Enabling Diagnostic Imaging and Targeted Alpha Therapy with New Chelators - PROJECT SUMMARY Targeted internal radionuclide therapy is a highly efficacious form of cancer treatment that employs administered radiopharmaceutical agents to destroy malignant cells. Radiopharmaceutical agents of this type require both a biological targeting vector, which selectively recognizes and binds to receptors that are overexpressed on cancer cells, and a bifunctional chelating agent, which stably binds to and attaches the radionuclide to the targeting vector. The radionuclide can be chosen for their different nuclear decay properties, potentially rendering it valuable for theranostic applications, as long as its coordination chemistry is compatible with the bifunctional chelator. Conventionally, beta particle emitters have been leveraged for therapy, but recent clinical studies have revealed the efficacy of alpha particle emitters. The use of alpha emitters is hindered, however, by a lack of gamma photon or positron emissions, which prevents their use in diagnosis, and by their unconventional coordination chemistries, which make it difficult to find a suitable bifunctional chelator. Another limitation for the use of alpha emitters is the lack of widespread availability of many of the promising radioisotope candidates, like actinium-225. This project will address both of these challenges in alpha particle emitter targeted internal therapy by designing new bifunctional chelators that can be simultaneously used with diagnostic gamma- or positron-emitting radionuclides and can also be used to chelate more widely available alpha-emitting radioisotopes that are not supply chain limited. In Specific Aim 1, chelators for the alternative, but readily accessible, alpha emitter lead-212 will be pursued. These chelators will be modified so that they can simultaneously bind aluminum, gallium, and scandium to support highly stable and easily formed metal-fluorine bonds with the fluorine-18 positron emission tomography diagnostic isotope. Specific Aim 2 will address a long-standing challenge to develop chelators for the clinically used radium-223 alpha emitter, with corresponding diagnostic capabilities provided by the partner radionuclide barium-131. We will use an innovative approach, called the ClickZip reaction, to accomplish this objective. Lastly, Specific Aim 3 will develop bifunctional versions of the most promising chelators identified in Aims 1 and 2. These chelators will then be conjugated to biological targeting vectors and evaluated in mice for their ability to deliver these therapeutic and diagnostic radionuclides to tumor sites in vivo. Through these three aims, this work will expand the accessibility of targeted radionuclide therapy with alpha emitters by developing chelators for easily obtained radioisotopes, as well as their diagnostic partners. The ability to use diagnostic partners for these therapeutic alpha emitters is critically important for predicting patient dosimetry, disease staging, and response. Collectively, the successful execution of this project will give rise to theranostic alpha-emitting therapeutic agents capable of curing and diagnosing human disease.
