Development of Superior Chelation Chemistry for 89Zr-ImmunoPET Imaging
开发用于 89Zr-ImmunoPET 成像的高级螯合化学
基本信息
- 批准号:10256794
- 负责人:
- 金额:$ 38.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAntibodiesBT 474BindingBiodistributionBiologicalBiological MarkersBloodBone MarrowBreastChelating AgentsChemistryClinicalClinical ResearchClinical TrialsColon CarcinomaComplexDataDeferoxamineDevelopmentDiagnosisDiscipline of Nuclear MedicineDiseaseDissociationDrug KineticsDurapatiteEdetic AcidEvaluationFemaleGenerationsHalf-LifeHumanImageImaging TechniquesImmunoPETIn SituIn VitroIncubatedInvestigationKineticsLS174T colon cancer cell lineLabelLeadLibrariesLigandsMetabolismMineralsModelingMolecular TargetMusNude MiceOrganPositronPositron-Emission TomographyRadiation ToxicityRadioactivityRadioimmunoconjugateRadioisotopesRadiolabeledRadionuclide therapyRadiopharmaceuticalsReactionResearchRoentgen RaysSeriesSerumStagingStructureSystemTargeted RadiotherapyTechnologyTemperatureTissuesToxic effectTracerTrastuzumabVariantWomanXenograft procedureZirconiumabsorptionantibody conjugateauthoritybasebonecancer imagingcellular imagingchelationclinical developmentcomplex IVdesigndosimetryexperiencefluorodeoxyglucoseimaging agentimaging probeimaging studyimmunoreactivityimprovedin vivoin vivo evaluationinnovationmalemalignant breast neoplasmmetabolic abnormality assessmentmetastatic colorectalneoplastic cellnon-invasive imagingnovelpanitumumabpreclinical studypreclinical trialprematureresponsesmall moleculespecific biomarkerstooltumoruptake
项目摘要
ABSTRACT
Positron emission tomography (PET) is a sensitive and non-invasive imaging technique applicable to diagnosis
and staging of various diseases. Research efforts have been devoted to develop tumor-specific PET imaging
probes. Zirconium-89 (89Zr, t1/2 = 78 h) is a positron-emitting radionuclide suitable for targeted PET imaging of
tumors using an antibody with a relatively long biological half-life.
89Zr is known to display a high binding affinity for bone mineral, hydroxylapatite (HA). Premature release of 89Zr
from 89Zr-based biomolecules during clinical PET imaging can lead to high accumulation of radioactivity in bone
and generate radiation toxicity including bone marrow toxicity. Less stable 89Zr-labeled PET tracers also result
in diminished image quality and inaccurate dosimetry. Therefore, a stable 89Zr-complex using an optimal chelator
should be employed for safe and sensitive immuno-PET imaging. Such an effective chelator is also required for
practical labeling of a temperature-sensitive antibody with highly energetic 89Zr under mild reaction conditions to
minimize radiolytic damage resulting from extended exposure of the antibody.
Clinical potential of 89Zr-radiopharmaceuticals for PET imaging of cancers has been well demonstrated in
numerous preclinical and clinical trials. While DFO (desferrioxamine B) is currently used as the standard for
chelation of 89Zr, DFO-antibody conjugates labeled with 89Zr have limited in vivo stability resulting in high
accumulation in normal organs and tissues, including bone.
The objective of this investigation is to create fluorescent novel chelators of 89Zr built on the structurally unique
coordinating groups and chelation chemistry that the PI invented. Innovative aspects of this investigation include
i) development of new small molecule donors with high binding affinity for 89Zr and ii) construction of new ligand
platforms that can form a highly stable complex with 89Zr and iii) application of novel self-fluorescent chelators
for in situ analysis of unbound 89Zr and bound 89Zr complexes.
Specific aims of this proposal are i) rational design of novel chelation chemistry with high affinity for 89Zr(IV); ii)
library synthesis of the new chelators with structural variations; iii) evaluation of new chelators for radiolabeling
kinetics and complex stability with 89Zr and spectrophotometric and fluorescent analysis of 89Zr complexes; iv)
selection and conjugation of the best (see above criteria) chelators to a model antibody; v) biodistribution,
pharmacokinetics, metabolism, and PET imaging studies of the best chelator-antibody conjugates using tumor
bearing mice. Completion of this study is proposed to materialize superior 89Zr chelation chemistry that will
contribute to development of clinically viable PET tracers for sensitive and safe imaging of various diseases and
accurate dosimetry of targeted radiotherapy using different α- or β--emitting radionuclides.
抽象的
正电子发射断层扫描(PET)是一种灵敏的非侵入性成像技术,适用于诊断
以及各种疾病的分期。研究工作致力于开发肿瘤特异性 PET 成像
探针。 Zirconia-89 (89Zr, t1/2 = 78 h) 是一种正电子发射放射性核素,适用于以下物质的靶向 PET 成像:
使用生物半衰期相对较长的抗体来治疗肿瘤。
已知 89Zr 对骨矿物质羟基磷灰石 (HA) 具有高结合亲和力。 89Zr过早释放
临床 PET 成像过程中基于 89Zr 的生物分子可能导致骨中放射性物质大量积累
并产生包括骨髓毒性在内的放射毒性。还导致 89Zr 标记的 PET 示踪剂稳定性较差
图像质量下降和剂量测定不准确。因此,使用最佳螯合剂的稳定 89Zr 络合物
应用于安全且灵敏的免疫 PET 成像。还需要这种有效的螯合剂
在温和反应条件下用高能 89Zr 实际标记温度敏感抗体
最大限度地减少因抗体长时间暴露而造成的放射分解损伤。
89Zr 放射性药物用于癌症 PET 成像的临床潜力已在
大量的临床前和临床试验。目前,DFO(去铁胺 B)被用作
89Zr 的螯合,用 89Zr 标记的 DFO-抗体缀合物体内稳定性有限,导致高
在正常器官和组织(包括骨骼)中积累。
本研究的目的是创建基于结构独特的 89Zr 荧光新型螯合剂
PI 发明的配位基团和螯合化学。本次调查的创新之处包括
i) 开发对 89Zr 具有高结合亲和力的新小分子供体和 ii) 构建新配体
可以与 89Zr 形成高度稳定的复合物的平台和 iii) 新型自荧光螯合剂的应用
用于未结合 89Zr 和结合 89Zr 配合物的原位分析。
该提案的具体目标是 i) 合理设计对 89Zr(IV) 具有高亲和力的新型螯合化学;二)
具有结构变化的新螯合剂的文库合成; iii) 放射性标记新螯合剂的评估
89Zr 的动力学和络合物稳定性以及 89Zr 络合物的分光光度和荧光分析;四)
选择最佳(参见上述标准)螯合剂并将其与模型抗体结合; v) 生物分布,
使用肿瘤进行最佳螯合剂-抗体偶联物的药代动力学、代谢和 PET 成像研究
承载老鼠。完成这项研究旨在实现卓越的 89Zr 螯合化学,这将
致力于开发临床上可行的 PET 示踪剂,用于各种疾病的灵敏且安全的成像
使用不同的 α 或 β 发射放射性核素进行靶向放射治疗的精确剂量测定。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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HYUN-SOON CHONG其他文献
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{{ truncateString('HYUN-SOON CHONG', 18)}}的其他基金
New Bifunctional Ligands for Radioimmunotherapy
用于放射免疫治疗的新型双功能配体
- 批准号:
9206456 - 财政年份:2006
- 资助金额:
$ 38.65万 - 项目类别:
New Bifunctional Ligands for Radioimmunotherapy
用于放射免疫治疗的新型双功能配体
- 批准号:
8784193 - 财政年份:2006
- 资助金额:
$ 38.65万 - 项目类别:
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用于放射免疫治疗的新型双功能配体
- 批准号:
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New bifunctional ligands for radioimmunotherapy
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New bifunctional ligands for radioimmunotherapy
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