Matrix metalloproteinases (MMPs) have been implicated in several pathogenic processes surrounding cancer progression including cell proliferation, invasion, angiogenesis, and metastasis. The ability to detect MMP activity non- invasively with high spatial resolution and full-body penetration would provide a powerful'tool for detecting invasive cancers and assessing the response to therapeutic intervention. Current methods, which rely on fluorescent techniques, are limited in their spatial resolution and depth of tissue penetration. The goal of the proposed research is to develop a nanoparticle-based approach for targeting and enhancing MRI contrast agents and thereby provide non-invasive mapping of protease activity. Specifically, iron oxide nanoparticles will be designed to be dispersed in their native state but self-assemble upon protease-mediated activation. Self-assembled iron oxide nanoparticles will cause a local shift in T2 relaxivity that can be imaged noninvasively by MRI. The experimental plan includes synthesis and characterization of nanomaterials, investigation of self-assembly in vitro and in vivo (in xenograft tumors in mice), and noninvasive imaging by MRI. Looking beyond oncology, this general approach of enzymatically-triggered nanoparticle self-assembly will lay the groundwork for a new paradigm for site-specific mapping of many human diseases. ? ? ?
| Harris, Todd J; Green, Jordan J; Fung, Peter W et al. (2010) Tissue-specific gene delivery via nanoparticle coating. Biomaterials 31:998-1006 |
| Harris, Todd J; von Maltzahn, Geoffrey; Lord, Matthew E et al. (2008) Protease-triggered unveiling of bioactive nanoparticles. Small 4:1307-12 |
| Harris, Todd J; von Maltzahn, Geoffrey; Derfus, Austin M et al. (2006) Proteolytic actuation of nanoparticle self-assembly. Angew Chem Int Ed Engl 45:3161-5 |
