Targeting alpha particle-emitting radionuclides to the nuclei of cancer cells

将发射α粒子的放射性核素靶向癌细胞的细胞核

• 批准号: 7394610
• 负责人: THOMAS P. QUINN
• 金额: $ 11.6万
• 依托单位: ALPHAMED, INC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394610
• 关键词: 4-Nle-7-Phe-alpha-mSH; Alpha Particles; Animal Cancer Model; Animal Model; Animals; Antigen Targeting; Applications Grants; Astatine; Binding; Biodistribution; Biological; Biological Assay; Bismuth; Caliber; Cell Death; Cell Nucleus; Cell Survival; Cells; Classification; Clinical Trials; Coupled; Cytoplasm; Data; Daughter; Deposition; Detection; Development; Disease; Dose; Dose-Rate; Drug Kinetics; Drug or chemical Tissue Distribution; Effectiveness; Exhibits; External Beam Radiation Therapy; Goals; Grant; Guidelines; Health; Heterogeneity; Human; In Vitro; Incidence; Kinetics; Label; Laboratories; Length; Life; Life Expectancy; Linear Energy Transfer; Localized; Malignant Neoplasms; Mammals; Maximum Tolerated Dose; Melanoma Cell; Metastatic Melanoma; Mus; Neoplasm Metastasis; Neoplasms; Nuclear; Numbers; Organ; Oxygen; Parents; Patients; Peptide Synthesis; Peptides; Phase; Primary Neoplasm; Probability; Production; Property; Radiation; Radiation therapy; Radioactivity; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Relative (related person); Research; Resistance; Scheme; Serous; Small Business Technology Transfer Research; Solid Neoplasm; Staging; Survival Analysis; Targeted Radiotherapy; Testing; Therapeutic; Therapeutic Index; Tissues; Toxicity Tests; Treatment Efficacy; Tumor Cell Nuclei; alpha-Melanocyte stimulating hormone; base; cancer cell; cancer radionuclide therapy; cancer therapy; cancer type; cell killing; cost; cytotoxic; cytotoxicity; design; fluorescence imaging; improved; in vivo; killings; melanoma; milligram; neoplastic cell; particle; peptide analog; pre-clinical therapy; preclinical study; prototype; radiotracer; size; tumor

DESCRIPTION (provided by applicant): This proposal outlines a body of research to evaluate the cytotoxicity and therapeutic efficacy of radiolabeled alpha-melanocyte stimulating hormone (a-MSH) peptide analogs that target a-particle emitting radioisotopes to the nuclei of melanoma cells. The selective targeting of alpha-particle emitting radioisotopes for cancer therapy is emerging as an exciting and potentially powerful new treatment strategy in targeted radiotherapy. Alpha-radiation is so densely ionizing that it forms destructive radicals directly, independent of oxygen content of the tissue and its cytotoxicity is independent of the dose rate, resulting in potentially powerful therapeutic index. The pathlengths of a-particles are short, on the order of 55-80 ¿m (~4-6 cell diameters), therefore, the cytotoxic properties of a-particles are highly focused, which minimizes collateral radiation damage of healthy tissues. Based on microdosimetry studies on a-particle cytotoxicity, it appears that a-particles must traverse the cell nucleus to be effective in causing cell death. Designing a biological targeting vehicle that would deposit an a-emitter in the nucleus of a cell would be highly advantageous. To that end a prototype nuclear targeting a-MSH peptide (DOTA-NT-MSH) was developed and shown to localize in the nuclei of melanoma cell by fluorescence imaging. The goal of the proposed research is to determine the efficacy targeting a- emitting radionuclides to the nucleus in vitro at the cellular level and in vivo in melanoma animal models. The specific objectives of this research are: 1) optimize the radiolabeling efficiency and purification of the nuclear targeting peptide with 212 Pb the parent of the alpha emitter 212 Bi, 2) examine the in vitro subcellular distribution and cytotoxicity of 212 Pb-labeled DOTA-NT-MSH and a control DOTA-nonspecific peptide, 3) determine the biodistribution of DOTA-NT-MSH and DOTA-NDPMSH peptides in melanoma bearing mice. Malignant melanoma is a serous health problem due to an increase in incidence and resistance to conventional chemotherapeutics and external beam radiation. In spite of recent advances in cancer therapy, the median life expectancy for patients with disseminated metastatic disease remains at 12-15 months. There is a clear need for the development of new and efficacious therapy agents to attack malignant melanoma. The development of targeted a-therapy for malignant melanoma is attractive since the short particle pathlength of a-emitters is particularly well match small clusters of disseminated tumor cells that characterize metastatic disease. Preliminary results from our laboratory have demonstrated that peptide targeted a-emitters are very effective in treating melanoma in pre-clinical therapy studies. Refinement of the peptide-targeted a-therapy approach through nuclear localization of radionuclides should result in improved therapeutic efficacy at potentially lower doses due to higher cell killing efficiencies. Peptide targeted alpha-therapy for metastatic melanoma has the potential to provide tumor-specific and efficacious treatment of advanced stage disease, which is resistant to current therapeutic approaches.

描述（由申请人提供）：该提案概述了一系列研究，以评估放射性标记的α-黑素细胞刺激激素（a-MSH）肽类似物的细胞毒性和治疗效果，这些肽类似物将发射放射性同位素的α粒子靶向黑色素瘤细胞的细胞核。用于癌症治疗的α粒子发射放射性同位素的选择性靶向正在成为靶向放射治疗中令人兴奋且潜在强大的新治疗策略。 α-辐射电离如此密集，以至于它直接形成破坏性自由基，与组织的氧含量无关，并且其细胞毒性与剂量率无关，从而产生潜在的强大治疗指数。 a-粒子的路径长度很短，约为 55-80 µm（约 4-6 个细胞直径），因此，a-粒子的细胞毒性特性高度集中，从而最大限度地减少健康组织的附带辐射损伤。根据对α粒子细胞毒性的微剂量测定研究，α粒子似乎必须穿过细胞核才能有效引起细胞死亡。设计一种将α发射体沉积在细胞核中的生物靶向载体将是非常有利的。为此，开发了一种原型核靶向 a-MSH 肽 (DOTA-NT-MSH)，并通过荧光成像显示其定位于黑色素瘤细胞的细胞核中。拟议研究的目标是确定在体外细胞水平和体内黑色素瘤动物模型中将a发射放射性核素靶向细胞核的功效。本研究的具体目标是：1) 优化 212 Pb α 发射体 212 Bi 母体的核靶向肽的放射性标记效率和纯化，2) 检查 212 Pb 标记的 DOTA-NT-MSH 和对照 DOTA 非特异性肽的体外亚细胞分布和细胞毒性，3) 确定 DOTA-NT-MSH 的生物分布和 携带黑色素瘤的小鼠中的 DOTA-NDPMSH 肽。恶性黑色素瘤是一个严重的健康问题，因为其发病率增加以及对传统化疗和外照射的抵抗力增加。尽管癌症治疗最近取得了进展，但患有播散性转移性疾病的患者的中位预期寿命仍为 12-15 个月。显然需要开发新的有效治疗剂来攻击恶性黑色素瘤。恶性黑色素瘤的靶向α-疗法的发展很有吸引力，因为α-发射体的短粒子路径特别适合表征转移性疾病的播散性肿瘤细胞小簇。我们实验室的初步结果表明，在临床前治疗研究中，肽靶向α发射体对于治疗黑色素瘤非常有效。通过放射性核素的核定位来改进肽靶向α治疗方法，由于细胞杀伤效率更高，因此可以在潜在较低剂量下提高治疗效果。针对转移性黑色素瘤的肽靶向α疗法有可能为对当前治疗方法耐药的晚期疾病提供肿瘤特异性和有效的治疗。