Cancer Therapy with Targeted Radioactive Nanoparticles

描述(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方法。在这份申请导师定量研究职业发展奖(K25)的申请书中，候选人建议通过以纳米颗粒(NP)的形式包装放射性同位素来提高RAIT在恶性实体肿瘤治疗中的疗效。该项目是候选人Brian Smith博士和导师Gregory Adams博士之间的独特合作，Gregory Adams博士是一位受人尊敬的放射免疫治疗专家。中心假设是，免疫靶向的放射性纳米颗粒将被证明比RAIT结合物更有效地治疗实体肿瘤。这一假设将用放射性金属Re和单链抗体(ScFv)来验证，Re有两种有用的RAIT同位素，单链抗体(ScFv)针对肿瘤相关的HER2/neu抗原。提出了三套实验方案。第一组(目标1)侧重于合成水溶性Re纳米颗粒。第二组(目标2)涉及单链抗体分子与纳米粒子的结合，以及这些纳米粒子放射免疫结合物(NPRIC)的体外性能的量化。这些结果将指导合成参数的改变，以制备具有良好性能的体内应用的NPRIC。在第三组(目标3)中，将研究优化的NPRIC在免疫缺陷小鼠移植肿瘤中的生物分布和治疗效果。 该项目的实施将为受过材料科学家培训的史密斯博士提供必要的知识和技能，以便在将纳米技术应用于癌症检测和治疗方面从事跨学科的职业生涯。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方面的培训，包括免疫化学和放射化学，以及(C)正确进行动物研究的培训。

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.