Tumor Targeting and Diagnostic Applications of Glycosylated Nanotubes

糖基化纳米管的肿瘤靶向和诊断应用

• 批准号: 8520254
• 负责人: Ravi N Singh
• 金额: $ 22.59万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-25 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520254
• 关键词: Area; Area Under Curve; Beta Particle; Binding; Biodistribution; Blood; Cancer Diagnostics; Cancer cell line; Cancerous; Carbon; Carbon Nanotubes; Carrier Proteins; Cell Line; Coagulation Process; Data; Deoxyglucose; Detection; Development; Diagnosis; Diagnostic; Drug Delivery Systems; Drug Kinetics; Engineering; Exhibits; Feces; Fullerenes; Future; Gene Delivery; Glucose; Glucose Transporter; Goals; Half-Life; Health; Heating; Human; Image; Imaging Device; Imaging Techniques; Imaging technology; In Vitro; Infrared Rays; Label; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Mediator of activation protein; Metabolism; Monitor; Mus; Nanotubes; New Agents; Organ; Phase; Platelet Activation; Platelet Count measurement; Positron; Positron-Emission Tomography; Property; Radiolabeled; Recurrence; Research; Research Proposals; Staging; Surface; Technology; Testing; Therapeutic; Therapeutic Uses; Thermal Ablation Therapy; Time; Toxic effect; Transducers; Tube; Urine; Water; Work; base; cancer cell; cancer therapy; cancer type; clinically relevant; density; glucose receptor; glucose uptake; human cancer mouse model; improved; in vivo; intravenous injection; malignant breast neoplasm; molecular imaging; molecular recognition; multimodality; nanohorn; nanomaterials; optical imaging; particle; pre-clinical; radiotracer; single walled carbon nanotube; sugar; tumor; tumor progression; uptake; urinary

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.

正电子发射断层扫描(PET)是对多种癌症进行分期和监测的最准确的方法。 尽管检测大于2厘米的肿瘤的准确率很高，但PET可能会漏掉大约三分之一的 小于1厘米的浸润性癌症。因为早期准确的诊断仍然是最有效的方法 在治疗癌症方面，使用成像技术检测和监测癌症的进步将产生 对人类健康的巨大影响。本研究的目标是开发一种基于多壁分子的新型药物。 碳纳米管(MWCNT)用于晚期乳腺癌的诊断和监测。MWCNT包括 石墨烯碳板轧制成多壁管子，具有许多使它们 在生物医学应用中非常有用，包括靶向分子成像。癌细胞有 糖、葡萄糖正常代谢的改变，表现为葡萄糖摄取增加和 葡萄糖清除量降低。在这项研究提案中要检验的假设是，MWCNT靶向 葡萄糖受体将被癌细胞高效地摄取，这种多壁碳纳米管可以 被设计成有效的PET成像/癌症诊断剂。纳米管将在化学上 被设计成在它们的表面显示脱氧葡萄糖，这将使它们成为水溶性的，并针对它们 肿瘤。结合到MWCNT上的脱氧葡萄糖将用正电子发射体18F标记，从而使纳米管 作为正电子发射断层扫描(PET)的灵敏成像工具。MWCNT也将被标记为 与β辐射发射体~3H-脱氧葡萄糖一起，用于长期的生物分布和清除研究。碳素 纳米管为PET等靶向分子成像技术提供了许多优势：最重要的是它们的 能够为每个靶向分子识别提供大量显像剂，这可以提高 成像的敏感性；其次，他们可以提供几种不同类型的显像剂(例如 磁共振成像或光声剂)来执行多模式成像；第三，它们可以 用于治疗应用，包括化疗药物或基因输送，并用作 光热治疗癌症。总的来说，拟议的研究将提供：1)一种新的糖基化多壁碳纳米管 可通过放射性标记进行追踪；2)与血液相容性有关的临床相关问题的数据；以及 糖基化药物的毒性(血栓形成)、生物分布、血液、尿液和粪便清除的临床前数据 将多壁碳纳米管静脉注射到小鼠体内，所有这些都将是未来任何翻译应用所必需的； 3)一种新的、临床前优化的纳米医学平台技术，专门针对 诊断浸润性乳腺癌，但对许多类型的癌症具有广泛的适用性。预计这将是 代理将作为未来癌症联合治疗和诊断的多模式平台的基础 申请。