The development of radiolabeled probes for imaging and therapy which target the chemokine CXCR4

开发针对趋化因子 CXCR4 的成像和治疗用放射性标记探针

基本信息

批准号：
9051677
负责人：
Alejandro Amor-Coarasa
金额：
$ 5.61万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-13 至 2018-07-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9051677
关键词：
AMD3100 Accounting Adenocarcinoma Cell Affect Affinity Animal Model Animals Binding Biodistribution Biological Assay Biological Availability Biopsy Breast CXC Chemokines CXCL12 gene CXCR4 Receptors Cancerous Cell Culture Techniques Cell Line Cells Cellular biology Clinical Trials Colon Computer software Development Disease Drug Kinetics Evaluation Fellowship Formulation Future Growth HIV Receptors Human Image Immunologic Deficiency Syndromes Individual Injectable Knowledge Label Lead Libraries Ligand Binding Ligands Link Location Lung Lymphocyte Malignant Neoplasms Mentorship Metastatic Neoplasm to the Bone Methods Modeling Modification Molecular Models Molecular Structure Morbidity - disease rate Multiple Myeloma Normal Cell Nude Mice Operative Surgical Procedures Organ PC3 cell line Patients Pharmaceutical Preparations Procedures Prostate Prostate Adenocarcinoma Publications Publishing Radio Radioactive Radioisotopes Radiolabeled Radiopharmaceuticals Research Signal Transduction Site Solid Neoplasm Specificity Specimen Staging Stromal Cell-Derived Factor 1 Synthesis Chemistry Techniques Testing Tissues Training Validation Writing analog animal imaging base cancer cell cancer type career chemokine chemokine receptor chemoradiation cost design imaging agent imaging probe improved in vivo in vivo imaging member molecular imaging molecular modeling neoplastic cell non-invasive imaging outcome forecast overexpression pre-clinical prognostic tool public health relevance radioligand radiotracer receptor skills small molecule success theranostics tumor tumor specificity uptake

项目摘要

DESCRIPTION (provided by applicant): CXCR4 related research has escalated to currently yield a total of 9,201 NCBI publications by March 2015. A total of 3,046 of the 9,201 publications have been cancer related, with 1,586 published within the past 5 years. CXCR4 was first discovered as one of the co-receptors for HIV, and thereafter was found to be expressive in multiple cancers including breast, prostate, lung, colon and multiple myeloma. These malignancies account for 48.8% of all cancers in the USA in 2014, and this does not take into account the many other cancers for which CXCR4 overexpression has not yet been studied. Furthermore, CXCR4 has been identified as having increased expression and importance in higher staged, higher grade, metastatic disease. Non- invasive imaging of overexpressed CXCR4 is an important prognostic tool since the receptor can provide survival and proliferation signals to neoplastic cells. Currently, there is no method to non-invasively evaluate CXCR4 expression within solid tumors. Tests are thus limited to biopsies, which are restricted to a specific site, may give false negative results, and carry with it cost and morbidity. This also assumes that we already the cancer's specific location, such that we can adequately target the biopsy. The development of targeted CXCR4 imaging probes will also open a possibility for the use of CXCR4 directed therapy as a "Theranostic" model, where probes can be labeled with 18F, 11C and/or 124I radioisotopes for imaging, and with 131I for therapy. The ligands library proposed in this project will be based on high affinity small molecular structures modified for swift radiolabeling. Existing lead compounds with high CXCR4 binding affinities will be modified for radiolabeling without significantly affecting their binding affinity. Complete radiolabeling/purification/formulation procedures will be created to obtain a USP injectable solution that can be replicated for future human studies. Imaging agents will be tested in vivo, and the biodistribution, bioavailability, and pharmacokinetics of the drugs will be determined. The best radio-ligands maybe considered for future human clinical trials. The proposed training plan includes cell biology, organic synthetic chemistry, and small animal imaging training. Several complemental courses will also be included to improve scientific writing skills and other necessary knowledge for the design of radiopharmaceuticals. An image oriented surgery, pathological analysis of recovered specimens, and oncological treatment mentorship is also planned to link all involved fields in cancer management and broaden the trainee's understanding of the individual parts involved. The training fellowship has been design to assure the success of the trainee in his future academic career.

描述（由适用提供）：CXCR4相关研究已升级，目前已在2015年3月到2015年3月产生9,201个NCBI出版物。在9,201个出版物中，总共有3,046个与癌症有关，在过去的5年内发表了1,586个。 CXCR4首先被发现为HIV的共受体之一，此后发现在包括乳腺癌，前列腺，肺，肺和多发性骨髓瘤在内的多种癌症中具有表现力。这些疾病占2014年美国所有癌症的48.8％，这并未考虑到尚未研究CXCR4过表达的许多其他癌症。此外，CXCR4已被确定为在高级，高级转移性疾病中的表达和重要性增加。过表达CXCR4的非侵入性成像是重要的预后工具，因为接收器可以向肿瘤细胞提供生存和增殖信号。当前，没有方法可以非侵入性评估实体瘤中的CXCR4表达。因此，测试仅限于仅限于特定地点的活检，可能会产生虚假的负面结果，并带有成本和发病率。这也假定我们已经是癌症的特定位置，因此我们可以充分针对活检。有针对性的CXCR4成像问题的开发也将为使用CXCR4定向治疗作为“疗法”模型开辟可能性，在这种模型中，可以将问题与18F，11C和/或124I的放射性分析标记进行成像，并使用131i进行治疗。该项目中提出的配体库将基于修改用于快速放射性标记的高亲和力小分子结构。具有高CXCR4结合亲和力的现有铅化合物将用于放射性标记，而不会显着影响其结合亲和力。将创建完整的放射性标记/纯化/配方程序，以获取可以为将来的人类研究复制的USP注射解决方案。将在体内测试成像剂，并确定药物的生物分布，生物利用度和药代动力学。最好的无线电配体可以考虑未来的人类临床试验。拟议的培训计划包括细胞生物学，有机合成化学和小动物成像训练。还将包括几门补充课程，以提高科学写作技巧和其他必要的放射性药物设计知识。还计划以图像为导向的手术，对恢复标本的病理分析以及肿瘤学治疗心态，以将癌症管理中的所有涉及领域联系起来，并扩大受训者对所涉及各个部分的理解。培训奖学金是为了确保在未来的学术生涯中确保实习生的成功。