| Depression is a kind of affective mental illness that seriously jeopardizes the physical and mental health of human beings.In recent years,it has been found that the incidence of depression gradually increases.Although antidepressant drugs have significant effects in vitro models,99%of small molecules and 100%of macromolecular drugs cannot enter the brain due to the blood brain barrier(BBB).Thus lacking effective targeting drug delivery systems has become a bottleneck in the treatment of depression.In this study,PGP peptide(proline-glycine-proline)with high affinity to neutrophils was modified on the surface of drug-loaded nanoparticles,using neutrophils in pathology.Under the condition,the PGP modified nanoparticle can be highly uptaken by the CXCR2 of neutrophils,and then carries the drug-loaded nanoparticles together during the process of the neutrophil leap across the BBB.Reach the target site to release the drug and achieve targeted delivery of lesions in the brain.This topic is based on the investigation and optimization of the PGP-modified nanoparticle technology even formulation,and then the affinity targeting of cells in vitro and vivo.Targeting mechanisms,in vitro antioxidant activity,antidepressant effects in vivo were systematically evaluated.Firstly,the method of HPLC analysis of baicalein was established.The methodological investigation results showed that baicalein could be completely separated from impurities in this condition.The precision,accuracy and repeatability of RGD were all less than 3%,which met the quantitative and qualitative detection requirements.The nanoparticles containing baicalein were prepared by emulsion ultrasonic method.The encapsulation efficiency and drug loading were used as indicators.The optimized formulation was baicalein:the ratio of stearic acid:lecithin:poloxamer was 2.4:8:1:2.4,the average particle size of baicalein solid lipid nanoparticles prepared according to the optimal formulation was 128.6±8 nm,the encapsulation efficiency was 99.7%,and the drug loading was 29.36%.The prepared baicalein solid lipid nanoparticles have uniform particle size distribution,high encapsulation efficiency and simple process.The in vitro affinity evaluation results showed that the affinity of the nanoparticles to HL-60 was significantly improved by PGP modification,which was 3.6 times higher than that of normal nanoparticles and 15.2 times higher than that of the solution group.The drug-loaded PGP-NP was combined with HL-60.There was no significant degradation of the drug within 2 hours and significantly improved the ability of the drug to cross the BBB model in vitro.Fluorescent labeled PGP-NP was intravenously administered to mice.The results showed that NP surface-modified PGP could increase the binding rate of neutrophils in vivo,which was 7.1 times higher than that of normal nanoparticles.The experimental results of intracerebral distribution in model rats showed that PGP-NP has a obvious brain-targeting effect and can accumulate in lesions in the brain with neutrophils.The drug concentration is 4.6 times higher than that of normal nanoparticles,25.9 times higher than the solution group.Description the neutrophils-mediated brain-targeted drug delivery system has a good brain-targeting effect in model animals.PGP-NP can significantly enhance antioxidant activity of baicalin in vitro model,reduce the mitochondrial damage caused by ferrous sulfate and lactate dehydrogenase release.In vivo pharmacodynamic studies showed that PGP-NP could significantly increase the activity increase the climbing and increase the percentage of sugar water intake in model mice.In summary,the design of PGP-modified nanoparticles can achieve drug delivery to lesion in the brain by combining with neutrophils in vivo,and improve the antidepressant effect of baicalein.It provides a novel ideas and scientific references for targeted treatment of depression. |
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