New PET /near IR-fluorescence tools for multimodal imaging in oncology

用于肿瘤学多模态成像的新型 PET/近红外荧光工具

• 批准号: 8300566
• 负责人: Richard Ting
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300566
• 关键词: Address; Affect; Anti-CEA Antibody; Antibodies; Antineoplastic Agents; Behavior; Biodistribution; Blood - brain barrier anatomy; Cancer Biology; Cancer Model; Cancer cell line; Characteristics; Charge; Clinical; Colorectal Cancer; Data; Databases; Development; Discipline of Nuclear Medicine; Drug Transport; Dyes; Engineering; Extinction (Psychology); Fluorescence; Future; Generations; Goals; Histology; Image; Integrins; Intracellular Transport; Label; Libraries; Ligands; Lymphatic; Malignant Neoplasms; Malignant neoplasm of brain; Mentors; Mind; Modality; Modification; Molecular; Molecular Weight; Monitor; Multimodal Imaging; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Organ; Patients; Peptide antibodies; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase III Clinical Trials; Photochemotherapy; Positron-Emission Tomography; Preclinical Drug Evaluation; Process; Progress Reports; Property; Proteins; Publishing; Radiopharmaceuticals; Research; Resolution; Shapes; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tracer; Training; Tumor Angiogenesis; Tumor Biology; Update; aqueous; cancer imaging; design; direct application; experience; fluorophore; high throughput screening; imaging probe; in vivo; inhibitor/antagonist; malignant breast neoplasm; molecular imaging; multimodality; novel; oncology; prevent; quantum; radiotracer; research study; small molecule; success; tool; tumor

DESCRIPTION (provided by applicant): Richard Ting's K99/R00 application We have recently published the application of new 18F-PET/NIRF (Positron emission tomography/Near Infrared Fluorescence) multimodality imaging probes on the polydextran ligand Lymphoseek (tilmanocept, Neoprobe), a ligand currently in phase III clinical trials as a 99mTc labeled species for detecting lymphatic breast cancer metastasis. The K99 phase of this research applies this recent success to very different new molecules including peptides and proteins. We will apply the PET/NIRF probe to Angiopep 2, a 3 kD peptide for imaging drug transport across the blood brain barrier, and to 55 kD anti-CEA T84.66 diabody, a genetically engineered class of antibodies for imaging CEA positive tumors. These applications will allow us develop superior tracers for imaging colorectal cancer and drug transport. Another goal of the proposed K99 research is the generation of a library of different Integrin ?v?3 antagonists conjugated to PET/NIRF probes of differing molecular weights and charge. The imaging of this library will allow us to simultaneously select for the best probes for imaging tumor angiogenesis by PET and allow us to generate both PET and NIRF databases on the behavior of different moieties in vivo. This database would allow us to rationally design new drugs that accumulate in specific tissues (PET) while retaining the sub-cellular localization and inhibitory properties (observed by NIRF) for which they were selected. Data from the imaging of this library can be used to deliberately alter the in vivo biodistribution of new pharmaceuticals or select for probes that are specific for different forms of cancers. The first R00 phase aim attempts to advance PET/NIRF technology by exploiting the fact that fluorescence is the modality of choice for high-throughput drug screening, We will modify the cancer probes developed in the K99 with immobilizing technology to generate arrays that can indicate small changes in tumor biology, such as increased tumor aggressiveness, and help determine a patient's treatment regime. Desired compounds can be released from the array using aqueous 18F, to generate a PET probe, or combination of probes for corroborative in vivo imaging. The fluorophore on the array will then be substituted with photodynamic therapy (PDT) agents allowing for the selection of probes for PET guided endoscopic PDT applications. Finally, a new application that allows for kit-like radiotracer labeling will be applied to a new library of PET/NIRF small molecules that are capable of demonstrating intracellular transport. These molecules will possess exterior functionality that is similar to clinical 99mTc tracers in order to address the problem of recurrin 99mTc shortages, a current problem in nuclear medicine today. PUBLIC HEALTH RELEVANCE: This proposal builds on our recent success, 18F-PET/NIRF tilmanocept, a higher-resolution alternative to a phase III 99mTc-radiopharmaceutical for detecting lymphatic breast cancer metastasis. Our aim is to expand on this accomplishment by applying this PET/NIRF technology to new antibody, peptide, and small molecule probes for imaging tumor angiogenesis, drug transport, and colorectal cancer. In turn, these new probes will be utilized in advanced high-throughput NIRF arrays for detecting changes in tumor biology, identifying therapeutic agents, and generating new higher-resolution 18F-PET alternatives to our current 99mTc radiopharmaceuticals.

描述（由申请人提供）：Richard Ting 的 K99/R00 申请 我们最近发表了新型 18F-PET/NIRF（正电子发射断层扫描/近红外荧光）多模态成像探针在聚葡聚糖配体 Lymphoseek（tilmanocept、Neoprobe）上的应用，该配体目前作为 99mTc 标记物种处于 III 期临床试验中 用于检测乳腺癌淋巴转移。 这项研究的 K99 阶段将这一最新成功应用于非常不同的新分子，包括肽和蛋白质。我们将 PET/NIRF 探针应用于 Angiopep 2（一种用于对穿过血脑屏障的药物转运进行成像的 3 kD 肽）和 55 kD 抗 CEA T84.66 双抗体（一种用于对 CEA 阳性肿瘤进行成像的基因工程抗体）。这些应用将使我们能够开发出用于结直肠癌成像和药物运输的优质示踪剂。拟议的 K99 研究的另一个目标是生成与不同分子量和电荷的 PET/NIRF 探针缀合的不同整合素 αvβ3 拮抗剂库。该库的成像将使我们能够同时选择用于通过 PET 成像肿瘤血管生成的最佳探针，并允许我们生成有关体内不同部分行为的 PET 和 NIRF 数据库。该数据库将使我们能够合理地设计在特定组织 (PET) 中积累的新药物，同时保留它们被选择的亚细胞定位和抑制特性（通过 NIRF 观察到）。来自该库的成像数据可用于有意改变新药物的体内生物分布或选择适合的探针 针对不同形式的癌症。 第一个 R00 阶段目标试图通过利用荧光是高通量药物筛选的选择方式这一事实来推进 PET/NIRF 技术。我们将使用固定技术修改 K99 中开发的癌症探针，以生成可以指示肿瘤生物学微小变化（例如肿瘤侵袭性增加）的阵列，并帮助确定患者的治疗方案。可以使用 18F 水溶液从阵列中释放所需的化合物，以生成 PET 探针或探针组合，用于验证体内成像。然后，阵列上的荧光团将被光动力治疗 (PDT) 试剂取代，从而可以选择用于 PET 引导内窥镜 PDT 应用的探针。最后，一种允许类似试剂盒的放射性示踪剂标记的新应用程序将应用于能够证明细胞内转运的新 PET/NIRF 小分子库。这些分子将具有与临床 99mTc 示踪剂类似的外部功能，以解决当今核医学中经常出现的 99mTc 短缺问题。 公共健康相关性：该提案建立在我们最近成功的 18F-PET/NIRF tilmanocept 的基础上，这是一种用于检测乳腺癌淋巴转移的 III 期 99mTc 放射性药物的高分辨率替代品。我们的目标是通过将 PET/NIRF 技术应用于新的抗体、肽和小分子探针来扩展这一成就，以对肿瘤血管生成、药物转运和结直肠癌进行成像。反过来，这些新探针将用于先进的高通量 NIRF 阵列，用于检测肿瘤生物学的变化、识别治疗药物，并生成新的更高分辨率的 18F-PET 替代品来替代我们当前的 99mTc 放射性药物。