Direct identification of ready-to-use peptoid-DOTA theranostic systems

描述（由申请人提供）：直接鉴定即用肽- dota诊断系统将开发一种快速且具有成本效益的“诊断药物”技术，用于抗癌治疗和实时治疗随访。目前开发诊断药物的两种基本方法包括造影剂与治疗分子的化学连接，或者将这两种成分包装在一个大分子系统中，如脂质体。虽然化学修饰通常会削弱药物的原始活性，但大分子通常会表现出稳定性、生物分布和清除问题。努力

DESCRIPTION (provided by applicant): Direct identification of ready-to-use peptoid-DOTA theragnostic systems A rapid and cost effective technology for 'theragnostic agents' will be developed for use in anti-cancer therapy and real time treatment follow up. The two current basic approaches to develop theragnostic agents include the chemical linkage of a contrast agent to a therapeutic molecule, or to pack these two components inside a macromolecular system such as liposomes. While chemical modifications typically weaken the original activity of the drug, macromolecules generally exhibit stability, biodistribution and clearance issues. Efforts to combine significantly different components, such as therapeutics and contrast agents, as the last step create most of these problems. Our novel approach involves the synthesis of a single molecule that combines therapeutic and imaging components and thus validates the target of interest from the first step of the overall development process. The idea is to develop peptoid combinatorial libraries that are already coupled with a DOTA-contrast agent and directly identify '(peptoid)3-DOTA' molecules for cell surface receptors using our unique on-bead two-color cell assay. When a certain (peptoid)3-DOTA is picked up by the target receptor as the optimal binding ligand during the screen, the DOTA scaffold on that peptoid has already seen the target and signs that it would not interfere with the binding of the selected peptoid portion. Peptoids have been reported as great protein binding ligands with their own antagonist activities. In addition, the DOTA scaffold can be complexed with 90Y and used in radionuclide therapy. Diagnostically, this DOTA scaffold can be complexed with 68Ga or 64Cu for PET imaging and with Gd3+ for MR imaging applications. To build the library, DOTA scaffolds will be loaded on to the resin beads through one of its arms and the remaining 3 arms will be diversified using peptoid residues. This library will be screened against Epidermal Growth Factor Receptor (EGFR) and ephrin receptor A2 (EphA2) as model target systems that overexpress in many cancer types which ideally form multimeric clusters on the cell surface. Identified 'hit' compounds [(peptoid)3-DOTA] will be validated for binding and the antagonist potential will be evaluated by effects on EGFR and EphA2 receptor phosphorylation using standard western blot analysis. Finally, the Gd3+ complexes will be used in cellular level MR imaging assays to probe their imaging potential, leaving in vivo PET applications as the immediate future goals. The primary conceptual advancement of this proposal is the development and validation of a theragnostic agent as a 'single package from the first step'. Due to the versatility of peptoid chemistry, the overall development process can be completed rapidly and cost effectively. In addition, when considering the highly biological amenable features of peptoids, such as serum stability, non-immunogenicity and moderate clearance, one could expect enhanced pharamacokinetc properties of these peptoid-DOTA agents and therefore assure a rapid and economical conversion of bench level lead molecules into clinically applicable anti-cancer theragnostic agents in the future. PUBLIC HEALTH RELEVANCE: Agents that have both therapeutic and diagnostic capability ("theragnostic" agents) will verify that a drug has reached its target after one treatment and if te therapy is not working, that information will be known immediately so that therapy can be switched without delay, potentially saving a cancer patient's life. While conventional methods spend large sums of time and money trying to 'connect' existing therapeutic and imaging components as the final step, we propose developing a rapid, economical and facile method to 'directly' identify ready-to-use theragnostic agents. The technology proposed in this application can be applied on any type of cancer (or even other diseases), to create a global set of tools to detect, treat and monitor tumors thereby moving us one step closer to personalized medicine in the future.