The proposed studies will address the problem of in vivo stability of astatinated biomolecules. This problem severely limits the types of biomolecules that can be used as At-211 carriers for cancer therapy. At-211 is an alpha-emitting radionuclide that holds potential for treatment of metastatic cancer, cancer in compartmental spaces (e.g. peritoneal cavity), and cancers that are resistant to radiation therapy (e.g. melanoma). The goal is to obtain an At-211 bonding moiety (pendant group) that is stable to in vivo deastatination, and has a minimal effect on the in vivo properties of the targeting biomolecule. To reach this goal, three Specific Aims will be addressed.
Those aims are: (1) to prepare and evaluate a series of astatinated compounds to better understand which structural features increase the in vivo stability; (2) to prepare and evaluate functionalized astatinated borane cage molecules to determine if charge and lipophilicity will alter their in vivo properties, and (3) to demonstrate that pendant groups, which have optimal in vivo characteristics on astatinated model compounds, can be used to provide a stable attachment of At-211 to cancer targeting biomolecules with a minimum affect on their in vivo properties. In the first aim, the affect of (a) boron cage structure, (b) steric encumbrance around the astatine, and (c) higher bonding order of astatine on the in vivo stability will be examined through preparation of model compounds that incorporate those structural features. In the second aim, the effect of formal charge and lipophilicity on in vivo distribution and pharmacokinetics will be examined for a series of decaborate(2-) model compounds.
In third aim, a mAb Fab' fragment and three mAbs, a peptide (bombesin) derivative, and biotin derivatives will each be coupled with pendant groups found to have the best properties in Specific Aims 1 and 2, then astatinated and evaluated in vivo.
