Radiometal Chelates for Targeted Therapy of Melanoma

描述(申请人提供)：恶性黑色素瘤是一种发病率越来越高的破坏性疾病。虽然原发肿瘤可以通过手术成功切除，但转移性黑色素瘤还没有令人满意的治疗方法。该项目采用了一种新的黑色素瘤放射免疫治疗(RIT)方法，该方法利用了黑色素瘤的快速生长和释放黑色素的高细胞周转和裂解。黑色素可通过针对黑色素和放射性标记的人黑色素结合肽产生的放射性标记黑色素结合单抗(MAb)而被靶向输送细胞毒性辐射。这种方法对于恶性黑色素瘤是高度选择性的，因为正常组织中的黑色素由于其细胞内的位置而不能被多肽和单抗获得。这项建议的目标有两个：优化用于稳定Re-188和方便Re-188标记的免疫结合物，并展示放射性稀土在黑色素瘤治疗中的应用。这些目标的实现将有助于理解放射性核素的β能量和半衰期与黑色素瘤治疗效果的关系，从而促进转移性黑色素瘤的RIT的临床引入。此外，从这个项目中学到的概念可以转化为其他类型的放射治疗。总体目标归结为三个具体目标。具体目标1解决了导致氧化还原活性Re-188稳定性提高的配体的特征的鉴定。特定目标2将这些优化的配体与黑色素结合多肽连接，并研究这些多肽结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。目的3研究具有一定半衰期、β能量、剂量率和穿透深度的稀土元素对生物分布和治疗效果的影响。整个项目的结果将是扩大用于黑色素瘤放射治疗的放射性核素的选择，这将考虑肿瘤的大小、密度和在体内的分布以及单抗或肽在体内的停留时间。该项目也为发展PI的研究现状提供了机会。在这个项目中学到的体外和体内分析将增加她健全的无机化学和合成技能，以增加她在3年后申请R01无机放射治疗领域资金的竞争力。

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.