The goal of the research proposal entitled, """"""""Peptide-targeted alpha-particle emitting phage for ovarian cancer therapy,"""""""" is to develop peptide targeted bacteriophage (phage) ghost headpieces or capsids filled with nanoparticles of lead-212 (212Pb), the parent of the alpha-particle emitting radionuclide bismuth-212 (212Bi), for directed intraperitoneal ovarian cancer treatment. Alpha particles are helium 4He ions that result in high linear energy transfer (LET) upon emission, significantly higher than the LET of 2-particle emitting radionuclides or x-rays. It is hypothesized that Pb-212 loaded T7 phage capsids displaying the erbB-2 avid peptide KCCYSL will target ovarian tumors over-expressing the erbB2 receptor resulting in a tumor-localized therapeutic dose of alpha radiation, while minimizing undesirable radionuclide daughter redistribution.
The specific aims of the proposed research are (1) engineer T7 phage capsids that express the erbB-2 receptor avid peptide KCCYSL on their surfaces, (2) prepare large quantities of empty KCCYSL peptide displaying phage capsids then load them with condensed solid-state metallic 212Pb nanoparticles, (3) determine the radiochemical stability and ovarian cancer cell binding ability of the 212Pb loaded capsids, and (4) investigate the immunogenicity of the capsids and perform initial biodistribution studies of the 212Pb-labeled KCCYSL capsids in vivo in an erbB-2 positive SK-OV-3 ovarian tumor xenograft model. Ovarian carcinoma has the highest mortality of any gynecologic cancer, in part due to its late detection. Peritoneal spread is an important feature in the natural history of the disease;failure to control disease within the peritoneal cavity is a major cause of treatment failure. It is envisioned that radiolabeled capsids would be injected into the peritoneal cavity. The KCCYSL peptides displayed on the surfaces of the capsids will target them to erbB-2 expressing ovarian tumors, irradiating them with alpha-particles. Peptide-targeted alpha emitting phage is a novel approach to targeted radionuclide therapy that couples the therapeutic effectiveness of alpha particles with ability to dramatically reduce side effects from daughter redistribution by encapsulation of the radionuclide, resulting in an innovative approach to ovarian cancer treatment.
Ovarian carcinoma has the highest mortality of any gynecologic cancer, which is largely due to late detection and the fact that most patients have disease outside the pelvis at the time of diagnosis. The engineering and development of novel peptide-targeted alpha particle emitting phage capsids will offer an innovative approach to the treatment of ovarian cancer that has spread intraperitoneally.
