Cationic albumin-conjugated pegylated nanoparticles as novel drug carrier for brain delivery
Cationic albumin-conjugated pegylated nanoparticles as novel drug carrier for brain delivery
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DOI：
10.1016/j.jconrel.2005.03.027
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发表时间：
2005-10-20
影响因子：
10.8
通讯作者：
Fu, SK
中科院分区：
文献类型：
--
作者：
Lu, W;Zhang, Y;Fu, SK
本文开发了一种新型脑内给药载体--阳离子牛血清白蛋白（CBSA）偶联聚乙二醇-聚丙交酯（PEG-PLA）纳米颗粒（CBSA-NP），并评价了其作用。分别以甲氧基聚乙二醇（PEG）和马来酰亚胺聚乙二醇（MAE imide-PEG）为引发剂，以丙交酯（D，L-丙交酯）为单体，通过开环聚合反应合成了甲氧基聚乙二醇-聚乳酸（MAE imide-PEG-PLA）共聚物，并采用复乳-溶剂挥发法制备了聚乙二醇纳米粒。将天然牛血清白蛋白（BSA）阳离子化和硫醇化，然后通过位于纳米颗粒表面周围的PEG远端的马来酰亚胺官能团进行缀合。透射电子显微镜（TEM）和动态光散射结果表明CBSA-NP具有圆形和规则的形状，平均直径约为100 nm。通过X射线光电子能谱（XPS）检测到纳米粒子表面的氮，透射电镜（TEM）观察到纳米粒子表面的胶体金染色，证明CBSA共价结合在纳米粒子表面。为了评价脑内给药的效果，以BSA结合聚乙二醇化纳米粒（BSA-NP）作为对照组，并将6-香豆素掺入纳米粒中作为荧光探针。CBSA-NP与BSA-NP摄取实验的定性和定量结果表明，在37 ℃、不同浓度和孵育时间下，大鼠脑毛细血管内皮细胞（BCECs）摄取的CBSA-NP明显多于BSA-NP。小鼠尾静脉注射60 mg/kg CBSA-NP或BSA-NP后，脑冠状切片荧光显微镜显示CBSA-NP在侧脑室、第三脑室和室周区的蓄积量高于BSA-NP。在CBSA缀合的和未缀合的聚乙二醇化纳米颗粒之间，BCEC的活力没有差异。体内外实验结果表明，CBSA-NP是一种有前途的脑内给药载体，且毒性低。(c)2005 Elsevier B. V.保留所有权利。
In this paper, a novel drug carrier for brain delivery, cationic bovine serum albumin (CBSA) conjugated with poly(ethyleneglycol)-poly(lactide) (PEG-PLA) nanoparticle (CBSA-NP), was developed and its effects were evaluated. The copolymers of methoxy-PEG-PLA and maleimide-PEG-PLA were synthesized by ring opening polymerization of D,L-lactide initiated by methoxy-PEG and maleimide-PEG, respectively, which were applied to prepare pegylated nanoparticles by means of double emulsion and solvent evaporation procedure. Native bovine serum albumin (BSA) was cationized and thiolated, followed by conjugation through the maleimide function located at the distal end of PEG surrounding the nanoparticle's surface. Transmission electron micrograph (TEM) and dynamic light scattering results showed that CBSA-NP had a round and regular shape with a mean diameter around 100 nm. Surface nitrogen was detected by X-ray photoelectron spectroscopy (XPS), and colloidal gold stained around the nanoparticle's surface was visualized in TEM, which proved that CBSA was covalently conjugated onto its surface. To evaluate the effects of brain delivery, BSA conjugated with pegylated nanoparticles (BSA-NP) was used as the control group and 6-coumarin was incorporated into the nanoparticles as the fluorescent probe. The qualitative and quantitative results of CBSA-NP uptake experiment compared with those of BSA-NP showed that rat brain capillary endothelial cells (BCECs) took in much more CBSA-NP than BSA-NP at 37 degrees C, at different concentrations and time incubations. After a dose of 60 mg/kg CBSA-NP or BSA-NP injection in mice caudal vein, fluorescent microscopy of brain coronal sections showed a higher accumulation of CBSA-NP in the lateral ventricle, third ventricle and periventricular region than that of BSA-NP. There was no difference on BCECs' viability between CBSA-conjugated and -unconjugated pegylated nanoparticles. The significant results in vitro and in vivo showed that CBSA-NP was a promising brain drug delivery carrier with low toxicity. (c) 2005 Elsevier B.V. All rights reserved.