Preparation Of Brain-targeted Rapamycin Nanoparticles And Its Therapeutic Effect On Neurological Diseases

Objective: Brain targeting rapamycin(T-rapa)were prepared and compared with ordinary formulation of rapamycin in rat models of epilepsy and cerebral ischemia reperfusion injury in terms of efficacy and adverse reactions,so as to optimize the efficacy of rapamycin in the treatment of neurological diseases.Methods: The preparation of rapamycin polybutylcyanoacrylate nanoparticles was optimized by single factor analysis and orthogonal test.Pilocarpine was used to induce epilepsy in rats.And rat model of cerebral ischemia reperfusion injury was established by string method.After the administration of T-rapa and ordinary formulation of rapamycin,the weight of the rats was recorded and the effect of the drug on their growth and development was observed.The differences of protein expression in brain tissues of the two models were analyzed by western blot.Fluoro-Jade B(FJB),Timm's staining and video-EEG were used to observe and monitor the neuronal death,mossy fiber germination and seizure activity in rats after epileptic.The severity of neurological impairment after cerebral ischemia-reperfusion injury was scored,and the volume of cerebral infarction and the level of inflammatory factors in rats were analyzed by TTC staining and ELISA.Results: The average size of RAPA-PBCN prepared by the optimal formulation was 225.4±3.1 nm,the average zeta potential was-20.8±1.31 m V,and the drug loading was 27.01±0.24%.After the above prepared nanoparticles were applied to the treatment of epilepsy in rats,we find that RAPA-PBCN had better effect on the inhibition of the abnormal activation of m TOR signaling pathway,decrease in mossy fiber germination and decrease in the frequency of spontaneous seizures in rats.On the contrary,it had milder effect on the inhibition of weight gain in rats.In the model of cerebral ischemiareperfusion in jury,compared to ordinary formulation of RAPA,the same dose of RAPA-PBCN was more effective in reducing the severity score of neurological impairment,significantly inhibiting the abnormal activation of m TOR signaling pathway in ischemic penumbra tissue,more effective in reducing the infarction volume of brain tissue and the release of IL-6 and TNF-?,and also less effective in inhibiting the immune system of rats.Conclusion: The RAPA-PBCN prepared with the best formula of BCA 30 ?l,Dex 70 100 mg,p H=2 was optimum in particle size and brain targeting,and it also could more effectively cross the blood-brain barrier than ordinary RAPA,thus producing better therapeutic effect and less adverse reactions on rats in the two animal models.It is suggested that RAPA-PBCN can be used as a better dosage form for the treatment of nervous system diseases.