4 research outputs found
Therapy of Organophosphate Poisoning via Intranasal Administration of 2-PAM-Loaded Chitosomes
Chitosan-decorated liposomes were proposed for the first time for the intranasal delivery of acetylcholinesterase (AChE) reactivator pralidoxime chloride (2-PAM) to the brain as a therapy for organophosphorus compounds (OPs) poisoning. Firstly, the chitosome composition based on phospholipids, cholesterol, chitosans (Cs) of different molecular weights, and its arginine derivative was developed and optimized. The use of the polymer modification led to an increase in the encapsulation efficiency toward rhodamine B (RhB; ~85%) and 2-PAM (~60%) by 20% compared to conventional liposomes. The formation of monodispersed and stable nanosized particles with a hydrodynamic diameter of up to 130 nm was shown using dynamic light scattering. The addition of the polymers recharged the liposome surface (from −15 mV to +20 mV), which demonstrates the successful deposition of Cs on the vesicles. In vitro spectrophotometric analysis showed a slow release of substrates (RhB and 2-PAM) from the nanocontainers, while the concentration and Cs type did not significantly affect the chitosome permeability. Flow cytometry and fluorescence microscopy qualitatively and quantitatively demonstrated the penetration of the developed chitosomes into normal Chang liver and M-HeLa cervical cancer cells. At the final stage, the ability of the formulated 2-PAM to reactivate brain AChE was assessed in a model of paraoxon-induced poisoning in an in vivo test. Intranasal administration of 2-PAM-containing chitosomes allows it to reach the degree of enzyme reactivation up to 35 ± 4%
Oxime Therapy for Brain AChE Reactivation and Neuroprotection after Organophosphate Poisoning
One of the main problems in the treatment of poisoning with organophosphorus (OPs) inhibitors of acetylcholinesterase (AChE) is low ability of existing reactivators of AChE that are used as antidotes to cross the blood-brain barrier (BBB). In this work, modified cationic liposomes were developed that can penetrate through the BBB and deliver the reactivator of AChE pralidoxime chloride (2-PAM) into the brain. Liposomes were obtained on the basis of phosphatidylcholine and imidazolium surfactants. To obtain the composition optimized in terms of charge, stability, and toxicity, the molar ratio of surfactant/lipid was varied. For the systems, physicochemical parameters, release profiles of the substrates (rhodamine B, 2-PAM), hemolytic activity and ability to cause hemagglutination were evaluated. Screening of liposome penetration through the BBB, analysis of 2-PAM pharmacokinetics, and in vivo AChE reactivation showed that modified liposomes readily pass into the brain and reactivate brain AChE in rats poisoned with paraoxon (POX) by 25%. For the first time, an assessment was made of the ability of imidazolium liposomes loaded with 2-PAM to reduce the death of neurons in the brains of mice. It was shown that intravenous administration of liposomal 2-PAM can significantly reduce POX-induced neuronal death in the hippocampus
Polyelectrolyte Capsules with Tunable Shell Behavior Fabricated by the Simple Layer-by-Layer Technique for the Control of the Release and Reactivity of Small Guests
A novel simple protocol for the layer-by-layer coating
of uncharged
organic substrates (hydrophobic carboxylic acid esters, CAEs) and
control of their loading/release behavior has been developed. The
approach involves the preliminary treatment of CAEs with the cationic
surfactant cetyltrimethylammonium bromide followed by polyÂ(acrylic
acid)/polyethyleneimine alternate deposition. The basic hydrolysis
of the substrates is used to spectrophotometrically control the loading/release
behavior through monitoring the absorbency of the reaction product <i>p</i>-nitrophenolate ion. Unlike the reactivity of free CAEs,
highly sensitive to the solution pH, and the presence of micellar
catalysts, the reaction rate of the loaded substrates is unaffected
by reaction conditions and can be administered by the capsule design
(numbers of deposition cycles, adjusted pH, ultrasonication). The
developed protocol makes it possible to omit the use of the sacrificial
template and stages of its removal. Capsules corresponding to the
biorelevant size criterion, with diameter of ≤200 nm, are obtained.
They can be successfully applied for sustaining the dosage of different
specimens with the desirable rate and for the control of the guest
reactivity by tuning the shell permeability