A bifunctional ligand that can rapidly form a stable complex with a metal while conjugated to a tumor-targeting moiety is essential for... Show moreA bifunctional ligand that can rapidly form a stable complex with a metal while conjugated to a tumor-targeting moiety is essential for targeted therapy and imaging of cancer. New bifunctional chelators in the NETA and DEPA series were developed for targeted radiation cancer therapy. The chelators showed rapid complexation kinetics with 90Y and 177Lu, and the corresponding radiolabeled complexes were stable in vitro and in vivo. Trastuzumab, Panitumumab, and c(RGDyK) conjugates (targeting HER-2, HER-1, and integrin αvβ3, respectively) of the novel bifunctional ligands were prepared. The conjugates displayed fast complexation kinetics with 90Y, 177Lu, and 205/6Bi, and the antibody and peptide conjugates labeled with 90Y, 177Lu, or 205/6Bi exhibited excellent stability and tumor targeting in mice bearing human colorectal cancer (LS-174T). Transferrin (Tf) and bile acid (BA) conjugates of novel chelators in the NE3TA series were prepared for targeted iron chelation therapy (ICT) and positron emission tomography (PET) imaging applications of cancer. Tf and BA conjugates of NE3TA had high cytotoxicity on HeLa, HT29, and PC3 cancer cells. The Tf-N-NE3TA and BA-N-NE3TA also displayed rapid complexation kinetics with 64Cu, and the Tf and BA conjugates of N-NE3TA labeled with 64Cu were stable and had high cellular uptake in HeLa and PC3 cancer cells. Tf-N-NE3TA was further conjugated with a fluorescence dye (Cy5.5) to develop targeted theranostic agent of cancer. Tf-N-NE3TA-Cy5.5 showed great radiolabeling efficiency with 64Cu, and the Tf-N-NE3TA-Cy5.5 labeled with 64Cu exhibited high cellular uptake in HeLa, HT29, and PC3 cancer cells. In summary, we have developed new bifunctional ligands having excellent chelation chemistry of 90Y, 177Lu, 205/6Bi, and 64Cu, and the tumor-specific antibody and peptide conjugates of the novel bifunctional chelators have a great potential for targeted cancer therapy and imaging as well as theranostic applications of cancer. Ph.D. in Biology, July 2014 Show less
