Schmieder Anne H, Winter Patrick M, Caruthers Shelton D, Harris Thomas D, Williams Todd A, Allen John S, Lacy Elizabeth K, Zhang Huiying, Scott Michael J, Hu Grace, Robertson J David, Wickline Samuel A, Lanza Gregory M
Department of Biomedical Engineering, Washington University, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Magn Reson Med. 2005 Mar;53(3):621-7. doi: 10.1002/mrm.20391.
Neovascularization is a critical component in the progression of malignant melanoma. The objective of this study was to determine whether alpha(nu)beta(3)-targeted paramagnetic nanoparticles can detect and characterize sparse alpha(nu)beta integrin expression on neovasculature induced by nascent melanoma xenografts ( approximately 30 mm(3)) at 1.5T. Athymic nude mice bearing human melanoma tumors were intravenously injected with alpha(v)beta(3)-integrin-targeted paramagnetic nanoparticles, nontargeted paramagnetic nanoparticles, or alpha(v)beta(3)-targeted-nonparamagnetic nanoparticles 2 hr before they were injected with alpha(v)beta(3)-integrin-targeted paramagnetic nanoparticles (i.e., in vivo competitive blockade) and imaged with MRI. Contrast enhancement of neovascularity in animals that received alpha(nu)beta(3)-targeted paramagnetic nanoparticles increased 173% by 120 min. Signal contrast with nontargeted paramagnetic nanoparticles was approximately 50% less than that in the targeted group (P < 0.05). Molecular MRI results were corroborated by histology. In a competitive cell adhesion assay, incubation of alpha(nu)beta(3)-expressing cells with targeted nanoparticles significantly inhibited binding to a vitronectin-coated surface, confirming the bioactivity of the targeted nanoparticles. The present study lowers the limit previously reported for detecting sparse biomarkers with molecular MRI in vivo. This technique may be employed to noninvasively detect very small regions of angiogenesis associated with nascent melanoma tumors, and to phenotype and stage early melanoma in a clinical setting.
新生血管形成是恶性黑色素瘤进展的关键组成部分。本研究的目的是确定α（ν）β（3）靶向的顺磁性纳米颗粒是否能够在1.5T磁场下检测并表征由新生黑色素瘤异种移植物（约30立方毫米）诱导的新生血管上稀疏的α（ν）β整合素表达。携带人黑色素瘤肿瘤的无胸腺裸鼠在静脉注射α（ν）β（3）整合素靶向的顺磁性纳米颗粒、非靶向顺磁性纳米颗粒或α（ν）β（3）靶向的非顺磁性纳米颗粒2小时后，再注射α（ν）β（3）整合素靶向的顺磁性纳米颗粒（即体内竞争性阻断），然后进行MRI成像。接受α（ν）β（3）靶向顺磁性纳米颗粒的动物新生血管的对比增强在120分钟时增加了173%。与非靶向顺磁性纳米颗粒的信号对比约比靶向组少50%（P<0.05）。分子MRI结果得到了组织学的证实。在竞争性细胞黏附试验中，将表达α（ν）β（3）的细胞与靶向纳米颗粒孵育可显著抑制其与玻连蛋白包被表面的结合，证实了靶向纳米颗粒的生物活性。本研究降低了先前报道的体内用分子MRI检测稀疏生物标志物的下限。该技术可用于非侵入性检测与新生黑色素瘤肿瘤相关的非常小的血管生成区域，并在临床环境中对早期黑色素瘤进行表型分析和分期。
