Intranasal Chitosan-Coated Obidoxime Nanoliposomes for Soman Gas Neutralization

Background: Organophosphorus nerve agents (OPNAS), including soman (GD), irreversibly inhibit acetylcholinesterase (AChE), leading to cholinergic crisis and death within minutes [۱,۲]. Current intramuscular antidotes (atropine + oximes) face critical limitations: delayed absorption (۵-۱۰ min), poor blood-brain barrier (BBB) penetration (<۶% brain uptake), and needle dependency in mass casualties [۳-۵]. The intranasal route offers direct nose-to-brain delivery via olfactory and trigeminal pathways, bypassing the BBB [۶-۸]. Research Methodology: Obidoxime-loaded nanoliposomes were designed via thin-film hydration (SPC: cholesterol: DSPE-PEG۲۰۰۰ ۶۵:۳۰:۵ molar ratio) followed by probe sonication. Surface modification with chitosan (۰.۵% w/v, ۵۰ kDa, ۸۵% deacetylation) was performed by electrostatic deposition [۹]. Drug release kinetics were characterized using three standard mathematical models: Korsmeyer-Peppas (for mechanism identification), Higuchi (for diffusion-controlled release), and Weibull (for empirical description of release profiles) [۱۰-۱۲]. A novel phenomenological airflow-responsive release model was developed to account for shear effects on release, explicitly derived from drug-delivery principles rather than constitutive mechanics [۱۳]. Cohesive zone modeling (CZM) with bilinear traction-separation law quantified mucoadhesion. CFD simulations (ANSYS Fluent, k-w SST turbulence model) predicted olfactory deposition [۱۴,۱۵]. Findings: Optimized chitosan-coated nanoliposomes exhibited: size ۱۱۸±۱۵ nm (PDI ۰.۲۱), ζ=+۳۲±۴ mV (reversal from -۱۲.۴ mV), EE=۷۸.۵±۴.۸%, σ_max=۱۸.۵±۲.۵ kPa (۳× increase vs. uncoated), G_c=۰.۳۱±۰.۰۵ J/m². Korsmeyer-Peppas analysis yielded exponent n=۰.۲۱۸±۰.۰۲۸ for coated liposomes, confirming Fickian diffusion (n<۰.۴۳) as the dominant release mechanism. Weibull B=۰.۷۶±۰.۰۵ indicated complex release dynamics with initial burst followed by sustained phase. The proposed airflow-responsive model predicted a shear-enhanced release factor of ۲.۲ at elevated shear rates (γ̇=۵۰ s⁻¹) compared to static conditions. Olfactory deposition fraction: ۱۴±۲% (coated) vs. ۵±۱% (free solution); predicted brain uptake enhancement ratio =۲.۷±۰.۳; swallowed fraction: ۵±۱% [۱۶,۱۷]. Conclusion: The chitosan-coated obidoxime nanoliposomal nasal spray represents a promising computationally designed platform for rapid nose-to-brain antidote delivery. The predicted enhancement of release under elevated respiratory airflow remains a theoretical model output and requires dedicated in vitro airflow-controlled release studies and in vivo validation. All brain uptake values reported are model-derived estimates and should not be interpreted as experimentally verified pharmacokinetic outcomes. CFD-derived deposition fractions represent computational predictions under idealized anatomical conditions. Current findings should be considered model-based predictions requiring future experimental validation before clinical translation.

کلیدواژه ها:

Nanoliposome ، intranasal delivery ، obidoxime ، soman ، Korsmeyer-Peppas model ، cohesive zone model ، mucoadhesion ، nose-to-brain ، chemical warfare agents