Targeting TF/CD44v6 for In Vivo Nano-generated alpha-therapy of Ovarian Cancer
靶向 TF/CD44v6 用于卵巢癌体内纳米α疗法
基本信息
- 批准号:8769083
- 负责人:
- 金额:$ 16.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcidsAdenocarcinomaAffinityAggressive behaviorAmino AcidsAntibodiesBacteriophagesBindingBiodistributionBiological AssayBiological AvailabilityBiological MarkersBiomedical EngineeringBloodCD44 geneCarcinomaCell LineCellsChemicalsComplexConfocal MicroscopyDataDevelopmentDiagnosisDiagnosticDiagnostic ImagingDisaccharidesDiseaseDisease ResistanceDoseDrug KineticsDrug resistanceEnergy TransferEngineeringEnsureEventExhibitsExposure toFatal OutcomeFlow CytometryGoalsHalf-LifeHomingHumanHyaluronic AcidHyaluronic Acid BindingImageIn VitroInvestigationKidneyLabelLigandsLinear Energy TransferMalignant NeoplasmsMalignant neoplasm of ovaryMusNatureNeoplasm MetastasisOrganOvarianOvarian CarcinomaPatientsPeptidesPhage DisplayPropertyRNA SplicingRadialRadiationRadioactivityRadioisotopesRadiolabeledRecurrenceRenal clearance functionResearchResistanceRoboticsSignal TransductionSiteSolutionsSpecificityStagingSurvival RateTechnologyTherapeuticTimeTissuesToxic effectVariantXenograft procedurebasecancer cellcancer therapycyclencytotoxicityglycosylationhepcidinhigh throughput screeningimmunogenicityin vivoin vivo imagingkillingsnanonanoparticlenoveloptical imagingoutcome forecastovarian neoplasmparticlepublic health relevanceradiotracerreceptorscaffoldscreeningsingle photon emission computed tomographytheranosticstumoruptake
项目摘要
DESCRIPTION (provided by applicant): The goal of this research is to use radiolabeled engineered peptide scaffolds for development of sensitive ovarian carcinoma diagnostic and therapeutic (theranostic) agents using a matched pair 203Pb/212Pb in vivo ¿-particle generator. The high linear energy transfer of a-particle is significantly higher than that of b-particle emittng radionuclides commonly used for therapy. Although the survival rates of early stage ovarian cancer are high, late stage disease is often fatal. The poor prognosis of ovarian cancer results from complicated diagnosis due to a largely asymptomatic disease development, the presence of aggressive metastatic cells, as well as a lack of biomarkers for disease stages. We propose to target the carcinoma-specific Thomsen- Friedenreich (TF) glycoantigen and the ovarian carcinoma biomarker CD44v6, a tumor-specific splice variant of the hyaluronic acid (HA) receptor CD44. CD44v6 glycosylation results in increased HA binding and internalization, leading to a multitude of signaling events. TF disaccharide is displayed on CD44, likely in the cancer-specific v6 region and is associated with invasion and metastasis. It is hypothesized that targeting this TF/CD44v6 glycoepitope will afford the specific localization of a-particle radiation
radioactivity to tumors for both imaging and therapy. The targeting vehicle employed will be an engineered derivative of 25 amino acid hepcidin that binds TF/CD44v6 and exhibits optimum in vivo properties compared to antibodies or small peptides, including high in vivo stability and rapid clearance through the kidney, thereby increasing tumor retention and reducing non-target organ radiation. Prolonged bioavailability and minimal exposure to healthy tissues may be further accomplished by delivery of HA to ensure internalization of the TF/CD44v6 peptide. The specific aims of the proposed research are to 1): select and characterize TF/CD44v6-avid phage display derived peptides; 2) bioengineer TF/CD44v6-avid peptide(s) into hepcidin scaffolds and characterize biotinylated and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated forms for their in vitro ovarian cancer cell binding properties; and 3) determine the pharmacokinetics, biodistribution and tumor-targeting ability of both 212Pb and 203Pb-labeled peptide conjugates in vivo in human ovarian carcinoma xenografted mice. The effect of HA treatment on the tumor retention of the radiolabeled hepcidin peptide scaffold will be determined by biodistribution studies. In order to visualize tumor homing, the peptide construct will be labeled with 203Pb for single photon emission computed tomography imaging. The proposed in vivo targeting of ovarian cancers with a-particle labeled peptide scaffolds has wide applicability for the imaging and treatment of ovarian cancer, which is important because early ovarian cancer is often asymptomatic and late stage ovarian cancer is usually fatal. Further, the technology proposed can be applied to target and kill other cancer cells, especially since TF is present on >80% of adenocarcinomas.
描述(由申请人提供):本研究的目标是使用放射性标记的工程肽支架,使用匹配的 203Pb/212Pb 体内 ¿ 粒子发生器来开发敏感的卵巢癌诊断和治疗(治疗诊断)剂。 a 粒子的高线性能量传递明显高于通常用于治疗的发射放射性核素的 b 粒子。尽管早期卵巢癌的生存率很高,但晚期疾病往往是致命的。卵巢癌的预后不良是由于疾病发展很大程度上无症状、存在侵袭性转移细胞以及缺乏疾病阶段的生物标志物而造成的复杂诊断。我们建议以癌症特异性 Thomsen-Friedenreich (TF) 糖抗原和卵巢癌生物标志物 CD44v6 为目标,CD44v6 是透明质酸 (HA) 受体 CD44 的肿瘤特异性剪接变体。 CD44v6 糖基化导致 HA 结合和内化增加,从而导致大量信号传导事件。 TF 二糖显示在 CD44 上,可能位于癌症特异性 v6 区域,与侵袭和转移相关。据推测,靶向该 TF/CD44v6 糖表位将提供 a 粒子辐射的特异性定位
用于成像和治疗的肿瘤放射性。所采用的靶向载体将是25个氨基酸的铁调素的工程化衍生物,它与TF/CD44v6结合,并与抗体或小肽相比表现出最佳的体内特性,包括高体内稳定性和通过肾脏的快速清除,从而增加肿瘤保留并减少非靶器官辐射。通过递送HA以确保TF/CD44v6肽的内化,可以进一步实现延长的生物利用度和最小化对健康组织的暴露。本研究的具体目标是 1):选择并表征 TF/CD44v6-avid 噬菌体展示衍生肽; 2) 将 TF/CD44v6-avid 肽生物工程化为铁调素支架,并表征生物素化和 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸 (DOTA) 缀合形式的体外卵巢癌细胞结合特性; 3) 确定 212Pb 和 203Pb 标记的肽缀合物在人卵巢癌异种移植小鼠体内的药代动力学、生物分布和肿瘤靶向能力。 HA治疗对放射性标记的铁调素肽支架的肿瘤保留的影响将通过生物分布研究来确定。为了可视化肿瘤归巢,肽构建体将用 203Pb 标记,用于单光子发射计算机断层扫描成像。所提出的用α粒子标记的肽支架体内靶向卵巢癌对于卵巢癌的成像和治疗具有广泛的适用性,这很重要,因为早期卵巢癌通常无症状,而晚期卵巢癌通常是致命的。此外,所提出的技术可用于靶向和杀死其他癌细胞,特别是因为 TF 存在于 > 80% 的腺癌中。
项目成果
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{{ truncateString('SUSAN L DEUTSCHER', 18)}}的其他基金
Targeting TF/CD44v6 for In Vivo Nano-generated alpha-therapy of Ovarian Cancer
靶向 TF/CD44v6 体内纳米α疗法治疗卵巢癌
- 批准号:
8878206 - 财政年份:2014
- 资助金额:
$ 16.6万 - 项目类别:
Multivalent Nanophage Engineered as Dual Receptor Cancer Theranostic Agents.
多价纳米噬菌体被设计为双受体癌症治疗剂。
- 批准号:
8569062 - 财政年份:2013
- 资助金额:
$ 16.6万 - 项目类别:
Phage Display for Improved Peptide-Based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
10343781 - 财政年份:2011
- 资助金额:
$ 16.6万 - 项目类别:
Phage Display for Improved Peptide-based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
8263685 - 财政年份:2011
- 资助金额:
$ 16.6万 - 项目类别:
Phage Display for Improved Peptide-Based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
10554256 - 财政年份:2011
- 资助金额:
$ 16.6万 - 项目类别:
Phage Display for Improved Peptide-Based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
10115970 - 财政年份:2011
- 资助金额:
$ 16.6万 - 项目类别:
Phage Display for Improved Peptide-based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
8398936 - 财政年份:2011
- 资助金额:
$ 16.6万 - 项目类别:
Phage Display for Improved Peptide-Based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
9236073 - 财政年份:2011
- 资助金额:
$ 16.6万 - 项目类别:
Phage Display for Improved Peptide-based Tumor Targeting and Imaging Agents
用于改进基于肽的肿瘤靶向和成像剂的噬菌体展示
- 批准号:
8138754 - 财政年份:2011
- 资助金额:
$ 16.6万 - 项目类别:
Improved Peptide-based Tumor Targeting Agents Using Phage Display
使用噬菌体展示改进基于肽的肿瘤靶向剂
- 批准号:
7775087 - 财政年份:2009
- 资助金额:
$ 16.6万 - 项目类别:
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