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

概要/摘要-限制30行- Richard Ting的K99/R 00应用程序 我们最近发表了新的18F-PET/NIRF（正电子发射）的应用 断层扫描/近红外荧光）多模态成像探针 Phosphoseek（替马诺塞，Neoprobe），目前作为99 mTc标记物质处于III期临床试验的配体 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探针应用于血管肽2，一种用于成像药物的3 kD肽 转运穿过血脑屏障，并与55 kD抗CEA T84.66双抗体，一种基因工程 用于成像CEA阳性肿瘤的一类抗体。这些应用程序将使我们能够开发上级 用于结肠直肠癌和药物转运成像的示踪剂。K99研究的另一个目标是 产生与不同的PET/NIRF探针缀合的不同整联蛋白αvβ3拮抗剂的文库， 分子量和电荷。这个图书馆的成像将使我们能够同时选择最好的 通过PET成像肿瘤血管生成的探针，使我们能够生成PET和NIRF数据库， 不同部分在体内的行为。这个数据库将使我们能够合理地设计新药， 在特定组织（PET）中积累，同时保留亚细胞定位和抑制特性 （通过NIRF观察）他们被选中的原因。来自该库的成像的数据可用于 故意改变新药物的体内生物分布或选择特异于 不同形式的癌症。 第一个R 00阶段的目标是通过利用以下事实来推进PET/NIRF技术， 荧光是高通量药物筛选的首选模式，我们将修改癌症探针， 在K99开发的固定技术，以产生阵列，可以指示在 肿瘤生物学，如增加的肿瘤侵袭性，并帮助确定患者的治疗方案。 可以使用18F水溶液从阵列释放所需化合物，以产生PET探针，或 用于确证体内成像的探针的组合。然后，阵列上的荧光团将被 用光动力疗法（PDT）试剂替代，允许选择用于PET引导的探针 内窥镜PDT应用。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是 应用于一个新的PET/NIRF小分子库，能够证明细胞内 运输这些分子将具有与临床99 mTc示踪剂相似的外部功能， 以解决反复出现的99 mTc短缺问题，这是当今核医学中的一个当前问题。

SUMMARY/ABSTRACT - limit 30 lines – 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 αvβ3 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 recurring 99mTc shortages, a current problem in nuclear medicine today.