Tumor Targeting and Diagnostic Applications of Glycosylated Nanotubes

描述（由申请人提供）：正电子发射断层扫描（PET）是最准确的方法来分期和监测许多类型的癌症。尽管PET在检测大于2cm的肿瘤时准确率很高，但对于小于1cm的浸润性肿瘤，PET可能会漏掉大约三分之一。由于早期和准确的诊断仍然是治疗癌症最有效的方法，使用成像技术检测和监测癌症的改进将对人类健康产生巨大影响。本研究的目的是开发一种基于多壁碳纳米管（MWCNT）的新型药物，用于晚期乳腺癌的诊断和监测。MWCNT由石墨烯碳片卷成多壁管组成，具有许多特性，使其在生物医学应用中非常有用，包括靶向分子成像。癌细胞对糖、葡萄糖的正常代谢发生改变，表现为葡萄糖摄取增加，葡萄糖清除减少。本研究拟验证的假设是靶向葡萄糖受体的MWCNT将被癌细胞高效吸收，并且这种MWCNT可以被设计成有效的PET成像/癌症诊断试剂。纳米管将经过化学工程处理，在其表面显示脱氧葡萄糖，使其具有水溶性，并将其用于肿瘤。与MWCNT结合的脱氧葡萄糖将被标记为正电子发射器18F，使纳米管能够作为正电子发射断层扫描（PET）的敏感成像工具。MWCNT还将被标记为β辐射发射器，3h -脱氧葡萄糖，用于长期的生物分布和清除研究。碳纳米管为PET等靶向分子成像技术提供了许多优势：最重要的是它们能够为每个靶向分子识别提供大量显像剂，这可以提高成像的灵敏度；其次，它们可以提供几种不同类型的显像剂（如磁共振成像或光声显像剂）来进行多模态成像；第三，它们可以用于治疗应用，包括化疗药物或基因传递，以及作为光热癌症治疗的介质。总的来说，拟议的研究将提供：1)一种新的糖基化的MWCNT，可以通过放射性标记进行追踪；2)与血液相容性相关的临床相关问题的数据，以及静脉注射到小鼠体内的糖基化MWCNT的毒性（凝块形成）、生物分布、血液、尿液和粪便清除的临床前数据，所有这些对于任何未来的转化应用都是必不可少的；3)一种新的、临床前优化的纳米医学平台技术，专门用于靶向和诊断浸润性乳腺癌，但广泛适用于许多类型的癌症。预计该药物将作为未来癌症联合治疗和诊断应用的多模式平台的基础。

DESCRIPTION (provided by applicant): Positron emission tomography (PET) is the most accurate way to stage and monitor many types of cancer. Although accuracy in detecting tumors larger than 2 cm is high, PET may miss approximately one third of invasive cancers smaller that 1 centimeter. As early and accurate diagnosis is still the most effective approach to treating cancer, improvements in the use of imaging technology to detect and monitor cancer will have a dramatic effect on human health. The goal of this research is to develop a new agent based on multiwalled carbon nanotubes (MWCNT) for the diagnosis and monitoring of advanced breast cancer. MWCNT consist of sheets of graphene carbon rolled into multiwalled tubes and possess many properties that make them extremely useful in biomedical applications, including targeted molecular imaging. Cancer cells have alterations in the normal metabolism of the sugar, glucose, and exhibit increased glucose uptake and decreased glucose clearance. The hypothesis to be tested in this research proposal is that MWCNT targeted to glucose receptors will be taken up by cancer cells with high efficiency, and that such MWCNT can be engineered to be effective PET imaging/ cancer diagnostic agents. The nanotubes will be chemically engineered to display deoxyglucose on their surface, which will render them water soluble, and target them to tumors. Deoxyglucose bound to MWCNT will be labelled with the positron emitter, 18F, enabling the nanotubes to serve as a sensitive imaging tool for positron emission tomograpghy (PET). MWCNT also will be labeled with the beta radiation emitter, 3H-deoxyglucose, for long-term biodistribution and clearance studies. Carbon nanotubes offer many advantages for targeted molecular imaging techniques such as PET: foremost is their ability to deliver large numbers of imaging agents per each targeted molecular recognition, which can improve the sensitivity of imaging; secondly, they can deliver several different types of imaging agents (such as magnetic resonance imaging or photoacoustic agents) to perform multimodality imaging; thirdly, they can be used for therapeutic applications including chemotherapeutic drug or gene delivery, and as mediators for photothermal cancer therapy. Collective, the proposed research will provide: 1) a new, glycosylated MWCNT which can be traced by radiolabelling; 2) data on clinically-relevant issues relating to blood compatibility, and preclinical data on toxicity (clot formation), biodistribution, blood, urinary, and fecal clearance of glycosylated MWCNT injected intravenously into mice, all of which will be essential for any future translational applications; 3) a new, preclinically-optimized nanomedical platform technology, developed specifically to target and diagnose invasive breast cancer, but with broad applicability to many types of cancer. It is anticipated that this agent will serve as the basis for a multimodal platform for future combined cancer therapy and diagnostic applications. PUBLIC HEALTH RELEVANCE: The goal of this research is to develop a new agent based on multiwalled carbon nanotubes (MWCNT) for use as a Positron emission tomography (PET) imaging agent for the diagnosis and monitoring of advanced breast cancer in humans. PET is the most accurate way to stage and monitor many types of cancer. Although accuracy in detecting tumors larger than 2 cm is high, PET may miss approximately one third of invasive cancers smaller that 1 centimeter. As early and accurate diagnosis is still the most effective approach to treating cancer, improvements in the use of imaging technology to detect and monitor cancer will have a dramatic effect on human health. It is anticipated that the nanotube-based imaging agent will serve as the basis for a multimodal platform for future combined cancer therapy and diagnostic applications.