Diagaradjane Parmeswaran, Orenstein-Cardona Jacobo M, Colón-Casasnovas Norman E, Deorukhkar Amit, Shentu Shujun, Kuno Norihito, Schwartz David L, Gelovani Juri G, Krishnan Sunil
Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2008 Feb 1;14(3):731-41. doi: 10.1158/1078-0432.CCR-07-1958.
To develop and validate an optical imaging nanoprobe for the discrimination of epidermal growth factor (EGF) receptor (EGFR)-overexpressing tumors from surrounding normal tissues that also expresses EGFR.
Near-infrared (NIR) quantum dots (QD) were coupled to EGF using thiol-maleimide conjugation to create EGF-QD nanoprobes. In vitro binding affinity of these nanoprobes and unconjugated QDs was evaluated in a panel of cell lines, with and without anti-EGFR antibody pretreatment. Serial optical imaging of HCT116 xenograft tumors was done after systemic injection of QD and EGF-QD.
EGF-QD showed EGFR-specific binding in vitro. In vivo imaging showed three distinct phases, tumor influx ( approximately 3 min), clearance ( approximately 60 min), and accumulation (1-6 h), of EGF-QD nanoprobes. Both QD and EGF-QD showed comparable nonspecific rapid tumor influx and clearance followed by attainment of an apparent dynamic equilibrium at approximately 60 min. Subsequently (1-6 h), whereas QD concentration gradually decreased in tumors, EGF-QDs progressively accumulated in tumors. On delayed imaging at 24 h, tumor fluorescence decreased to near-baseline levels for both QD and EGF-QD. Ex vivo whole-organ fluorescence, tissue homogenate fluorescence, and confocal microscopic analyses confirmed tumor-specific accumulation of EGF-QD at 4 h. Immunofluorescence images showed diffuse colocalization of EGF-QD fluorescence within EGFR-expressing tumor parenchyma compared with patchy perivascular sequestration of QD.
These results represent the first pharmacokinetic characterization of a robust EGFR imaging nanoprobe. The measurable contrast enhancement of tumors 4 h after systemic administration of EGF-QD and its subsequent normalization at 24 h imply that this nanoprobe may permit quantifiable and repetitive imaging of EGFR expression.
开发并验证一种光学成像纳米探针，用于区分表皮生长因子（EGF）受体（EGFR）过表达的肿瘤与周围同样表达EGFR的正常组织。
使用硫醇-马来酰亚胺共轭将近红外（NIR）量子点（QD）与EGF偶联，以制备EGF-QD纳米探针。在一组细胞系中，对这些纳米探针和未偶联的QD在有无抗EGFR抗体预处理的情况下进行体外结合亲和力评估。在全身注射QD和EGF-QD后，对HCT116异种移植瘤进行连续光学成像。
EGF-QD在体外显示出EGFR特异性结合。体内成像显示EGF-QD纳米探针有三个不同阶段，即肿瘤摄取（约3分钟）、清除（约60分钟）和蓄积（1 - 6小时）。QD和EGF-QD均显示出相似的非特异性快速肿瘤摄取和清除，随后在约60分钟达到明显的动态平衡。随后（1 - 6小时），虽然QD在肿瘤中的浓度逐渐降低，但EGF-QD在肿瘤中逐渐蓄积。在24小时延迟成像时，QD和EGF-QD的肿瘤荧光均降至接近基线水平。离体全器官荧光、组织匀浆荧光和共聚焦显微镜分析证实4小时时EGF-QD在肿瘤中特异性蓄积。免疫荧光图像显示，与QD在血管周围的散在滞留相比，EGF-QD荧光在表达EGFR的肿瘤实质内呈弥漫性共定位。
这些结果代表了一种强大的EGFR成像纳米探针的首次药代动力学特征。全身给药EGF-QD后4小时肿瘤可测量的对比度增强及其随后在24小时恢复正常，这意味着该纳米探针可能允许对EGFR表达进行可量化和重复性成像。
Zotero 插件