Hydrogel nanoparticles of retinol acetate via modified rapid expansion of supercritical solution: design, optimization, and anticancer evaluation

Polymeric nanoparticles are promising drug carriers due to their biocompatibility, sustained release, and improved therapeutic efficacy; however, conventional fabrication methods often suffer from broad size distribution, low encapsulation efficiency, and instability. To address these limitations, Sonication Assisted Particle Production using Supercritical Solution (SAPSS®), a modified RESS technique integrating ultrasonication and mechanical mixing, was developed to prepare and optimize HPMC K-100M hydrogel nanoparticles encapsulating retinol acetate using DOE, RSM, and ANOVA. The optimized formulation (retinol acetate: HPMC K-100M, 1:1 w/w) produced at 290 bar and 75 °C for 45 min with 1% Tween 80 yielded nanoparticles of 138.6 ± 1 nm, PDI 0.583 ± 0.03, zeta potential −14.9 ± 2.0 mV, encapsulation efficiency 99.02 ± 0.2%, and yield 66.4 ± 0.3%. FTIR, DSC, and XRD confirmed amorphous encapsulation and drug-polymer interactions, while SEM demonstrated spherical, discrete morphology. In vitro release studies revealed sustained drug release across physiological pH, with mucoadhesive strength supporting gastrointestinal retention. Cytotoxicity assays on COLO-205 cells, doxorubicin showed >90% cytotoxicity, free retinol acetate caused only 10–25% cell death, while HPMC-encapsulated retinol acetate nanoparticles produced enhanced, dose-dependent cytotoxicity of 25%, 35%, and 55% at 100, 200, and 300 µg/mL, respectively, with negligible toxicity from blank HPMC. Overall, SAPSS® provides a green, scalable approach for fabricating stable therapeutic nanoparticles.