Prostate cancer is in desperate need of improved, targeted diagnostic and therapeutic agents. This year alone, there will be more than 37,000 deaths from prostate cancer, and the lifetime risk of an American man dying from prostate cancer (3.4%) is greater than that of a woman dying of breast cancer (3.0%). The sponsor's laboratory has previously described a high-affinity (9 nM), 311 Da small molecule that binds specifically to prostate-specific membrane antigen (PSMA), which is expressed at high levels in prostate and prostate cancer. However, this """"""""GPI"""""""" molecule, and indeed most monomeric small molecule targeting ligands, are difficult to affinity-mature any further. Based on the pioneering work of the Whitesides group on the thermodynamics of multivalent interactions, the sponsor's laboratory has recently described multimeric versions of GPI that improve affinity. However, even multivalent molecules cannot obtain the highest theoretical binding affinity without careful control of ligand spacing (to match average cell surface receptor density) and rigidity (to minimize entropic losses associated with the binding event). The applicant for this F-32 award is a chemist with significant experience in organic synthesis. In the sponsor's laboratory, he will work on a problem of fundamental importance to molecular imaging and targeted therapeutics, the creation of multivalent chemical platforms that are capable, in one-step, of affinity maturating monomeric, moderate-affinity small molecule ligands into super-high affinity, multimeric agents. The applicant will focus on chemical modification of adamantane cores with rigid, hydrophilic oligopiperidine linkers of defined lengths and bond angles. Such linkers will provide precise spacing of ligands for cell surface contact, will minimize entropic losses during cell binding, and will maximize the efficiency of bulking and effector molecule conjugation. Using prostate cancer xenografts expressing PSMA, and radiolabeling of his multimeric ligands with 99mTc, the applicant will be trained by the sponsor in in vivo optimization of targeted agents, and will learn the principles of biodistribution, pharmacokinetics, and in vivo imaging. The applicant will also be trained in the use of state-of-the-art imaging instruments, including micro SPECT/CT. In summary, this F-32 post-doctoral fellowship will start with an outstanding candidate and will apply his prior knowledge base to a scientific problem of paramount importance. More importantly, his prior training in organic chemistry will be complemented with new training in in vitro and in vivo optimization of targeted diagnostic and therapeutic agents.
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