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Development of Radioactive Nanocomposites to Treat the Prostate Cancer Microvasculature

Principal Investigator: KHAN, MOHAMED KHAN K
Program: PCRP
Proposal Number: PC020237
Award Number: DAMD17-03-1-0018
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $397,261.00


In order to grow, tumors must build microvessels to supply nutrients for sustained growth. This process is called angiogenesis. It has been shown in numerous animal model systems that if angiogenesis is blocked, tumors can halt growth or even shrink. The tumor microvessels have a different structure than normal microvessels in the body (capillaries), are leakier, and have different proteins and other antigens exposed. It may be possible to exploit the leakiness of these angiogenic tumor microvessels to deliver high doses of radiation directly to the tumor. It may also be possible to bind radioactive carrying particles directly to the differing binding sites presented on the angiogenic tumor microvessels. Novel nanometer-sized molecules built of subunits called dendrimers can be made. The spherical nanoparticles can be made with different discrete sizes, and differing surface charges (+, -, neutral). Also, peptides or other proteins that bind specifically to the new binding sites presented by tumor microvessels can be attached to the surface of these nanoparticles and directly target the angiogenic tumor microvessels. These nanoparticles can be complexed (filled) with metals such as gold { Au }, now becoming nanocomposites, and these metals can be made radioactive. The radioactive nanocomposites could therefore deliver larger amounts of radioactivity to prostate tumors or the tumor microvessels than currently possible with antibody or other delivery systems today. We plan to design, synthesize, characterize, and test the distribution nanocomposites with differing size and charged surfaces to determine whether any nanocomposites have the ability to travel through the leaky tumor microvessels and deposit in the tumor, while remaining in the tighter walled normal vessels and eventually getting dumped out in the urine or bile. This will be tested in prostate tumor bearing mice, using intravascularly injected radioactive nanocomposites, and with the organs and tissues of the mice being harvested and the radioactivity (nanocomposites) counted by scintillation counting. We will also synthesize, characterize, and test the biodistribution of radioactive nanocomposites that have targeting peptides on their surface. The targeting peptides (RGD or cyclic RGD) have previously been shown to bind specifically to angiogenic microvasulature, like that found in prostate tumors. The eventual goal of this research will be to find a size/charge and/or targeted nanocomposite that can deliver radioactivity specifically to prostate tumors or the tumor angiogenic microvasculature. This should permit a novel form of radiotherapy in the future. In the future, nanocomposites found also will have immediate imaging and detection usefulness. Because the target is the angiogenic microvasculature, the nanocomposites should also be modifiable for treatment of other tumors and for delivery of agent to wounds, which are also angiogenic.