Penetratin-functionalized PEG-PLA nanoparticles for brain drug delivery
Penetratin-functionalized PEG-PLA nanoparticles for brain drug delivery
复制标题
用于脑药物输送的渗透素功能化 PEG-PLA 纳米颗粒
DOI：
10.1016/j.ijpharm.2012.07.029
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发表时间：
2012-10-15
影响因子：
5.8
通讯作者：
Chen, Hongzhuan
中科院分区：
文献类型：
--
作者：
Xia, Huimin;Gao, Xiaoling;Chen, Hongzhuan
纳米颗粒药物递送系统在脑部药物递送方面具有独特的优势。然而，它到达大脑的数量仍然不满意。细胞穿透肽（CPP）是一种促进细胞摄取各种分子货物的短肽，将是促进纳米颗粒大脑递送的合适候选者。然而，由于 CPP 功能化纳米颗粒的表面正电荷，这种效应可能会被快速系统清除所抵消。 Penetratin（碱性氨基酸含量相对较低的 CPP）在此被功能化为聚（乙二醇）-聚（乳酸）纳米颗粒（NP），以实现脑药物输送所需的药代动力学和生物分布曲线。获得的penetratin-NP的粒径为100 nm，zeta电位为-4.42 mV。通过X射线光电子能谱的表面化学成分分析证实了渗透蛋白的表面共轭。在 MDCK-MDR 细胞模型中，penetratin-NP 通过脂筏介导的内吞作用和高尔基体、溶酶体和微管参与的直接易位过程呈现增强的细胞积累。体内药代动力学和生物分布研究表明，与低分子量鱼精蛋白（精氨酸含量高的 CPP）功能化纳米颗粒相比，Penetratin-NP 表现出显着增强的脑摄取和减少在非靶组织中的积累。这些数据强烈暗示穿透蛋白-NP 可能代表一种有前途的脑靶向药物递送系统。研究结果还为通过表面电荷调节优化脑药物输送系统提供了重要基础。 (c) 2012 Elsevier B.V. 保留所有权利。
Nanoparticulate drug delivery system possesses distinct advantages for brain drug delivery. However, its amount that reach the brain is still not satisfied. Cell-penetrating peptides (CPPs), short peptides that facilitate cellular uptake of various molecular cargo, would be appropriate candidates for facilitating brain delivery of nanoparticles. However, such effect could be deprived by the rapid systemic clearance of CPPs-functionalized nanoparticles due to their positive surface charge. Penetratin (CPP with relatively low content of basic amino acids) was here functionalized to poly(ethylene glycol)-poly(lactic acid) nanoparticles (NP) to achieve desirable pharmacokinetic and biodistribution profiles for brain drug delivery. The obtained penetratin-NP showed a particle size of 100 nm and zeta potential of -4.42 mV. The surface conjugation of penetratin was confirmed by surface chemical compositions analysis via X-ray photo electron spectroscopy. In MDCK-MDR cell model, penetratin-NP presented enhanced cellular accumulation via both lipid raft-mediated endocytosis and direct translocation processes with the involvement of Golgi apparatus, lysosome and microtubules. In vivo pharmacokinetic and biodistribution studies showed that penetratin-NP exhibited a significantly enhanced brain uptake and reduced accumulation in the non-target tissues compared with low-molecular-weight protamine (CPP with high arginine content)-functionalized nanoparticles. These data strongly implicated that penetratin-NP might represent a promising brain-targeting drug delivery system. The findings also provided an important basis for the optimization of brain drug delivery systems via surface charge modulation. (c) 2012 Elsevier B.V. All rights reserved.