Objectives: This proposal will develop novel agents for imaging the tumor microvasculature present in all cancers. It proposes to design, synthesize, and characterize novel radioisotope containing nanoparticles (nanocomposite devices or NCDs) made from dendrimer templates and targeted at the angiogenic tumor microvasculature. This technology will encapsulate different radioisotopes within devices of defined size and targeting surface properties. The radioactivity delivered to a tumor is increased by increasing the particle size, or the number or specific activity of the guest atoms, without destroying the targeting ability of the NCD. By varying the particular guest atoms (metals/isotopes), different forms of imaging will be permitted (eg. film, SPECT, PET). These NCDs can deliver at least a log fold more radioactivity to tumors than possible with current antibody technologies, giving the added potential for imaging microscopic tumor burdens, and even molecular imaging. NCDs could permit combined imaging and therapy of all cancers.
Specific Aims : (1) To chemically link the angiogenic microvascular targeting peptide, RGD, onto the surface of gold or copper containing NCDs. (2) To carry out biodistribution and biosafety studies with RGD-surfaced 5nm {Au} nanocomposites and RGD-surfaced 5 nm {Cu} nanocomposites to determine whether we can exploit the targeting ability of RGD to deliver nanocomposites to the tumor microvasculature (3) To carry out imaging of the RGD-surfaced NCDs a) lntracellularly, b) intratumorally, and c) in the whole animal. Design and Methods: (1) The NCDs will be made from PAMAM polymer templates, and then linked to RGD or, alternatively they may be made from RGD pre-substituted templates with the later introduction of gold (or copper) based on the principle of reactive encapsulation. Next, {198Au} and {64Cu} NCDs will be developed by direct activation or by using conventional radiochemistry. (2) Specificity of binding studies will be carried out by intravenous injection of the NCDs into B16 melanoma or MatLyLu prostate tumor bearing mice, and isolation of the organs/tissues for analysis of NCD content, and competitive injection of excess RGD. Biosafety studies include daily weights and a detailed toxicity table. (3) intracellular, intratumoral, and whole animal imaging will be accomplished via Transmission Electron Micrography (TEM), an autoradiography and immunohistochemical method, and SPECT imaging respectively.
