Different Insight into Amphiphilic PEG-PLA Copolymers: Influence of Macromolecular Architecture on the Micelle Formation and Cellular Uptake
Different Insight into Amphiphilic PEG-PLA Copolymers: Influence of Macromolecular Architecture on the Micelle Formation and Cellular Uptake
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DOI：
10.1021/bm401812r
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发表时间：
2014-01-01
影响因子：
6.2
通讯作者：
Pappalardo, Daniela
中科院分区：
文献类型：
--
作者：
Garofalo, Cinzia;Capuano, Giovanna;Pappalardo, Daniela
胶束载体作为药物释放系统(DDSS)的一个限制因素是其在水溶液中的低稳定性。本研究合成了通式为mpeg-(Pla)(N)(n=1、2或4；mpeg=聚乙二醇单甲醚2K或5K Da；pla=无规或全规聚丙交酯)的树状共聚物，考察了结构和化学组成对胶束形成和稳定性的影响。采用“核优先”的合成路线，得到了质量比约为1：1wt/wt的共聚物。动态光散射(DLS)、场发射扫描电子显微镜(FESEM)和Zeta电位测量表明，mEg(2K)-(Pd，LLA)(2)共聚物具有2000 Da的mpeg链和两个无规聚乳酸嵌段，能够形成单分散的稳定胶束。为了分析胶束与肿瘤细胞之间的相互作用，合成了FITC偶联的mpeg-(Pla)(N)。在两种不同的肿瘤细胞系：HEK293t和HeLa细胞上测试了衍生胶束。荧光激活细胞分类器(FACS)分析表明，FITC标记的mEg(2K)-(Pd，LLA)(2)共聚物对肿瘤细胞具有高效的染色效果。结果表明，聚乙二醇的大小和聚乳酸的结构都控制着胶束与生物体系之间的生物相互作用。此外，共聚焦显微镜分析显示，与mpeg(2K)-(pd，lla)(2)孵育后的肿瘤细胞染色定位于肿瘤细胞内。事实上，mpeg(2K)-(pd，lla)(2)紫杉醇胶束具有很强的抗肿瘤细胞毒作用。
One constrain in the use of micellar carriers as drug delivery systems (DDSs) is their low stability in aqueous solution. In this study "tree-shaped" copolymers of general formula mPEG-(PLA)(n) (n = 1, 2 or 4; mPEG = poly(ethylene glycol) monomethylether 2K or 5K Da; PLA = atactic or isotactic poly(lactide)) were synthesized to evaluate the architecture and chemical composition effect on the micelles formation and stability. Copolymers with mPEG/PLA ratio of about 1:1 wt/wt were obtained using a "core-first" synthetic route. Dynamic Light Scattering (DLS), Field Emission Scanning Electron Microscopy (FESEM), and Zeta Potential measurements showed that mPEG(2K)-(PD,LLA)(2) copolymer, characterized by mPEG chain of 2000 Da and two blocks of atactic PLA, was able to form monodisperse and stable micelles. To analyze the interaction among micelles and tumor cells, FITC conjugated mPEG-(PLA)(n) were synthesized. The derived micelles were tested on two, histological different, tumor cell lines: HEK293t and HeLa cells. Fluorescence Activated Cells Sorter (FACS) analysis showed that the FITC conjugated mPEG(2K)-(PD,LLA)(2) copolymer stain tumor cells with high efficiency. Our data demonstrate that both PEG size and PLA structure control the biological interaction between the micelles and biological systems. Moreover, using confocal microscopy analysis, the staining of tumor cells obtained after incubation with mPEG(2K)-(PD,LLA)(2) was shown to be localized inside the tumor cells. Indeed, the mPEG(2K)-(PD,LLA)(2) paclitaxel-loaded micelles mediate a potent antitumor cytotoxicity effect.