The proposed project will employ imaging to develop and test a proof-of-principle for molecular-targeted therapy. We will synthesize five radiotracers capable of testing the hypothesis that a molecular targeted therapeutic agent can produce greater tumor accumulation than a non-targeted agent and that imaging can be used to guide the design. The consequence will be a new agent with a higher therapeutic index;the contribution will be a confirmation of the design paradigm that uses molecular imaging to guide the design of chemotherapeutic agents. The first set of experiments will compare in tumor-bearing mice the non-targeted AP5346 polymer labeled with ln-111 with a Vitamin B12 targeted AP5346 polymer with the same radiolabels. If the target-polymer has a larger tumor-to-muscle (TMR) ratio at selected times, the polymer will be labeled with either F-18 or Br-76 depending on the clearance half times. If the targeted polymer has an inferior TMR ratio, the Vit B12 mol% will be increased and re-evaluated. The next key experiment will be to evaluate the optimal targeted compounds in vivo to compare Ft in DNA with tumor radioactivity measurements using PET and planar imaging. The final Specific Aim will study the optimal targeted and non-targeted polymer in a therapy trial in mice. The design of the therapy protocol will follow the protocol used to study the original polymer AP5346. The proposal makes use of a polymer with 10 mol% of targeting agent to increase avidity for the tumor compared to a non-targeted polymer that has already shown promise as a potent chemotherapeutic. This increase in avidity should lead to increased target concentration and thereby increase the sensitivity to changes due to chemotherapy. We included contingency plans to vary the mol% because the literature shows that the binding affinity (avidity) is not a straightforward linear relationship between the mol% loading and polymer localization. The elucidation of the optimal avidity will be an important outcome. Confirmation of this hypothesis will provide proof-of-principle for the concept of molecular targeted cancer therapy and the motivation to translate the optimal polymer into the cancer clinic. If this project is successful the significance will be: (1) we will have proof that a targeted chemotherapeutic agent can deliver a greater payload to the therapeutic site of action, the tumor's DNA;(2) we will demonstrate that an imaging reporter can be used to externally monitor the delivery of Platinum to DNA;and (3) we will produce a set of chemotherapeutic agents with imaging reporters that will be ready for GMPgrade synthesis and the FDA approval process. The possibility that an imaging agent can be developed as a biomarker for individualized therapy would be a significant advance. In this proposal, the baseline compound is a promising chemotherapeutic. This increases the potential impact of such a study given that the hypothesis is a targeted polymer will outperform a non-targeted polymer.
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