Peptide-Targeted Radioactive Composite Nanodevices Treating Prostate Cancer

Principal Investigator: KHAN, MOHAMED K
Program: PCRP
Proposal Number: PC061019
Award Number: W81XWH-07-1-0504
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $607,128.00


This research involves the development of adjustable nanoscale devices to deliver radioisotopes to tumors that take advantage of the distinct features of tumor microvasculature for the delivery of radiation agents for the improved cancer treatment. To sustain the growth of a tumor, cancer cells instruct the endothelial cells of existing blood vessel to keep building new blood vessel branches to feed the growing cancer. During this process (angiogenesis), protein markers that are unique to active angiogenesis are presented on the endothelial cell surface of the microvasculature. One of these unique cell markers is the alpha-v-beta-3 receptor, which binds specifically to cyclic RGD peptides. Clinical trials are now ongoing based on anti-angiogenic therapy with this peptide for metastatic prostate cancer. Based on this knowledge, we have coupled cyclic RGDfK peptide to the surface of radioisotope carrying nanodevices such that the device will be delivered by the bloodstream to the actively growing tumor vessels. The nanodevice used in this study is based on nontoxic PAMAM dendrimers that we have previously studied and for which we have done toxicity analysis. These nanodevices have the capacity to carry several hundreds of radioactive gold atoms per one nanodevice, providing enough radiation to kill tumor cells. The surface of the nanodevice permits us to carry out chemistry, for example, to attach homing peptides such as RGD, and to regulate biologic interactions. Since this approach delivers radiation specifically to the blood supply of the tumor in very small doses, it may treat all types of prostate cancer. By this approach, even the smallest nanodevice can deliver a 10-fold higher radiation dose to prostate tumors than previously possible with all other systemic technologies. Once the microvasculature is targeted, the tumor-bound devices irradiate the endothelial cells and nearby prostate tumor cells. This will cut off the oxygen and nutrients to the tumors, thus killing or restricting growth by starvation and also directly kill prostate tumor cells. We have successfully fabricated the cyclic RGDfK carrying gold composite nanodevice and carried out preliminary studies in test tubes to show the ability of these devices to bind to their specific receptors on angiogenic human endothelial cells.