2 research outputs found
Surface modification of pralidoxime chloride-loaded solid lipid nanoparticles for enhanced brain reactivation of organophosphorus-inhibited AChE: pharmacokinetics in rat
The nanotechnological approach is an innovative strategy of high potential to achieve reactivation of organophosphorus-inhibited acetylcholinesterase in central nervous system. It was previously shown that pralidoxime chloride-loaded solid lipid nanoparticles (2-PAM-SLNs) are able to protect the brain against pesticide (paraoxon) central toxicity. In the present work, we increased brain AChE reactivation efficacy by PEGylation of 2-PAM-SLNs using PEG-lipid N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt) (DSPE-PEG2000) as a surface-modifier of SLNs. To perform pharmacokinetic study, a simple, sensitive (LLOQ 1.0ng/ml) high-performance liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization by multiple reaction monitoring mode (HPLC-APCI-MS) was developed. The method was compared to mass spectrometry with electrospray ionization. The method was validated for linearity, accuracy, precision, extraction recovery, matrix effect and stability. Acetophenone oxime was used as the internal standard for the quantification of 2-PAM in rat plasma and brain tissue after intravenous administration. 2-PAM-DSPE-PEG2000-SLNs of mean size about 80nm (PDI=0.26), zeta-potential of 55mV and of high in vitro stability, prolonged the elimination phase of 2-PAM from the bloodstream more than 3 times compared to free 2-PAM. An increase in reactivation of POX-inhibited human brain acetylcholinesterase up to 36.08±4.3% after intravenous administration of 2-PAM-DSPE-PEG2000-SLNs (dose of 2-PAM is 5mg/kg) was achieved. The result is one of the first examples where this level of brain acetylcholinesterase reactivation was achieved. Thus, the implementation of different approaches for targeting and modifying nanoparticles surface gives hope for improving the antidotal treatment of organophosphorus poisoning by marketed reactivators.This research (the HPLC-MS part of this work) was carried out using
facilities of the CSF-SAC FRC KSC RAS was financial support from the
government assignment for FRC Kazan Scientific Center of Russian
Academy of Sciences to D.N.B., I.Kh.R, V.M.B. This work (the part
preparation, characterization, and stability, release analysis, reactivation
of brain AChE in vivo of 2-PAM-DSPE-PEG2000-SLNs) was supported
by Russian Science Foundation (project Nâ—¦ 19-73-30012) to T.N.
P., E.A.B., I.V.Z., K.A.P. The authors are indebted to Prof. L.Ya.
Zakharova who initiated this work. They express to her their thanks for
her interest and constant support. The authors are indebted to Prof.
Patrick Masson (KFU, Kazan) for his critical reading and editing of the
manuscript. The authors are grateful to Dr. Sofya V. Lushchekina
(Emanuel Institute RAS, Moscow) for her assistanceinfo:eu-repo/semantics/publishedVersio