This application describes the design of new gold nanoparticle based bioconjugates derived from synthetic bombesin (BBN) analogues to produce a new generation of site-directed computed tomography (CT) imaging agents for specific in vivo targeting of breast cancer cells. With the overarching goal of visualizing smaller lesion (and therefore earlier cancer detection) with better specificity, this work has the potential to increase the survival rate from breast cancer. Specifically, this application will explore whether targeted gold nanoparticles are capable of producing contrast enhancement (increased x-ray attenuation) so that CT can be used in precise and accurate functional/molecular imaging of breast cancer.
Our specific aims for the proposed project are to: (i) Optimize synthetic protocols for targeted gold nanoparticles (AuNPs) conjugated to tumor specific peptide; (ii) Determine the concentrations of gold nanoparticles necessary to induce image contrast in CT imaging using anthropomorphic phantom models of the human breast, including malignant lesions; and (iii) Investigate the utility of Bombesin conjugated AuNPs as image enhancers in computer tomographic (CT) imaging of breast tumors in SCID mice implanted with human breast cancer xenografts. Phantom studies will be performed to evaluate the concentration of AuNP required to produce sufficient contrast to effectively detect breast cancer for a specifically designed Breast CT scanner. This assessment will be done with respect to radiation dose and the size of the lesion; it is anticipated that improved contrast will lead to earlier detection of minimal breast cancer (in situ and minimally invasive). Approaches and methods to conjugate different sizes and shapes of gold nanoparticles (AuNPs) with synthetic BBN analogues that maintain or enhance high breast cancer cell binding with good in vitro and in vivo stability, will be developed. The most promising targeted AuNP-BBN candidates will be evaluated in SCID mice implanted with breast tumor xenografts, to assess their ability to target breast tumors. The goal of these studies is to provide targeted AuNP-BBN analogues that could be developed, via human clinical trials, into effective molecular imaging agents for early diagnostic application in breast tumor patients. The specific objective of our application encompassing the development of new molecular imaging probes, for the early detection of breast cancer, using nanotechnology principles is directly relevant to the overall outcomes sought within the current RFA """"""""PAR-06-475- Nanoscience and nanotechnology in Biology and Medicine (R21)"""""""". The proposed work will develop an enhancement of current Computer Tomography (CT) imaging of the breast. The research will utilize nanosized gold particles that are approximately 1000 times smaller than a human cell to generate X-ray contrast that would be detected by a CT-imaging instrument external to the body. If molecules specific to breast cancer are attached to the gold nanoparticles so that they locate in the cells of breast cancer, the contrast generated would allow the cancer to be more readily detected. This has the potential to improve the early detection and diagnosis of breast cancer. ? ? ?
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