Cancer Therapy with Targeted Radioactive Nanoparticles

描述（由申请人提供）：将放射免疫疗法（RAIT）与纳米技术相结合，可以实现新的癌症治疗。在此申请指导定量研究职业发展奖（K25）中，候选人建议通过将放射性同位素以纳米颗粒（NPs）的形式包装来提高RAIT在恶性实体肿瘤中的疗效。该项目是候选人布莱恩·史密斯博士和导师格雷戈里·亚当斯博士之间的独特合作，格雷戈里·亚当斯博士是一位受人尊敬的放射免疫治疗专家。中心假设是免疫靶向放射性纳米粒子将被证明比典型的RAIT偶联物在治疗实体瘤方面更有效。这一假设将使用放射性金属铼（它有两种有用的RAIT同位素）和针对肿瘤相关HER2/新抗原的单链Fv （scFv）抗体进行测试。提出了三组实验。第一组（目标1）侧重于水溶性铼NPs的合成。第二组（目标2）涉及scFv分子与纳米颗粒的附着，以及这些纳米颗粒放射免疫偶联物（NPRICs）的体外性能的定量。这些结果将指导合成参数的改变，以生产具有在体内应用前景的NPRICs。在第三组（Aim 3）中，将研究优化后的NPRICs在免疫缺陷小鼠异种肿瘤移植中的生物分布和治疗效果。

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.