Cancer Therapy with Targeted Radioactive Nanoparticles

描述（由申请人提供）：通过将放射免疫疗法（赖特）与纳米技术结合，可以实现新型癌症治疗。在本申请的指导定量研究职业发展奖（K25）中，候选人提出通过以纳米颗粒（NP）的形式包装放射性同位素来提高赖特在恶性实体瘤中的疗效。该项目是候选人Brian Smith博士和导师Gregory亚当斯博士之间的独特合作，他是放射免疫治疗方面的受人尊敬的专家。中心假设是，免疫靶向放射性纳米粒子将证明比典型的赖特缀合物更有效地治疗实体瘤。这一假设将使用放射性金属铼（具有两种用于赖特的有用同位素）和靶向肿瘤相关HER 2/neu抗原的单链Fv（scFv）抗体进行测试。提出了三组实验。第一组（目标1）集中于水溶性CNONP的合成。第二组（目的2）涉及scFv分子与NP的连接，以及这些纳米颗粒放射免疫缀合物（NPRIC）的体外性能的定量。这些结果将指导合成参数的改变，以产生具有有前途的特性的NPRIC用于体内应用。在第三组（目标3）中，将在具有肿瘤异种移植物的免疫缺陷小鼠中研究优化的NPRIC的生物分布和治疗功效。 该项目的执行将为史密斯博士提供必要的知识和技能，使其能够在纳米技术应用于癌症检测和治疗方面从事跨学科职业。具体的职业目标是（a）核医学，免疫学和癌症生理学领域的教育，（B）生物医学实验室实践培训，包括免疫化学和放射化学，以及（c）动物研究的正确进行培训。

DESCRIPTION (provided by applicant): Novel cancer treatments could be realized by marrying radioimmunotherapy (RAIT) with nanotechnology. In this application for a Mentored Quantitative Research Career Development Award (K25), the Candidate proposes to increase the efficacy of RAIT in the setting of malignant solid tumors by packaging radioisotopes in the form of nanoparticles (NPs). This project is a unique collaboration between Candidate Dr. Brian Smith and Mentor Dr. Gregory Adams, who is a respected expert in radioimmunotherapy. The central hypothesis is that immunologically targeted radioactive nanoparticles will prove more therapeutically effective against solid tumors than is typical for RAIT conjugates. This hypothesis will be tested using rhenium radiometal, which has two useful isotopes for RAIT, and single chain Fv (scFv) antibodies which target the tumor-associated HER2/neu antigen. Three sets of experiments are proposed. The first set (Aim 1) focuses on the synthesis of water soluble rhenium NPs. The second set (Aim 2) relates to attachment of scFv molecules to the NPs, and to quantification of the in vitro performance of these nanoparticle radioimmunoconjugates (NPRICs). The results will guide changes to the synthesis parameters in order to produce NPRICs with promising properties for in vivo application. In the third set (Aim 3), the biodistribution and treatment efficacy of optimized NPRICs will be studied in immunodeficient mice with tumor xenografts. Execution of this project will provide Dr. Smith, who is trained as a materials scientist, with the necessary knowledge and skills to pursue a cross-disciplinary career in the application of nanotechnology to cancer detection and treatment. Specific career goals are (a) education in the areas of nuclear medicine, immunology, and cancer physiology, (b) training in biomedical laboratory practices including immunochemistry and radiochemistry, and (c) training in the proper conduct of animal studies.