Tang Rui, Xue Jianpeng, Xu Baogang, Shen Duanwen, Sudlow Gail P, Achilefu Samuel
Department of Radiology, Washington University in St. Louis, School of Medicine , St. Louis, Missouri 63110, United States.
ACS Nano. 2015 Jan 27;9(1):220-30. doi: 10.1021/nn5071183. Epub 2015 Jan 7.
The large size of many near-infrared (NIR) fluorescent nanoparticles prevents rapid extravasation from blood vessels and subsequent diffusion to tumors. This confines in vivo uptake to the peritumoral space and results in high liver retention. In this study, we developed a viscosity modulated approach to synthesize ultrasmall silver sulfide quantum dots (QDs) with distinct tunable light emission from 500 to 1200 nm and a QD core diameter between 1.5 and 9 nm. Conjugation of a tumor-avid cyclic pentapeptide (Arg-Gly-Asp-DPhe-Lys) resulted in monodisperse, water-soluble QDs (hydrodynamic diameter < 10 nm) without loss of the peptide's high binding affinity to tumor-associated integrins (KI = 1.8 nM/peptide). Fluorescence and electron microscopy showed that selective integrin-mediated internalization was observed only in cancer cells treated with the peptide-labeled QDs, demonstrating that the unlabeled hydrophilic nanoparticles exhibit characteristics of negatively charged fluorescent dye molecules, which typically do not internalize in cells. The biodistribution profiles of intravenously administered QDs in different mouse models of cancer reveal an exceptionally high tumor-to-liver uptake ratio, suggesting that the small sized QDs evaded conventional opsonization and subsequent high uptake in the liver and spleen. The seamless tunability of the QDs over a wide spectral range with only a small increase in size, as well as the ease of labeling the bright and noncytotoxic QDs with biomolecules, provides a platform for multiplexing information, tracking the trafficking of single molecules in cells, and selectively targeting disease biomarkers in living organisms without premature QD opsonization in circulating blood.
许多近红外（NIR）荧光纳米颗粒尺寸较大，难以迅速从血管渗出并扩散至肿瘤。这使得其在体内的摄取局限于肿瘤周围间隙，并导致肝脏高滞留率。在本研究中，我们开发了一种粘度调制方法来合成超小硫化银量子点（QDs），其发射光在500至1200 nm范围内具有明显的可调性，量子点核心直径在1.5至9 nm之间。与肿瘤亲和性环状五肽（精氨酸 - 甘氨酸 - 天冬氨酸 - 二苯丙氨酸 - 赖氨酸）共轭后，得到了单分散、水溶性量子点（流体动力学直径<10 nm），且该肽对肿瘤相关整合素的高结合亲和力未丧失（解离常数KI = 1.8 nM/肽）。荧光和电子显微镜显示，仅在用肽标记的量子点处理的癌细胞中观察到了选择性整合素介导的内化作用，这表明未标记的亲水性纳米颗粒表现出带负电荷荧光染料分子的特性，通常不会在细胞内内化。在不同癌症小鼠模型中静脉注射量子点后的生物分布情况显示，肿瘤与肝脏的摄取率之比极高，这表明小尺寸量子点避免了传统的调理作用以及随后在肝脏和脾脏中的高摄取。量子点在宽光谱范围内具有无缝可调性，尺寸仅略有增加，并且易于用生物分子标记明亮且无细胞毒性的量子点，这为信息复用、追踪细胞中单个分子的运输以及在活生物体中选择性靶向疾病生物标志物提供了一个平台，同时避免了循环血液中量子点过早的调理作用。
