Tumor Targeting and Diagnostic Applications of Glycosylated Nanotubes

正电子发射断层扫描（PET）是对许多类型的癌症进行分期和监测的最准确方法。 虽然检测大于2 cm的肿瘤的准确性很高，但PET可能会错过大约三分之一的肿瘤。 小于1厘米的侵袭性癌症早期准确的诊断仍然是最有效的方法 在治疗癌症方面，使用成像技术来检测和监测癌症的改进将具有 对人类健康的巨大影响。本研究的目的是开发一种基于多壁的智能体 碳纳米管（MWCNT）用于晚期乳腺癌的诊断和监测。MWCNT由以下组成： 石墨烯碳片卷成多壁管，并具有许多特性，使其 在生物医学应用中非常有用，包括靶向分子成像。癌细胞具有 糖、葡萄糖的正常代谢改变，并表现出葡萄糖摄取增加， 葡萄糖清除率降低。在这项研究提案中要检验的假设是，MWCNT靶向 将被癌细胞以高效率摄取，并且这种MWCNT可以被 被设计成有效的PET成像/癌症诊断剂。纳米管将通过化学方法 工程化以在其表面上展示脱氧葡萄糖，这将使它们可溶于水，并将它们靶向 肿瘤的脱氧葡萄糖结合到多壁碳纳米管将被标记的正电子发射体，18 F，使纳米管 用作正电子发射断层摄影（PET）的灵敏成像工具。MWCNT也将被标记为 使用β辐射发射体3H-脱氧葡萄糖进行长期生物分布和清除研究。碳 纳米管为靶向分子成像技术如PET提供了许多优点：最重要的是它们的 每个靶向分子识别递送大量成像剂的能力，这可以改善 成像的灵敏度;其次，它们可以递送几种不同类型的成像剂（例如， 磁共振成像或光声剂）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递送，以及作为介体 光热癌症疗法集体，拟议的研究将提供：1）一个新的，糖基化的多壁碳纳米管 可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 关于糖基化的毒性（凝块形成）、生物分布、血液、尿液和粪便清除率的临床前数据 将MWCNT静脉注射到小鼠体内，所有这些对于未来的任何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，专门针对靶向和 诊断浸润性乳腺癌，但广泛适用于许多类型的癌症。预计这一 该试剂将作为未来联合癌症治疗和诊断的多模式平台的基础。 应用.

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.