The goal of this project is to synthesize., characterize and evaluate promising tumor angiogenesis targeting peptide conjugates. Preliminary studies suggest that these agents may provide the means to detect a broad range of neovascular disease with greater sensitivity than modalities currently in use. In cancer imaging, the accuracy of scintigraphy is largely determined by the ratio of tumor uptake to background activity (T/B). Radiopharmceuticals with high T/B have high uptake in neoplastic tissue with low deposition in normal parenchyma. This project will systematically assess novel radiopharmaceutical agents designed to take advantage of unique aspects of tumor neovasculature with the expectation that they will yield high T/B and will guide the development of useful tumor diagnostics. Two aspects of tumor vessels are likely to be important for agent uptake. First, the luminal surfaces of neovascular endothelia provide unique, highly accessible, molecular targets and second, tumor vessels are more permeable to macromolecules than are normal vessels. Therefore, we hypothesize that (1) human tumor vasculature will concentrate Tc-99m-MAG3-RGD4C via specific coupling of the peptide RGD4C (ACDCRGDCFCG) to the alphaVbeta3 integrin target associated with tumor angiogenesis and (2) that human tumor vasculature will concentrate Tc-99m-MAG3-dextran compounds via its associated increased vascular permeability to the macromolecules. T/B will be assessed in severe combined immunodeficient (SCID) mice bearing human tumor xenografts of either high or low vascular density by necropsy following IV injection of radiopharmaceutical and gamma camera imaging to 2 and 24 hours. We will also explore the cumulative benefits of specific angiogenesis marker targeting and enhanced tumor vessel permeability, by comparing the xenograft uptake of Tc-99m-MAG3-dextran-RGD4C peptide conjugate to the control conjugates Tc-99m-radiolabeled MAG3-dextran-RGE4C. RGE4C has no specific binding to alphaVbet3. The successful completion of these aims will provide critical information on the means to optimize the tumor to background ratio, reduce undesirable uptake in the liver, and produce highly sensitive and specific diagnostic agents for human neoplastic disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA081492-01A1
Application #
6131584
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Menkens, Anne E
Project Start
2000-03-20
Project End
2000-07-31
Budget Start
2000-03-20
Budget End
2000-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$6,063
Indirect Cost
Name
Albany Medical College
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Mitra, Amitava; Nan, Anjan; Papadimitriou, John C et al. (2006) Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy. Nucl Med Biol 33:43-52
Mitra, Amitava; Nan, Anjan; Line, Bruce R et al. (2006) Nanocarriers for nuclear imaging and radiotherapy of cancer. Curr Pharm Des 12:4729-49
Line, Bruce R; Mitra, Amitava; Nan, Anjan et al. (2005) Targeting tumor angiogenesis: comparison of peptide and polymer-peptide conjugates. J Nucl Med 46:1552-60