Evaluation of Polymeric Nanomedicines Targeted to PSMA: Effect of Ligand on Targeting Efficiency
Evaluation of Polymeric Nanomedicines Targeted to PSMA: Effect of Ligand on Targeting Efficiency
复制标题
DOI：
10.1021/acs.biomac.5b00913
复制
发表时间：
2015-10-01
影响因子：
6.2
通讯作者：
Thurecht, Kristofer J.
中科院分区：
文献类型：
--
作者：
Fuchs, Adrian V.;Tse, Brian W. C.;Thurecht, Kristofer J.
靶向纳米药物提供了一种极大地增强治疗药物在动物特定组织中积累的策略。在这项研究中，我们报道了一些不同的配体对前列腺特异性膜抗原(PSMA)的相对靶向效率，这些配体通过相同的化学物质共价连接到一个聚合物纳米载体上。靶向配体包括一个小分子(谷氨酸尿素)、一个多肽配体和一个单抗(J591)。使用超支化聚合物(HBP)作为纳米载体，并包含一个用于跟踪/分析的荧光团，而悬挂的官能链末端提供了一个手柄来连接配体。用流式细胞仪和共聚焦显微镜检测各配体的体外靶向效率，比较不同PSMA表达状态(PC3-PIP(PSMA+)和PC3-Flu(PSMA-))的PC3-PIP(PSMA+)和PC3-Flu(PSMA-)对HBPs的结合和内化程度。将HBP-多肽结合物静脉注射BALB/c裸鼠皮下PC3-PIP和PC3-Flu-Pca瘤体内，并用荧光成像进行评价。与PC3-Flu相比，PC3-PIP在肿瘤组织中的蓄积增强突出了该系统作为未来成像和治疗载体的适用性。
Targeted nanomedicines offer a strategy for greatly enhancing accumulation of a therapeutic within a specific tissue in animals. In this study, we report on the comparative targeting efficiency toward prostate-specific membrane antigen (PSMA) of a number of different ligands that are covalently attached by the same chemistry to a polymeric nanocarrier. The targeting ligands included a small molecule (glutamate urea), a peptide ligand, and a monoclonal antibody (J591). A hyperbranched polymer (HBP) was utilized as the nanocarrier and contained a fluorophore for tracking/analysis, whereas the pendant functional chain-ends provided a handle for ligand conjugation. Targeting efficiency of each ligand was assessed in vitro using flow cytometry and confocal microscopy to compare degree of binding and internalization of the HBPs by human prostate cancer (PCa) cell lines with different PSMA expression status (PC3-PIP (PSMA+) and PC3-FLU (PSMA-). The peptide ligand was further investigated in vivo, in which BALB/c nude mice bearing subcutaneous PC3-PIP and PC3-FLU PCa tumors were injected intravenously with the HBP-peptide conjugate and assessed by fluorescence imaging. Enhanced accumulation in the tumor tissue of PC3-PIP compared to PC3-FLU highlighted the applicability of this system as a future imaging and therapeutic delivery vehicle.