Radiometal Chelates for Targeted Therapy of Melanoma

用于黑色素瘤靶向治疗的放射性金属螯合物

• 批准号: 7658223
• 负责人: LYNN CAROL FRANCESCONI
• 金额: $ 22.8万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-14 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658223
• 关键词: 90Y; Address; Amino Acids; Area; B-Cell NonHodgkins Lymphoma; Behavior; Binding; Biodistribution; Biological; Biological Assay; Cells; Clinical; Complex; Cytolysis; Development; Disease; Dose-Rate; Environment; FDA approved; Funding; Goals; Half-Life; Human; Immunoconjugates; In Vitro; Incidence; Inorganic Chemistry; Investigation; Isotopes; Lanthanoid Series Elements; Lead; Learning; Ligands; Link; Location; Malignant Neoplasms; Melanins; Metals; Metastatic Melanoma; Modality; Monoclonal Antibodies; Normal tissue morphology; Outcome; Outcome Study; Oxidation-Reduction; Patients; Penetration; Peptide Synthesis; Peptide antibodies; Peptides; Phase; Pigments; Primary Neoplasm; Property; Radiation; Radiation therapy; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Radiolabeled; Radionuclide therapy; Radiopharmaceuticals; Refractory; Relapse; Research; Research Infrastructure; Solid; Structure; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Translating; Treatment Efficacy; Work; Y 90 Ibritumomab Tiuxetan; base; cancer radiation therapy; chelation; cytotoxic; density; design; expectation; improved; in vivo; iodine-131-tositumomab; melanoma; metal complex; novel strategies; oxidation; particle; radiotracer; rapid growth; residence; skills; sound; stereochemistry; success; targeted delivery; tumor; vector

DESCRIPTION (provided by applicant): Malignant melanoma is a devastating disease with increasing incidence. While primary tumors can be successfully removed surgically, there is no satisfactory treatment for metastatic melanoma. This project employs a novel approach to radioimmunotherapy (RIT) of melanoma that takes advantage of the rapid growth of melanomas and the high cell turnover and lysis that releases melanin pigment. Melanin pigment can be targeted for delivery of cytotoxic radiation by a radiolabeled melanin-binding monoclonal antibody (mAb) generated against melanin and radiolabeled human melanin-binding peptides. This approach is highly selective for malignant melanoma because melanin in normal tissue is not accessible to the peptides and mAbs by virtue of its intracellular location. The objectives of this proposal are two-fold: to optimize immunoconjugates for stabilization of Re-188 and for convenience of Re-188 radiolabeling and to demonstrate the application of radiolanthanides for therapy of melanoma. Fulfillment of these objectives will provide an understanding of the relationship of beta energies and half-lives of radionuclides to therapeutic efficacy of melanoma, thus facilitating clinical introduction of RIT of metastatic melanoma. Moreover, the concepts that are learned from this project can be translated to other types of radiotherapy. The overall objectives are gathered into three specific aims. Specific aim 1 addresses identification of features of ligands that lead to improved stability of redox-active Re-188. Specific aim 2 links these optimized ligands to melanin-binding peptides and investigates the radiolabeling efficiency, Re-188 stability, and the in vitro and in vivo biological behavior of the peptide conjugates. Aim 3 investigates the impact of radiolanthanides that possess a range of half-lives, beta-energies, dose rates and penetration depths on biodistribution and therapeutic efficacy. The outcome of the entire project will be an expansion of the selection of radionuclides for radiotherapy of melanoma that will consider tumor size, density and disposition in the body as well as the mAb or peptide residence time in the body. This project also offers the opportunity to develop the PI's research status. The in vitro and in vivo assays learned in this project will add to her sound inorganic chemistry and synthetic skills to increase her competitiveness to apply for R01 funding in the area of inorganic radiotherapy at the end of 3 years.

描述（由申请人提供）：恶性黑色素瘤是一种毁灭性疾病，发病率增加。虽然原发性肿瘤可以通过手术成功地切除，但对于转移性黑色素瘤没有令人满意的治疗方法。该项目采用了一种新型的黑色素瘤放射免疫疗法（RIT）方法，该方法利用了黑色素瘤的快速生长以及高细胞更新和裂解，从而释放了黑色素颜料。黑色素颜料可以针对通过放射性标记的黑色素结合单克隆抗体（MAB）递送细胞毒性辐射，该抗体（MAB）抗黑色素和放射性标记的人类黑色素结合肽。这种方法对恶性黑色素瘤具有很高的选择性，因为正常组织中的黑色素因其细胞内的位置而无法获得正常组织中的黑色素。该提案的目标有两个方面：为了方便RE-188放射性标记，优化免疫偶联物，以方便起见，并证明放射性烷烷基在黑色素瘤治疗中的应用。实现这些目标将提供对β能量和放射性核素半衰期与黑色素瘤治疗功效的关系的理解，从而促进转移性黑色素瘤RIT的临床引入。此外，从该项目中学到的概念可以转化为其他类型的放射疗法。总体目标分为三个特定目标。具体目标1解决了配体特征的识别，从而改善了氧化还原活性RE-188的稳定性。具体的目标2将这些优化的配体与黑色素结合肽联系起来，并研究了肽缀合物的放射性标记效率，RE-188稳定性以及体外和体内生物学行为。 AIM 3研究了具有一系列半衰期，β-耐药，剂量率和穿透深度对生物分布和治疗功效的影响。整个项目的结果将是选择用于黑色素瘤放射疗法的放射性核素的扩展，该核素将考虑体内肿瘤的大小，密度和处置以及体内的MAB或肽停留时间。该项目还提供了开发PI研究状况的机会。该项目中学到的体外和体内分析将增加她的无机化学和合成技能，以提高她在3年结束的无机放射治疗领域申请R01资金的竞争力。