The focus of the proposed seed grant is to use a novel, low-cost, and flexible lithographic technology to fabricate nanoparticles with extremely uniform sizes and controlled, non-spherical shapes, and to evaluate the biological dynamics (i.e., particle transport and uptake) of these nanostructures in mouse models of human cancer. In particular, we propose to study the permeability of these nanoparticles through angiogenic blood vessels induced by tumors in order to evaluate the effects of nanoparticle shape and size. Angiogenesis [1-3] is critical for tumor growth, local invasion, and metastasis, and it is well established that neovascular vessels are structurally distinct, characterized by disorganized and incomplete enclosure, and can permit blood-borne materials to leak into the tumor volume [4-7]. Although such “leakiness” has been shown to be size-selective, these limits vary with tumor type and the microenvironment [8, 9]. We hypothesize that nanoparticles can selectively address tumor neovasculature when the shape and size of the particle has been optimized for extravasation.

To test our hypothesis, we will define sub-100 nm (critical-dimension) structures and form them into gold nanoparticles. These will be functionalized with a radionuclide chelate for noninvasive imaging. Our fabrication technique allows for varying the nanostructure size/shape and has sufficient throughput (> 3 cm²/hr; 10⁹ particles/cm²). Particles will be chelator-modified using SAM chemistry and administered intravenously into murine xenograft tumor models to determine their localization properties. Our short-term goal is to optimize size/shape combinations targeting angiogenic blood vessels. This project will also open the path to broad application of uniform nanoparticles of preselected shape, which can be made from biocompatible polymers and ferrites.