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: 8459516
• 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/8459516
• 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; Extinction (Psychology); Fluorescence; Future; Generations; Genetic Engineering; 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.

描述（由申请人提供）：Richard Ting的K99/R 00申请我们最近发表了新的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Phosphoseek（替马诺塞，Neoprobe）上的应用，该配体目前作为99 mTc标记物质处于III期临床试验中 用于检测乳腺癌淋巴转移。 这项研究的K99阶段将最近的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3 kD肽，用于成像药物转运穿过血脑屏障，和55 kD抗CEA T84.66双抗体，一种基因工程抗体，用于成像CEA阳性肿瘤。这些应用将使我们能够开发出用于成像结直肠癌和药物转运的上级示踪剂。建议K99研究的另一个目标是产生不同整合素的库？v？3种拮抗剂与不同分子量和电荷的PET/NIRF探针偶联。该文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，并使我们能够生成关于不同部分在体内行为的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，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）。来自该文库的成像的数据可用于有意改变新药物的体内生物分布或选择与新药物的体内生物分布一致的探针。 针对不同类型的癌症。 第一个R 00阶段的目标是通过利用荧光是高通量药物筛选的首选模式这一事实来推进PET/NIRF技术，我们将用固定技术修改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的阵列，例如肿瘤侵袭性增加，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化合物，以产生PET探针或用于确证体内成像的探针组合。然后，阵列上的荧光团将被光动力疗法（PDT）试剂取代，从而允许选择用于PET引导的内窥镜PDT应用的探针。最后，一个新的应用程序，允许试剂盒样放射性示踪剂标记将适用于一个新的库的PET/NIRF小分子，能够证明细胞内运输。这些分子将具有与临床99 mTc示踪剂类似的外部功能，以解决复发性99 mTc短缺的问题，这是当今核医学中的一个当前问题。