Intracellular delivery mechanism and brain delivery kinetics of biodegradable cationic bovine serum albumin-conjugated polymersomes.
Intracellular delivery mechanism and brain delivery kinetics of biodegradable cationic bovine serum albumin-conjugated polymersomes.
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可生物降解的阳离子牛血清白蛋白缀合聚合物囊泡的细胞内递送机制和脑递送动力学
DOI：
10.2147/ijn.s32514
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发表时间：
2012
影响因子：
8
通讯作者：
Mei H
中科院分区：
文献类型：
--
作者：
Pang Z;Gao H;Chen J;Shen S;Zhang B;Ren J;Guo L;Qian Y;Jiang X;Mei H
背景：制备了阳离子牛血清白蛋白(CBSA)偶联生物可降解多聚体(CBSA-PO)脑内给药系统，并对其细胞内给药机制和脑内给药动力学进行了研究。方法与结果用可生物降解的聚乙二醇聚己内酯(ɛ-PCL)制备聚合体，将硫代化的CBSA偶联到聚合体的表面。透射电子显微镜和动态光散射表明，CBSA-PO呈圆形、囊泡状，平均粒径约为100 nm。X-射线光电子能谱证实了CBSA与聚合体的偶联。BEnd.3细胞对CBSA-PO的摄取显著高于未结合聚合体，但可被低温、游离CBSA和多聚L赖氨酸抑制，表明内吞作用是能量驱动和吸收介导的。细胞活性检测证实了可生物降解的CBSA-PO具有良好的安全性。药代动力学结果表明，聚合体具有较长的循环时间，将CBSA偶联到聚合体上可使血脑屏障通透性表面积乘积增加3.6倍，每克脑内注射剂量百分比(%ID/g脑)增加2.1倍。毛细管耗竭实验表明，CBSA-PO以时间依赖的方式分布在脑实质内，几乎没有检测到聚合体，说明多聚体与CBSA的偶联显著改善了其跨脑血屏障的能力。结论CBSA-PO是一种很有前途的低毒药物脑内给药载体。
Background A novel brain drug delivery system using cationic bovine serum albumin (CBSA)-conjugated biodegradable polymersomes (CBSA-PO) was prepared, and its intracellular delivery mechanism and brain delivery kinetics were evaluated. Methods and results Biodegradable poly(ethylene glycol)-poly(ɛ-caprolactone) (PEG-PCL) was used to prepare the polymersomes, and thiolated CBSA was conjugated with the surface of the polymersome. Transmission electron microscopy and dynamic light scattering showed that the CBSA-PO had a round and vesicle-like shape, with a mean diameter of around 100 nm. Coupling of CBSA with polymersomes was confirmed by X-ray photoelectron spectroscopy. Uptake of CBSA-PO by bEnd.3 cells was significantly higher than that of unconjugated polymersomes, but was inhibited by low temperature, free CBSA, and poly-L-lysine, indicating that endocytosis was energy-driven and absorptive-mediated. Cell viability assays confirmed the good safety profile of biodegradable CBSA-PO. Pharmacokinetic results demonstrated that the polymersomes had long circulation times, and CBSA conjugation on the polymersomes significantly increased the blood–brain barrier permeability surface area product by 3.6-fold and the percentage of injected dose per gram brain (% ID/g brain) by 2.1-fold. Capillary depletion experiments showed that CBSA-PO was distributed into the brain parenchyma in a time-dependent manner, with few polymersomes detected, indicating that conjugation of polymersomes with CBSA significantly improved their transcytosis across the brain–blood barrier. Conclusion These results suggest that CBSA-PO is a promising drug brain delivery carrier with low toxicity.