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

直接鉴定即用型 peptoid-DOTA 治疗诊断系统

• 批准号: 8445545
• 负责人: Damith Gomika Udugamasooriya
• 金额: $ 23.85万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445545
• 关键词: 90Y; Animals; Binding; Binding Proteins; Binding Sites; Biodistribution; Biological; Biological Assay; Bypass; Cancer Patient; Cell Surface Receptors; Cell surface; Cells; Chemicals; Chemistry; Collection; Color; Complex; Contrast Media; Coupled; Detection; Development; Diagnostic; Disease; Eph Family Receptors; Epidermal Growth Factor Receptor; Exhibits; Fluorescence; Future; Goals; Homo; Human; Image; Ions; Lead; Left; Libraries; Life; Ligand Binding; Ligands; Link; Liposomes; Magnetic Resonance Imaging; Malignant Neoplasms; Medicine; Metals; Methods; Modeling; Modification; Monitor; One-Step dentin bonding system; Patients; Penetration; Peptoids; Pharmaceutical Preparations; Phosphorylation; Plant Resins; Positron-Emission Tomography; Process; Property; Publishing; Radionuclide therapy; Reporting; Serum; Sum; System; Technology; Therapeutic; Time; Tissues; Validation; Western Blotting; Work; arm; base; biological systems; cancer therapy; cancer type; combinatorial; cost; cost effective; follow-up; imaging modality; imaging probe; improved; in vivo; interest; macromolecule; novel strategies; oncology; overexpression; receptor; receptor binding; scaffold; single molecule; success; theranostics; tool; tumor

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.

描述（由申请人提供）：直接识别现成的肽-Dota Theragnostic系统，将开发用于“ Theragnostic Agents”的快速且具有成本效益的技术，用于抗癌治疗和实时治疗随访。开发毒剂的两种基本方法包括对比剂与治疗分子的化学连接，或将这两个成分堆积在大分子系统（例如脂质体）中。尽管化学修饰通常会削弱药物的原始活性，但大分子通常表现出稳定性，生物分布和清除问题。努力 将明显不同的组成部分（例如治疗剂和对比剂）结合在一起，因为最后一步会造成大多数这些问题。我们的新方法涉及将治疗和成像成分结合的单个分子的合成，因此从整体开发过程的第一步验证了感兴趣的目标。这个想法是要开发已经与DOTA对比剂结合的肽组合文库，并直接识别（肽）3-DOTA'分子，用于使用我们独特的珠子两种彩色细胞测定法，以用于细胞表面受体。当目标受体作为屏幕期间的最佳结合配体捡起特定（肽）3-DOTA时，该肽上的DOTA支架已经看到了靶标，并迹象表明它不会干扰所选肽的结合部分。据报道，肽是具有其自身拮抗剂活性的蛋白质结合。另外，DOTA支架可以与90年代复合并用于放射性核素治疗。诊断，该DOTA支架可以与68GA或64CU复合，用于PET成像，以及用于MR成像应用的GD3+。为了构建图书馆，Dota脚手架将通过其一个手臂之一加载到树脂珠上，其余的3臂将使用肽残留物进行多样化。该文库将针对表皮生长因子受体（EGFR）和Ephrin受体A2（Epha2）作为模型靶系统进行筛选，这些系统在许多癌症类型中过表达，它们理想地在细胞表面形成了多聚体簇。鉴定的“命中”化合物[（肽）3-DOTA]将通过结合验证，并通过使用标准的Western印迹分析来评估拮抗剂电位通过对EGFR和EPHA2受体磷酸化的影响。最后，GD3+复合物将用于细胞级别的MR成像测定法以探测其成像潜力，从而将体内宠物应用作为近期目标。该提案的主要概念进步是将theAgnostic代理作为“第一步的单个软件包”的开发和验证。由于肽化学的多功能性，可以迅速完成整体开发过程。此外，当考虑肽的高度生物学特征，例如血清稳定性，非免疫原性和中等间隙时，人们可能会期望这些肽-Dota剂的Pharamacokinetc特性增强将来进入临床适用的抗癌毒剂。 公共卫生相关性：具有治疗能力和诊断能力（“ Theragnotic”代理商）的药物将验证一种药物在一种治疗后已达到其靶标，如果TE治疗不起作用，该信息将立即知道，以便可以切换治疗。毫不拖延，有可能挽救癌症患者的生命。尽管传统方法花费了大量的时间和金钱，试图将现有的治疗和成像组件作为最后一步，但我们建议开发一种快速，经济和轻松的方法来“直接”“直接”识别现成的theragnostic剂。本应用程序中提出的技术可以应用于任何类型的癌症（甚至其他疾病）上，以创建一组全球的工具来检测，治疗和监测肿瘤，从而使我们将来更接近个性化医学。