therapies for oral squamous cell carcinoma (OSCC) has been limited by factors such as rapid mucus turnover, enzymatic degradation, and salivary clearance. These challenges, coupled with poor solubility and associated low bioavailability, have hampered clinical progress. To address these challenges, we present an effective method for encapsulation and sustained release of poorly soluble, apolar therapeutics via mucoadhesive protein nanoparticles (PNPs). To demonstrate feasibility, PNPs loaded with N-(4-hydroxyphenyl) retinamide (4HPR, fenretinide), a hydrophobic chemopreventive compound with low solubility were produced via a three-step process: 1) high-pressure homogenization to solubilize and stabilize 4HPR via association with human serum albumin (HSA), 2) electrohydrodynamic (EHD) jetting of albumin-bound 4HPR to formulate 4HPR-HSA PNPs, and 3) collection of the nanoparticles in the presence of a polycationic compound to infer mucoadhesive properties and physiological stability. This methodology resulted in the effective synthesis of environmentally stable 4HPR-loaded PNPs, which featured an average size of 192 ± 21 nm, a surface zeta potential of +31 ± 6 mV in water, and overall 4HPR loadings of up to 7.1 wt.%. In vitro activation of the apoptosis execution phase enzyme, caspase-3, confirmed sustained release and biological activity of 4HPR. Enhanced binding capacity with mucin (K_D = 6.1*10^-11 M) was confirmed through surface plasmon resonance (SPR) spectroscopy. This generalizable nanoparticle technology addresses a critical challenge in chemopreventive and targeted drug delivery, where clinical efficacy is limited by limited bioavailability and low drug concentrations of highly apolar agents.