Sustained delivery of 4-phenylbutyric acid via chitosan nanoparticles in foam for decontamination and treatment of lewisite-mediated skin injury.

Lewisite, a chemical warfare agent, induces severe skin injury by oxidative stress and endoplasmic reticulum (ER) dysfunction, necessitating innovative antidote strategies. This study developed chitosan nanoparticle-loaded foam formulations for rapid skin decontamination and sustained topical delivery of 4-phenylbutyric acid (4-PBA), an ER stress-reducing chaperone. Nanoparticles were synthesized via ionic gelation using low (LMW) and medium molecular weight (MMW) chitosan. The optimized formulations, N31 (LMW) and N35 (MMW), achieved drug loadings of 5.04 % and 10.09 % w/w, particle sizes of 141.88 ± 26.31 nm and 176.10 ± 36.97 nm, monodisperse distributions (PDI < 0.3), high entrapment efficiency (>93 %) and good stability with zeta potential of -16.67 mV and -19.37 mV, respectively. Incorporation into foam enabled both effective decontamination (>70 % efficiency) and sustained 4-PBA delivery. In vitro release studies demonstrated sustained drug release over 24 h. Permeation studies using dermatomed human skin revealed that nanoparticle formulations significantly reduced 4-PBA delivery: N35 decreased permeation by 38.4 % (214.35 ± 16.6 µg/cm2 vs. 348.10 ± 5.37 µg/cm2 for free 4-PBA), while N31 reduced it by 81.35 % (64.90 ± 6.89 µg/cm2). Both formulations retained efficacy in PAO challenged skin, with N35 delivering 158.54 ± 53.93 µg/cm2 and N31 138.25 ± 14.72 µg/cm2 over 24 h. Furthermore, in vivo studies showed that the optimized formulation with N35 chitosan (4-PBA N35 + N-acetyl cysteine (NAC)) significantly protects against PAO-induced skin injury and inflammatory cytokine production in Ptch1+/-/SKH-1 hairless mice. Thus, the translational feasibility and effective treatment by the foam formulated 4-PBA N35 + NAC against arsenical-induced skin injury is demonstrated.