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
基本信息
- 批准号:8398936
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAdverse effectsAffinityAntibodiesAntigen TargetingAntigensBacteriophagesBindingBreastBreast CarcinomaCancer DetectionCancer DiagnosticsCarbohydratesCarcinomaCause of DeathCell-Cell AdhesionCharacteristicsClinicClinicalCysteineDetectionDevelopmentDiagnosticDiagnostic ImagingDiseaseDisseminated Malignant NeoplasmDrug KineticsEmission-Computed TomographyEngineeringExcretory functionFemaleFoundationsFutureGalectin 3GenderGoalsHealthHealth Services ResearchHealthcareHumanImageIn VitroKidneyLabelLeadLibrariesLigandsMalignant NeoplasmsMalignant neoplasm of ovaryMalignant neoplasm of prostateMammary NeoplasmsMedicalMethodsMilitary PersonnelMissionModalityModelingMolecular BiologyMolecular ProbesMolecular WeightMusNeoplasm MetastasisOvarian CarcinomaOvaryPatientsPeptidesPhage DisplayPopulationPositronProstateProstate carcinomaProstatic NeoplasmsProtein EngineeringRadiochemistryRadioimmunoconjugateRadiolabeledRadiopharmaceuticalsResearchSignal PathwaySignal TransductionSpecificityStagingStructureTestingTherapeuticThompson-Friedenreich AntigenTranslatingTranslationsTreatment EfficacyTumor AntigensUnited StatesUnited States Department of Veterans AffairsVeteransWomanWorkbasecancer cellcancer diagnosiscancer imagingcancer therapyerbB-2 Receptorimprovedin vivoinnovationmalemalignant breast neoplasmmeetingsnovelnovel strategiesoptical imagingovarian neoplasmoverexpressionpolypeptidepublic health relevanceradiotracerresponsescaffoldscreeningsingle photon emission computed tomographytumortumor growthtumor specificitytumorigenesisuptake
项目摘要
DESCRIPTION (provided by applicant):
Cancer is the second leading cause of death in the United States and US Veterans. Over 28% of cancer diagnoses in US Veterans in 2009 were for prostate, breast, and ovarian carcinoma. However, these cancers are often asymptomatic in beginning stages of the disease. Prostate cancer is a major health problem in male Veterans and it has been estimated that over 25% already have prostate cancer. Gender-associated breast and ovarian cancers are also of concern, especially since one out of every 15 Veterans is female. A VA Center for Women has been established in order to better address the rising medical needs of our female Veterans. While screening and detection methods exist for these cancers, they all have limitations. It can be envisioned that the use of molecules that specifically target antigens on carcinomas and metastases will lead to improved cancer detection and treatment modalities. Radiolabeled antibodies and peptides are currently being explored as diagnostic cancer imaging agents. However, high molecular weight antibodies as well as small peptides may not be ideal as cancer imaging agents in vivo. Only a small number of radiolabeled antibodies and peptides possess the requisite high affinity, specificity, stability, and tumor uptake to serve as cancer imaging agents. Thus, finding new cancer targeting vehicles and cancer-associated antigens is a central goal of the field. Development of specific tumor-targeting molecules that can be used safely and non- invasively to detect and treat cancer is undeniably an important priority for the Veterans Administration if it is to meet the health care challenges of our past, current, and future military personnel. New peptide-based molecular probes to facilitate cancer imaging are rapidly evolving due to implementation of bacteriophage (phage) display approaches. While radiolabeled peptides have shown good tumor-targeting propensity in vitro, their translation into the clinic has been slowed by sub-optimal tumor retention and almost universal high renal uptake and retention. We have used phage display to obtain peptides that target the tumor-associated ErbB-2 receptor, galectin-3 (gal-3) and its carbohydrate ligand Thomsen- Friedenreich (TF) antigen, which are involved in cancer cell adhesion and signaling. We hypothesize that peptides that bind ErbB-2, gal-3, and TF grafted into constrained loops of polypeptide scaffolds once radiolabeled, will form the foundation for novel single photon emission computed tomography (SPECT) and positron emission computed tomography (PET) imaging agents for prostate, breast, and ovarian tumors. We will expand the applications of phage display to employ innovative functional selection approaches in vivo to improve the imaging and, potentially, therapeutic efficacy of the tumor-targeting radiolabeled peptides. The radiolabeled conjugates may serve as diagnostic radiopharmaceuticals for the detection of primary and metastatic cancer and indicators of response to therapy. In the long term, the peptides may function in vivo to reduce tumor growth and metastasis by blocking signaling pathways involved in tumorigenesis. Diverse molecular biology, protein engineering, radiochemistry, and optical imaging approaches will be employed. The objectives of this proposed research are to: 1) select phage display libraries based on the ErbB-2 and gal-3-targeting sequences in mice in order to identify phage and corresponding peptides with high tumor uptake and low kidney retention; 2) engineer the optimized peptide motifs into stable small molecular weight cysteine-constrained scaffolds for enhanced in vivo stability, affinity, and rapid excretion;
3) compare the in vivo SPECT imaging efficacy of 111Indium-radiolabeled ErbB-2-, gal-3-, and TF- targeting linear peptides and engineered peptide scaffolds in at least one appropriate tumor model (i.e. breast, prostate or ovary); and 4) develop 64Copper-labeled peptide counterparts for sensitive PET imaging. This work is significant and relevant to the VA mission because the peptides discovered here may translate into novel prostate, breast, and ovarian cancer diagnostics and therapeutics for our veterans.
描述(由申请人提供):
癌症是美国和美国退伍军人的第二大死亡原因。2009年,美国退伍军人中超过28%的癌症诊断是前列腺癌,乳腺癌和卵巢癌。然而,这些癌症在疾病的开始阶段通常是无症状的。前列腺癌是男性退伍军人的主要健康问题,据估计,超过25%的人已经患有前列腺癌。与性别相关的乳腺癌和卵巢癌也令人关切,特别是因为每15名退伍军人中就有一名是女性。为了更好地满足我们女性退伍军人日益增长的医疗需求,已经建立了一个退伍军人妇女中心。虽然存在针对这些癌症的筛查和检测方法,但它们都有局限性。可以设想,使用特异性靶向癌和转移灶上的抗原的分子将导致改进的癌症检测和治疗方式。放射性标记的抗体和肽目前正在探索作为诊断癌症的成像剂。然而,高分子量抗体以及小肽可能不是理想的体内癌症显像剂。只有少数放射性标记的抗体和肽具有必要的高亲和力、特异性、稳定性和肿瘤摄取,以用作癌症成像剂。因此,发现新的癌症靶向载体和癌症相关抗原是该领域的中心目标。开发可以安全和非侵入性地用于检测和治疗癌症的特异性肿瘤靶向分子是退伍军人管理局的一个重要优先事项,如果它要满足我们过去,现在和未来军事人员的医疗保健挑战。 由于噬菌体展示方法的实施,促进癌症成像的新的基于肽的分子探针正在迅速发展。虽然放射性标记的肽在体外显示出良好的肿瘤靶向倾向,但其向临床的转化因次优的肿瘤保留和几乎普遍的高肾摄取和保留而减慢。我们已经使用噬菌体展示来获得靶向肿瘤相关的ErbB-2受体、半乳糖凝集素-3(gal-3)及其碳水化合物配体Erbsen-Friedenreich(TF)抗原的肽,其参与癌细胞粘附和信号传导。我们假设,一旦放射性标记,结合ErbB-2,gal-3和TF移植到多肽支架的约束环的肽,将形成用于前列腺,乳腺和卵巢肿瘤的新型单光子发射计算机断层扫描(SPECT)和正电子发射计算机断层扫描(PET)成像剂的基础。我们将扩大噬菌体展示的应用,采用创新的功能选择方法在体内,以改善成像,并可能,肿瘤靶向放射性标记肽的治疗效果。放射性标记的缀合物可用作诊断放射性药物,用于检测原发性和转移性癌症以及对治疗的反应的指示剂。从长远来看,这些肽可以在体内发挥作用,通过阻断参与肿瘤发生的信号通路来减少肿瘤生长和转移。 将采用不同的分子生物学,蛋白质工程,放射化学和光学成像方法。本研究的目的是:1)在小鼠中筛选基于ErbB-2和gal-3靶向序列的噬菌体展示文库,以鉴定具有高肿瘤摄取和低肾滞留的噬菌体和相应的肽; 2)将优化的肽基序工程化为稳定的小分子量半胱氨酸限制性支架,以增强体内稳定性、亲和力和快速排泄;
3)在至少一种适当的肿瘤模型(即乳腺、前列腺或卵巢)中比较111铟放射性标记的ErbB-2-、gal-3-和TF-靶向线性肽和工程化肽支架的体内SPECT成像功效;和4)开发用于灵敏PET成像的64铜标记的肽对应物。这项工作是重要的,相关的VA使命,因为这里发现的肽可能会转化为新的前列腺癌,乳腺癌和卵巢癌的诊断和治疗我们的退伍军人。
项目成果
期刊论文数量(0)
专著数量(0)
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SUSAN L DEUTSCHER其他文献
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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 用于卵巢癌体内纳米α疗法
- 批准号:
8769083 - 财政年份:2014
- 资助金额:
-- - 项目类别:
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:
-- - 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:
-- - 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:
-- - 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:
-- - 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:
-- - 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:
-- - 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:
-- - 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:
-- - 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:
-- - 项目类别:
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