The specific aims of this project are to interact with Projects 1 and 2 to develop improved bifunctional chelating agent technology for clinical use. For the next grant period, our plans are to Continue work on peptide library production and screening. Our initial nine-residue, four-position library was configured to obey the constraints of pre-labeling, and thus lacks amino acids residues with charged side chains. It has produced several interesting candidates for biological testing. However, the presently available 90Y is of such quality that pre-labeling is less of a requirement than previously. Conventional post-labeling of DOTA peptide immunoconjugates allows use of peptides containing charged side chains. The inclusion of charged residues could lead to reagents with considerably better substrate properties as well as improved solubility. These will be synthesized, conjugated to antibodies, radiolabeled and tested as cathepsin substrates in vitro. Biodistribution animal studies will be carried out on conjugates of the peptides selected from in vitro studies. At the end of the proposed 3 year period, we expect to have thoroughly characterized the chemical and physiological properties of approximately 6-9 peptide linkers as candidates for human use. Taken as a set, these results will give us a useful perspective on the effects that can be achieved by this approach. The set of linkers developed should be of considerable use to other researchers in the area of drug delivery.
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