Applications of Core-Shell Ti02 Nanoconjugates

核壳型TiO2纳米复合物的应用

• 批准号: 7986911
• 负责人: GAYLE E. WOLOSCHAK
• 金额: $ 34.31万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986911
• 关键词: Animal Model; Animals; Biological Models; Biomedical Research; Biopolymers; Biotechnology; Blood; Carcinoma; Catheters; Cell Death; Cells; Cervical; Cervix carcinoma; Cultured Cells; DNA; Development; Disease; Drug Formulations; Funding; Genome; Glucose; Goals; Head and Neck Cancer; Head and Neck Neoplasms; Hepatic artery; Human; Interventional radiology; Learning; Length; Lighting; Liver; Liver neoplasms; Long-Term Effects; Magnetic Resonance Imaging; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modality; Modeling; Modification; Monitor; Nanoconjugate; Oncogenes; Operative Surgical Procedures; Oryctolagus cuniculus; Papilloma; Papillomavirus; Papillomavirus Infections; Peptide Nucleic Acids; Peptides; Production; Proteins; Reactive Oxygen Species; Regulon; System; TP53 gene; Testing; Therapeutic; Therapeutic Index; Time; Tissue Harvesting; Tissues; Tumor Tissue; Viral Genome; Viral Proteins; base; cancer therapy; cell killing; cell transformation; disease characteristic; human disease; improved; in vivo; interest; irradiation; nanocomposite; nanoparticle; neoplastic cell; novel; public health relevance; tumor; uptake

DESCRIPTION (provided by applicant): In this application, we propose to treat liver carcinoma in vivo, in a rabbit VX2 model, using TiO2 based composite nanoconjugates. During the previous funding period, this application was dedicated to the development of TiO2-biopolymer nanoconjugates as new vehicles for biotechnology. These studies found that, dependent on the nanoparticle coating, these nanoconjugates caused DNA scission or interacted with cellular proteins. Both of these activities can be used to interfere with cancer maintenance and progression. In addition, we have developed novel nanocomposites and nanoconjugate formulations that provide increase photocatalytic activity and modulate contrast for magnetic resonance imaging, leading to improved therapeutic potential and allowing for monitoring of composite nanoconjugate's delivery and retention. We now propose to combine these approaches and the rabbit liver carcinoma VX2 model, a cancer that develops due to papilloma virus infection, in order to attempt to use nanoconjugates therapeutically. We will pursue papilloma virus genome targets not only because they provide tumor- specific markers in this system but also because of their relevance to a portion of head and neck tumors and cervical carcinoma which are similarly infected; it is also quite possible that other tumor systems will be shown to have papilloma virus involvement as well. In addition, this system will provide a model for providing information on non-papilloma virus induced tumors and liver metastatic disease. The specific aims of this proposal are: AIM 1. Formulating composite nanoconjugates (CNCs) optimal for E6/E7 control of papilloma transformed cells and for ROS mediated cell destruction. AIM 2. Formulating the optimal combination of CNCs, scintillator nanoparticles and irradiation for E6/E7 control of papilloma transformed cells and for ROS mediated cell destruction. AIM 3. Testing the curative capacity of the two most optimal combinations of CNCs and scintillator NPs at different timepoints post irradiation Rabbit liver carcinoma is a particularly interesting animal model because it mimics well human liver carcinoma and interventional radiology approaches to deliver non-surgical interventions. Namely, the rabbit VX2 tumor model resembles human disease in that it has the disease- characteristic vasculature (the hepatic artery delivers blood to the tumor), and there exists the possibility of using a catheter to deliver therapeutics. In addition, virally induced cancers are an attractive model for targeting with nanoconjugates. Any breakthrough in this system could therefore aid in pursuit of anti-cancer therapies in papilloma induced cancers such as cervical and head and neck cancer. PUBLIC HEALTH RELEVANCE: The rabbit liver carcinoma model VX2 will be used to investigate the therapeutic potential of nanocomposites Fe3O4@TiO2-biopolymer (peptide nucleic acids and peptides) nanoconjugates against cancer. Papilloma virus expression is the cause of this liver carcinoma; tumor cells and viral genes and proteins will be targeted by composite nanoconjugates. The ability of composite nanoconjugates to target the tumor tissue, cause viral genome damage and tumor cell death will be tested in rabbits in vivo.

描述(申请人提供)：在本申请中，我们建议使用基于二氧化钛的复合纳米结合物，在兔VX2模型中治疗活体肝癌。在上一次资助期间，这项申请专门用于开发作为生物技术新载体的二氧化钛-生物聚合物纳米结合物。这些研究发现，依赖于纳米颗粒涂层，这些纳米偶联物会导致DNA断裂或与细胞蛋白质相互作用。这两种活动都可以用来干扰癌症的维持和进展。此外，我们开发了新型纳米复合材料和纳米结合物配方，为磁共振成像提供了更高的光催化活性和调节对比度，从而提高了治疗潜力，并允许监测复合纳米结合物的输送和保留。我们现在建议将这些方法与兔肝癌VX2模型相结合，VX2是一种由于乳头状瘤病毒感染而发展的癌症，以尝试使用纳米结合物进行治疗。我们将追求乳头瘤病毒基因组靶点，不仅因为它们在这个系统中提供了肿瘤特异性标记，而且因为它们与部分类似感染的头颈部肿瘤和宫颈癌相关；也很可能其他肿瘤系统也被证明与乳头瘤病毒有关。此外，该系统将为提供有关非乳头状瘤病毒诱导的肿瘤和肝转移疾病的信息提供一个模型。这项建议的具体目的是：目的1.制备复合纳米结合物(CNCs)，对E6/E7乳头状瘤转化细胞的控制和ROS介导的细胞破坏是最佳的。目的2.制备CNCS、纳米闪烁粒子和辐射的最佳组合，以控制E6/E7转化的乳头状瘤细胞和ROS介导的细胞破坏。目的3.在照射后的不同时间点测试两种最优的CNCs和闪烁体纳米粒子组合的治疗能力兔肝癌是一个特别有趣的动物模型，因为它很好地模拟了人类肝癌和介入放射学的非手术干预方法。也就是说，兔VX2肿瘤模型类似于人类疾病，因为它具有疾病特有的血管系统(肝动脉向肿瘤输送血液)，并且存在使用导管输送治疗药物的可能性。此外，病毒诱导的癌症是用纳米偶联物靶向的一个有吸引力的模型。因此，这一系统的任何突破都可能有助于寻求抗癌疗法来治疗乳头状瘤引起的癌症，如宫颈癌和头颈癌。 公共卫生相关性：将使用兔肝癌模型VX2来研究纳米复合材料Fe3O4@TiO2-生物聚合物(肽、核酸和肽)纳米结合物抗癌的治疗潜力。乳头状瘤病毒的表达是导致这种肝癌的原因；肿瘤细胞和病毒基因和蛋白质将成为复合纳米结合物的靶点。复合纳米结合物靶向肿瘤组织、导致病毒基因组损伤和肿瘤细胞死亡的能力将在体内进行测试。