Abstract
PURPOSE: In this study, cell membrane-coated nanoparticles (CMCNPs) were loaded with the organophosphorus antidote Pralidoxime Chloride (PAM) to improve the ability of the drug to penetrate the blood‒brain barrier (BBB) and evade immune clearance, providing a novel drug delivery strategy for the treatment of central organophosphorus poisoning. METHODS: 1) The cell membranes of mouse melanoma cells (B16F10), breast cancer cells (4T1), glioblastoma cells (GL261), and monocytic macrophage leukemia cells (RAW264.7) were extracted, and their purities were verified. The cell membranes were combined with PAM in mesoporous silica (SiO(2)) spheres by ultrasonic fusion to prepare the CMCNPs. 2) The immune evasion ability of CMCNPs was evaluated by laser confocal microscopy and flow cytometry after coculture with macrophages. 3) HPLC was used to screen the best CMCNPs through an in vitro BBB model. 4) After the CMCNPs were injected into malathion-poisoned mice, the phosphate chloride concentration in the peripheral blood and brain homogenates was tested, and the rate of acetylcholinesterase (AChE) reactivation was determined. RESULTS: All four types of CMCNPs were spherical particles with diameters of approximately 100 nm. Compared with unwrapped nanoparticles, CMCNPs exhibited a stronger immune evasion ability and enhanced BBB penetration ability in an in vitro BBB model. They also significantly prolonged the in vivo circulation time of PAM, increased its delivery dose to the central nervous system, and markedly increased cholinesterase activity in brain tissues. Furthermore, in an organophosphorus-poisoned mouse model, CMCNPs significantly improved the survival rate of intoxicated mice. CONCLUSION: In this study, CMCNPs with a significant BBB penetration ability and immune evasion ability were successfully prepared and improved the therapeutic effect of PAM on central organophosphate poisoning.