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Leveraging Metalloinsertors for the PET Imaging and Endoradiotherapy of MMR-Deficient Cancers

利用金属插入器对 MMR 缺陷癌症进行 PET 成像和腔内放射治疗

基本信息

批准号：
10537195
负责人：
Samantha Patricia Delaney
金额：
$ 3.22万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10537195
关键词：
Adenine Affinity Base Pair Mismatch Base Pairing Binding Biodistribution Biological Cell Proliferation Cells Chemicals Clinical Management Colorectal Cancer Complex Critical Pathways Cytosine DNA DNA Binding DNA Minor Groove Binding DNA Repair DNA Repair Pathway Data Development Diagnostic Eukaryotic Cell Evaluation Exhibits Exposure to Family Family member Generations Genome Genomic DNA Halogens Hand Hereditary Nonpolyposis Colorectal Neoplasms High Pressure Liquid Chromatography Human I131 isotope In Vitro Investigation Iodine Iodine Radioisotopes Label Lead Ligands Major Groove Malignant Neoplasms Mismatch Repair Mismatch Repair Deficiency Mus Mutation Nucleotides Patient-Focused Outcomes Patients Performance Phenanthrolines Play Polymerase Positron Positron-Emission Tomography Prognosis Protein Family Radiation therapy Radio Radiolabeled Radiopharmaceuticals Rhodium Role Single Nucleotide Polymorphism Site Solid Neoplasm Specificity Syndrome Technology Thermodynamics Thin Layer Chromatography Toxic effect Validation Variant Wit Work Xenograft procedure analog base cancer cell cellular development chemical synthesis colon cancer cell line dosimetry experimental study gene repair genome integrity genotoxicity imaging agent improved in vivo in vivo evaluation innovation mouse model novel nuclear imaging radiotracer scaffold subcutaneous theranostics therapeutic target tool tumor tumor behavior tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY / ABSTRACT DNA repair pathways are critical for maintaining the integrity of the genome. Yet polymerase errors and exposure to genotoxic chemicals may lead to the dysregulation of the mismatch repair (MMR) machinery, the family of proteins responsible for identifying and correcting mispaired bases in genomic DNA. When this machinery malfunctions - or is absent altogether - single base mismatches can accumulate, making cells prone to the generation of single nucleotide polymorphisms (SNPs) and, eventually, tumorigenesis. Indeed, up to 20% of all solid tumors have been shown to be MMR-deficient. Most notably, MMR-deficiency plays a significant role in the development of hereditary nonpolyposis colorectal cancer (HNPCC). The last twenty years have witnessed the development of octahedral rhodium complexes that selectively and specifically bind DNA mismatches. These compounds, known as ‘metalloinsertors’, have been shown to exhibit preferential anti- proliferative effects in vitro in MMR-deficient vs. MMR-proficient colorectal cancer cells and to inhibit tumor growth in vivo in a murine model of colorectal cancer. This F31 proposal is focused on the synthesis, in vitro evaluation, and in vivo validation of a novel family of radiopharmaceuticals based on the mismatch-targeting metalloinsertor RhPBC. We first plan to synthesize non- radioactive natI-RhPBC to facilitate the chemical and biological characterization of the probe. Subsequently, we will create analogues of the metalloinsertor labeled with radioisotopes of iodine - either positron-emitting iodine- 124 (124I; t1/2 ~ 4.2 d) or ß-emitting iodine-131 (131I; t1/2 ~ 8.0 d) - to create radiopharmaceuticals for PET imaging and endoradiotherapy, respectively. Specific Aim 1 will be focused on the chemical synthesis and analysis of all three compounds (natI-RhPBC, 124I-RhPBC, and 131I-RhPBC) as well as the biological characterization and in vitro evaluation of the compounds in a pair of isogenic human colorectal cancer cell lines that are identical except for their MMR-proficiency (HCT116N) or MMR-deficiency (HCT116O). In Specific Aim 2, PET imaging and biodistribution experiments will be used to evaluate the in vivo performance of 124I-RhPBC as a diagnostic and theranostic imaging agent in a murine model MMR-deficient colorectal cancer. And finally, Specific Aim 3 will be centered on the in vivo evaluation of 131I-RhPBC as a radiotherapeutic using biodistribution studies, dosimetry calculations, and longitudinal therapy studies in a murine models of MMR-deficient colorectal cancer. We contend that this project is both highly innovative and highly impactful. To the best of our knowledge, DNA mismatches have never before been a target for nuclear imaging and therapy, and octahedral rhodium complexes have not been harnessed as scaffolds for radiotracers. In the short term, this work could produce an imaging agent that could be a useful tool in the clinical management of patients with MMR-deficient tumors. In the longer term, this investigation could also yield a first-in-class radiotherapeutic that could be used against a variety of MMR-deficient tumors, improving prognoses and outcomes for patients with these malignancies.

项目总结/摘要 DNA修复途径对于维持基因组的完整性至关重要。然而，聚合酶的错误，暴露于遗传毒性化学物质可能导致错配修复（MMR）机制失调，负责识别和纠正基因组DNA中错配碱基的蛋白质家族。当这个机器故障-或完全没有-单碱基错配可以积累，使细胞容易产生单核苷酸多态性（SNP），并最终导致肿瘤发生。事实上，到20%的所有实体瘤已被证明是MMR缺陷的。最值得注意的是，MMR缺乏症在遗传性非息肉病性结直肠癌（HNPCC）的发展中起重要作用。过去的二十年已经见证了八面体铑络合物的发展，其选择性地和特异性地结合DNA 不匹配这些化合物，被称为“金属插入物”，已被证明表现出优先的抗- 在MMR缺陷型结肠直肠癌细胞与MMR功能型结肠直肠癌细胞中的体外增殖作用和抑制肿瘤生长的研究在结肠直肠癌的鼠模型中的体内生长。该F31提案集中于合成、体外评价和体内验证一个新的家族，基于错配靶向金属插入剂RhPBC的放射性药物。我们首先计划合成非- 放射性natI-RhPBC，以促进探针的化学和生物学表征。后续我们将创造出用碘的放射性同位素标记的金属插入物的类似物--正电子发射碘-- 124（124 I; t1/2 ~ 4.2 d）或放射性碘-131（131 I; t1/2 ~ 8.0 d）-用于PET成像的放射性药物和腔内放射治疗。具体目标1将侧重于化学合成和分析所有三种化合物（natI-RhPBC、124 I-RhPBC和131 I-RhPBC）以及生物学表征和化合物在一对等基因人结肠直肠癌细胞系中的体外评价，对于他们的MMR-熟练（HCT 116 N）或MMR-缺陷（HCT 116 O）。在特定目标2中，PET成像和生物分布实验将用于评价124 I-RhPBC作为诊断和治疗药物的体内性能。 MMR缺陷型结肠直肠癌小鼠模型中的治疗诊断显像剂。最后，《特定目标3》将集中于使用生物分布研究、剂量测定法对131 I-RhPBC作为放射性物质的体内评价计算和在MMR缺陷型结肠直肠癌的鼠模型中的纵向治疗研究。我们认为，这个项目既具有高度创新性，又具有高度影响力。据我们所知， DNA错配以前从未成为核成像和治疗的目标，复合物还没有被用作放射性示踪剂的支架。在短期内，这项工作可以产生一个成像剂，可能是一个有用的工具，在临床管理的患者与MMR缺陷的肿瘤。在从长远来看，这项研究还可能产生一流的放射性物质，可用于对抗多种MMR缺陷肿瘤，改善这些恶性肿瘤患者的预后和结局。