Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 9, Pages 4311-4316Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0910283107
Keywords
Molecular navigation; dendrimeric nanoparticles; molecular amplification; targeted imaging agent; transgenic tumor model
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Funding
- Howard Hughes Medical Institute
- Department of Defense Breast Cancer Research Program [W81XWH-05-1-0183]
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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 mu m, 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 mu M) 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.
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