Low molecular weight protamine-functionalized nanoparticles for drug delivery to the brain after intranasal administration
Low molecular weight protamine-functionalized nanoparticles for drug delivery to the brain after intranasal administration
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低分子量鱼精蛋白功能化纳米颗粒，用于鼻内给药后将药物输送至大脑
DOI：
10.1016/j.biomaterials.2011.09.004
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发表时间：
2011-12-01
期刊：
影响因子：
14
通讯作者：
Chen, Hongzhuan
中科院分区：
文献类型：
--
作者：
Xia, Huimin;Gao, Xiaoling;Chen, Hongzhuan
开发新的策略来加强药物对大脑的输送在中枢神经疾病的诊断和治疗中具有重要意义。低分子鱼精蛋白(LMWP)作为一种细胞穿透性多肽，具有细胞转移率高、多肽本身无毒性、作为药物载体的可行性等显著优点。因此，假设与LMWP偶联的纳米粒在鼻腔给药后应能有效地增强脑内给药。通过马来酰亚胺介导的共价键合过程，将LMWP功能化到聚乙二醇聚乳酸纳米粒(NP)表面。测定了LMWP的粒径分布、Zeta电位和表面含量等重要参数，证实了LMWP与纳米粒子表面的偶联。以16HBE140-细胞为细胞模型，发现LMWP-NP通过脂筏介导的内吞和直接转位过程比未修饰的NP具有显著的细胞蓄积作用，而不会引起明显的细胞毒性作用。鼻腔注射香豆素-6的LMWP-NP后，荧光探针在大鼠大脑、小脑、嗅束和嗅球的AUC(0-8h)分别是香豆素的2.03倍、2.55倍、2.68倍和2.82倍。脑分布分析表明，鼻腔给药后，LMWP-NP可沿嗅神经和三叉神经通路进入中枢神经系统。研究结果清楚地表明，LMWP可以极大地促进纳米粒的脑内给药，在潜在的诊断和治疗应用中，LMWP功能化的纳米粒似乎是一种有效和安全的鼻脑给药载体。(C)2011爱思唯尔有限公司。保留所有权利。
The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. Low-molecular-weight protamine (LMWP) as a cell-penetrating peptide possesses distinct advantages including high cell translocation potency, absence of toxicity of peptide itself, and the feasibility as an efficient carrier for delivering therapeutics. Therefore, it was hypothesized that brain delivery of nanoparticles conjugated with LMWP should be efficiently enhanced following intranasal administration. LMWP was functionalized to the surface of PEG-PLA nanoparticles (NP) via a maleimide-mediated covalent binding procedure. Important parameters such as particle size distribution, zeta potential and surface content were determined, which confirmed the conjugation of LMWP to the surface of nanoparticle. Using 16HBE14o- cells as the cell model, LMWP-NP was found to exhibit significantly enhanced cellular accumulation than that of unmodified NP via both lipid raft-mediated endocytosis and direct translocation processes without causing observable cytotoxic effects. Following intranasal administration of coumarin-6-loaded LMWP-NP, the AUC(0-8 h) of the fluorescent probe detected in the rat cerebrum, cerebellum, olfactory tract and olfactory bulb was found to be 2.03, 2.55, 2.68 and 2.82 folds, respectively, compared to that of coumarin carried by NP. Brain distribution analysis suggested LMWP-NP after intranasal administration could be delivered to the central nervous system along both the olfactory and trigeminal nerves pathways. The findings clearly indicated that the brain delivery of nanoparticles could be greatly facilitated by LMWP and the LMWP-functionalized nanoparticles appears as a effective and safe carrier for nose-to-brain drug delivery in potential diagnostic and therapeutic applications. (C) 2011 Elsevier Ltd. All rights reserved.