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:
- 金额:$ 3.22万
- 依托单位:
- 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:
- 关键词:AdenineAffinityBase Pair MismatchBase PairingBindingBiodistributionBiologicalCell ProliferationCellsChemicalsClinical ManagementColorectal CancerComplexCritical PathwaysCytosineDNADNA BindingDNA Minor Groove BindingDNA RepairDNA Repair PathwayDataDevelopmentDiagnosticEukaryotic CellEvaluationExhibitsExposure toFamilyFamily memberGenerationsGenomeGenomic DNAHalogensHandHereditary Nonpolyposis Colorectal NeoplasmsHigh Pressure Liquid ChromatographyHumanI131 isotopeIn VitroInvestigationIodineIodine RadioisotopesLabelLeadLigandsMajor GrooveMalignant NeoplasmsMismatch RepairMismatch Repair DeficiencyMusMutationNucleotidesPatient-Focused OutcomesPatientsPerformancePhenanthrolinesPlayPolymerasePositronPositron-Emission TomographyPrognosisProtein FamilyRadiation therapyRadioRadiolabeledRadiopharmaceuticalsRhodiumRoleSingle Nucleotide PolymorphismSiteSolid NeoplasmSpecificitySyndromeTechnologyThermodynamicsThin Layer ChromatographyToxic effectValidationVariantWitWorkXenograft procedureanalogbasecancer cellcellular developmentchemical synthesiscolon cancer cell linedosimetryexperimental studygene repairgenome integritygenotoxicityimaging agentimprovedin vivoin vivo evaluationinnovationmouse modelnovelnuclear imagingradiotracerscaffoldsubcutaneoustheranosticstherapeutic targettooltumortumor behaviortumor growthtumorigenesis
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。
项目成果
期刊论文数量(0)
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Samantha Patricia Delaney其他文献
Samantha Patricia Delaney的其他文献
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{{ truncateString('Samantha Patricia Delaney', 18)}}的其他基金
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
- 批准号:
10686864 - 财政年份:2022
- 资助金额:
$ 3.22万 - 项目类别:
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