The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles.
The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles.
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DOI：
10.1016/j.biomaterials.2011.01.021
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发表时间：
2011-05
期刊：
影响因子：
14
通讯作者：
Lam, Kit S.
中科院分区：
文献类型：
--
作者：
Xiao, Kai;Li, Yuanpei;Luo, Juntao;Lee, Joyce S.;Xiao, Wenwu;Gonik, Abby M.;Agarwal, Rinki G.;Lam, Kit S.
为了系统地阐明表面电荷对基于PEG-低聚胆酸的胶束纳米颗粒（NP）的细胞摄取和体内命运的影响，单体PEG-低聚胆酸树枝状聚合物（末端树枝状聚合物）的远端PEG末端各自用不同数量（n = 0、1、3和6）的阴离子天冬氨酸（负电荷）或阳离子赖氨酸（正电荷）衍生化。在水溶液中，这些末端树枝状聚合物自组装形成一系列具有不同表面电荷但具有相似粒径的胶束纳米粒子。在新鲜小鼠血清中调理后，RAW 264.7鼠巨噬细胞更有效地摄取具有高表面电荷（阳性或阴性）的NP。细胞摄取NP的机制研究表明，几种不同的内吞途径（例如，网格蛋白介导的内吞作用、小窝介导的内吞作用和巨胞饮作用）参与细胞摄取过程。在它们的细胞摄取后，发现大多数NP定位于溶酶体中。带正电荷的纳米粒子对RAW 264.7细胞表现出剂量依赖性的溶血活性和细胞毒性，与正表面电荷密度成正比;而带负电荷的纳米粒子没有表现出明显的溶血和细胞毒性。体内生物分布研究表明，对于高度带正电荷或负电荷的NP，不期望的肝脏摄取非常高，这可能是由于肝脏中巨噬细胞（枯否细胞）的主动吞噬作用。相比之下，当纳米粒子的表面电荷为轻微负电荷时，肝脏摄取非常低，但肿瘤摄取非常高。基于这些研究，我们可以得出结论，在纳米颗粒表面引入轻微的负电荷可以减少网状内皮系统（RES）如肝脏的不期望的清除，改善血液相容性，从而将抗癌药物更有效地递送到肿瘤部位。
To systematically elucidate the effect of surface charge on the cellular uptake and in vivo fate of PEG-oligocholic acid based micellar nanoparticles (NPs), the distal PEG termini of monomeric PEG-oligocholic acid dendrimers (telodendrimers) are each derivatized with different number (n = 0, 1, 3 and 6) of anionic aspartic acids (negative charge) or cationic lysines (positive charge). Under aqueous condition, these telodendrimers self-assemble to form a series of micellar NPs with various surface charges, but with similar particle sizes. NPs with high surface charge, either positive or negative, were taken up more efficiently by RAW 264.7 murine macrophages after opsonization in fresh mouse serum. Mechanistic studies of cellular uptake of NPs indicated that several distinct endocytic pathways (e.g., clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis) were involved in the cellular uptake process. After their cellular uptake, the majority of NPs were found to localize in the lysosome. Positively charged NPs exhibited dose-dependent hemolytic activities and cytotoxicities against RAW 264.7 cells proportional to the positive surface charge densities; whereas negatively charged NPs did not show obvious hemolytic and cytotoxic properties. In vivo biodistribution studies demonstrated that undesirable liver uptake was very high for highly positively or negatively charged NPs, which is likely due to active phagocytosis by macrophages (Kupffer cells) in the liver. In contrast, liver uptake was very low but tumor uptake was very high when the surface charge of NPs was slightly negative. Based on these studies, we can conclude that slightly negative charge may be introduced to the NPs surface to reduce the undesirable clearance by the reticuloendothelial system (RES) such as liver, improve the blood compatibility, thus deliver the anti-cancer drugs more efficiently to the tumor sites.
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影响因子：
4.9
作者：
Alexis F;Pridgen E;Molnar LK;Farokhzad OC
通讯作者：
Farokhzad OC
影响因子：
10.8
作者：
Nam, Hae Yun;Kwon, Seok Min;Jeong, Seo Young
通讯作者：
Jeong, Seo Young
影响因子：
14
作者：
Thorek, Daniel L. J.;Tsourkas, Andrew
通讯作者：
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影响因子：
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作者：
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通讯作者：
Kataoka, K
DOI：
10.1016/j.jconrel.2010.02.027
发表时间：
2010-06-15
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Li Y;Xiao K;Luo J;Lee J;Pan S;Lam KS
通讯作者：
Lam KS