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
• 负责人: SUSAN L DEUTSCHER
• 金额: $ 19.82万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878206
• 关键词: Acids; Adenocarcinoma; Affinity; Aggressive behavior; Amino Acids; Antibodies; Bacteriophages; Binding; Biodistribution; Biological Assay; Biological Availability; Biological Markers; Biomedical Engineering; Blood; CD44 gene; Carcinoma; Cell Line; Cells; Chemicals; Complex; Confocal Microscopy; Data; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Disaccharides; Disease; Disease Resistance; Dose; Drug Kinetics; Drug resistance; Energy Transfer; Engineering; Ensure; Event; Exhibits; Exposure to; Fatal Outcome; Flow Cytometry; Goals; Half-Life; Health; Homing; Human; Hyaluronic Acid; Hyaluronic Acid Binding; Image; In Vitro; Investigation; Kidney; Label; Ligands; Linear Energy Transfer; Malignant Neoplasms; Malignant neoplasm of ovary; Mus; Nature; Neoplasm Metastasis; Organ; Ovarian; Ovarian Carcinoma; Patients; Peptides; Phage Display; Property; RNA Splicing; Radial; Radiation; Radioactivity; Radioisotopes; Radiolabeled; Recurrence; Renal clearance function; Research; Resistance; Robotics; Signal Transduction; Site; Solutions; Specificity; Staging; Survival Rate; Technology; Therapeutic; Time; Tissues; Toxic effect; Variant; Xenograft procedure; base; cancer cell; cancer therapy; cyclen; cytotoxicity; glycosylation; hepcidin; high throughput screening; immunogenicity; in vivo; killings; nano; nanoparticle; novel; optical imaging; outcome forecast; ovarian neoplasm; particle; radiotracer; receptor; scaffold; screening; single photon emission computed tomography; theranostics; tumor; uptake

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 α-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）：本研究的目的是使用放射性标记工程肽支架，使用配对的203Pb/212Pb体内α-颗粒发生器，用于开发敏感的卵巢癌诊断和治疗（治疗）药物。a粒子的高线性能量转移明显高于b粒子发射的放射性核素，通常用于治疗。虽然早期卵巢癌的存活率很高，但晚期疾病往往是致命的。卵巢癌预后差的原因是由于疾病发展无症状，存在侵袭性转移细胞，以及缺乏疾病分期的生物标志物，导致诊断复杂。我们建议靶向肿瘤特异性Thomsen- Friedenreich （TF）糖抗原和卵巢癌生物标志物CD44v6（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，导致大量信号转导事件。TF双糖显示在CD44上，可能位于癌症特异性的v6区域，并与侵袭和转移有关。假设靶向这个TF/CD44v6糖表位可以提供a粒子辐射的特异性定位