Department of Pharmacology, Howard Hughes Medical Institute, Medical Scientist Training Program, University of California at San Diego, La Jolla, CA 92093-0647, USA.
Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4311-6. doi: 10.1073/pnas.0910283107. Epub 2010 Feb 16.
High-resolution imaging of molecules intrinsically involved in malignancy and metastasis would be of great value for clinical detection and staging of tumors. We now report in vivo visualization of matrix metalloproteinase activities by MRI and fluorescence of dendrimeric nanoparticles coated with activatable cell penetrating peptides (ACPPs), labeled with Cy5, gadolinium, or both. Uptake of such nanoparticles in tumors is 4- to 15-fold higher than for unconjugated ACPPs. With fluorescent molecules, we are able to detect residual tumor and metastases as small as 200 microm, which can be resected under fluorescence guidance and analyzed histopathologically with fluorescence microscopy. We show that uptake via this mechanism is comparable to that of other near infrared protease sensors, with the added advantage that the approach is translatable to MRI. Once activated, the Gd-labeled nanoparticles deposit high levels (30-50 microM) of Gd in tumor parenchyma with even higher amounts deposited in regions of infiltrative tumor, resulting in useful T(1) contrast lasting several days after injection. These results should improve MRI-guided clinical staging, presurgical planning, and intraoperative fluorescence-guided surgery. The approach may be generalizable to deliver radiation-sensitizing and chemotherapeutic agents.
高分辨率成像的分子内在涉及恶性肿瘤和转移将是非常有价值的临床检测和肿瘤分期。我们现在报告在体内可视化基质金属蛋白酶活性的 MRI 和荧光树枝状纳米粒子包被的可激活细胞穿透肽 (ACPPs)，标记为 Cy5、钆，或两者。这种纳米粒子的摄取肿瘤是 4 至 15 倍高于未结合的 ACPPs。与荧光分子，我们能够检测残余肿瘤和转移小至 200 微米，可切除荧光引导和分析组织病理学用荧光显微镜。我们表明，通过这种机制摄取是可比的其他近红外蛋白酶传感器，具有添加的优势，该方法是可转化为 MRI。一旦激活，标记的 Gd 纳米粒子沉积高水平 (30-50 μM) 的 Gd 在肿瘤实质与更高数量沉积在浸润性肿瘤区域，导致有用的 T(1)对比持续几天注射后。这些结果应提高 MRI 引导的临床分期、术前规划和术中荧光引导手术。这种方法可能是普遍的提供辐射增敏和化疗药物。
