Preparation of co-modified liposomes of α-cobrotoxin and its brain pharmacokinetics study in rats after intranasal administration / 中国药学杂志

ABSTRACT

OBJECTIVE: To investigate the brain pharmacokinetics of co-modified liposomes of α-cobrotoxin in rats after intranasal administration. METHODS: DSPE-PEG2000-Pep1 and DSPE-PEG2000-Pep2 were synthesized by Michael addition reaction. And their structures were verified by proton nuclear magnetic resonance spectroscopy (1H-NMR) and infrared spectroscopy (FTIR). Pep2(Pep1)-αCT-LP was prepared by the method of thin-film hydration and post-inserting, then its morphology, particle size, and Zeta potential were investigated. The encapsulation efficiency of liposomes was determined by ultrafiltration centrifugal method. The concentrations of αCT-LP, Pep1-αCT-LP, Pep2-αCT-LP, and Pep2(Pep1)-αCT-LP in periaqueductal gray (PAG) after intranasal administration were measured by microdialysis and the pharmacokinetical parameters were analyzed by PKSolver software. RESULTS: The structures of DSPE-PEG2000-Pep1 and DSPE-PEG2000-Pep2 were proved by 1H-NMR and FTIR. The prepared Pep2(Pep1)-αCT-LP was nearly spherical with uniform size, the mean particle size was (115.8±1.86) nm, and the Zeta potential was (-13.77±0.75) mV. Besides, the encapsulation efficiency was (32.75±1.12)%. The RESULTS ofin vivo test demonstrated that the αCT concentrations in PAG after intranasal administration of Pep2(Pep1)-αCT-LP were significantly increased compared with the groups of αCT-LP, Pep1-αCT-LP and Pep2-αCT-LP(P<0.05). Theρmax, tmax, and AUC0→∞ were (244.72±3.15) ng·mL-1, (88.01±4.19) min, (89 199.02±1 922.99) ng·min·mL-1, respectively. CONCLUSION: Pep2(Pep1)-αCT-LP can significantly increase the concentrations of αCT in periaqueductal gray, which provides a promising method for development of polypeptide agents for brain-targeting.