Applications of Core-Shell Ti02 Nanoconjugates

核壳型TiO2纳米复合物的应用

• 批准号: 8282644
• 负责人: GAYLE E. WOLOSCHAK
• 金额: $ 32.98万
• 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/8282644
• 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; Intervention; 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; Oryctolagus cuniculus; Papilloma; Papillomavirus; Papillomavirus Infections; Peptide Nucleic Acids; Peptides; Production; Proteins; Reactive Oxygen Species; Regulon; System; Testing; Therapeutic; Therapeutic Index; Time; Tissue Harvesting; Tissues; Tumor Tissue; Viral Genome; Viral Proteins; Virus; 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（由申请人提供）：在本申请中，我们建议使用基于 TiO2 的复合纳米缀合物在兔 VX2 模型中体内治疗肝癌。在上一个资助期间，该申请致力于开发 TiO2-生物聚合物纳米复合物作为生物技术的新载体。这些研究发现，依赖于纳米颗粒涂层，这些纳米缀合物会导致 DNA 断裂或与细胞蛋白质相互作用。这两种活性均可用于干扰癌症的维持和进展。此外，我们还开发了新型纳米复合材料和纳米缀合物配方，可提高光催化活性并调节磁共振成像对比度，从而提高治疗潜力并允许监测复合纳米缀合物的递送和保留。我们现在建议将这些方法与兔肝癌 VX2 模型（一种因乳头状瘤病毒感染而产生的癌症）相结合，以尝试使用纳米缀合物进行治疗。我们将追求乳头状瘤病毒基因组靶标，不仅因为它们在该系统中提供肿瘤特异性标记物，而且因为它们与部分类似感染的头颈肿瘤和宫颈癌相关；其他肿瘤系统也很可能被证明与乳头状瘤病毒有关。此外，该系统还将提供一个模型，用于提供有关非乳头瘤病毒诱发的肿瘤和肝转移性疾病的信息。该提案的具体目标是： AIM 1. 配制最适合 E6/E7 控制乳头状瘤转化细胞和 ROS 介导的细胞破坏的复合纳米缀合物 (CNC)。目的 2. 制定 CNC、闪烁体纳米粒子和辐射的最佳组合，用于乳头状瘤转化细胞的 E6/E7 控制和 ROS 介导的细胞破坏。目的 3. 在照射后不同时间点测试 CNC 和闪烁体 NP 的两种最佳组合的疗效兔肝癌是一种特别有趣的动物模型，因为它很好地模仿了人类肝癌和介入放射学方法来提供非手术干预。也就是说，兔VX2肿瘤模型类似于人类疾病，因为它具有疾病特征性脉管系统（肝动脉向肿瘤输送血液），并且存在使用导管来输送治疗的可能性。此外，病毒诱导的癌症是纳米缀合物靶向的一个有吸引力的模型。因此，该系统的任何突破都可能有助于针对乳头状瘤诱发的癌症（例如宫颈癌和头颈癌）寻求抗癌疗法。 公共健康相关性：兔肝癌模型 VX2 将用于研究纳米复合材料 Fe3O4@TiO2-生物聚合物（肽核酸和肽）纳米缀合物抗癌的治疗潜力。乳头状瘤病毒的表达是导致肝癌的原因；复合纳米缀合物将靶向肿瘤细胞、病毒基因和蛋白质。复合纳米缀合物靶向肿瘤组织、引起病毒基因组损伤和肿瘤细胞死亡的能力将在兔子体内进行测试。