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: 8133716
• 负责人: Ravi N Singh
• 金额: $ 12.97万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133716
• 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; public health relevance; radiotracer; single walled carbon nanotube; sugar; tumor; tumor progression; uptake; urinary

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.

描述（由申请人提供）：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方法。虽然检测大于2厘米的肿瘤的准确性很高，但PET可能会错过大约三分之一小于1厘米的浸润性癌症。由于早期和准确的诊断仍然是治疗癌症的最有效方法，因此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。本研究的目标是开发一种基于多壁碳纳米管（MWCNT）的新试剂，用于晚期乳腺癌的诊断和监测。多壁碳纳米管由卷成多壁管的石墨烯碳片组成，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。癌细胞在糖、葡萄糖的正常代谢中具有改变，并且表现出增加的葡萄糖摄取和减少的葡萄糖清除。在这项研究计划中要测试的假设是，靶向葡萄糖受体的MWCNT将被癌细胞高效吸收，并且这种MWCNT可以被工程改造成有效的PET成像/癌症诊断剂。纳米管将被化学工程化，以在其表面显示脱氧葡萄糖，这将使它们可溶于水，并将它们靶向肿瘤。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氟，使纳米管作为一个敏感的成像工具，正电子发射断层扫描（PET）。多壁碳纳米管也将标记β辐射发射体，3 H-脱氧葡萄糖，用于长期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：首先是它们能够为每个靶向分子识别提供大量成像剂，这可以提高成像的灵敏度;其次，它们可以提供多种不同类型的成像剂（诸如磁共振成像或光声剂）以执行多模态成像;第三，它们可用于治疗应用，包括化疗药物或基因递送，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，糖基化的多壁碳纳米管，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，以及毒性的临床前数据（凝块形成）、生物分布、血液、尿液和粪便清除，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，专门针对和诊断浸润性乳腺癌而开发，但对许多类型的癌症具有广泛的适用性。预计这种药物将作为未来联合癌症治疗和诊断应用的多模式平台的基础。 公共卫生关系：本研究的目标是开发一种基于多壁碳纳米管（MWCNT）的新试剂，用作正电子发射断层扫描（PET）成像剂，用于诊断和监测人类晚期乳腺癌。PET是对多种癌症进行分期和监测的最准确方法。虽然检测大于2厘米的肿瘤的准确性很高，但PET可能会错过大约三分之一小于1厘米的浸润性癌症。由于早期和准确的诊断仍然是治疗癌症的最有效方法，因此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。预计基于纳米管的成像剂将作为未来联合癌症治疗和诊断应用的多模式平台的基础。

项目成果

Improved local and systemic anti-tumor efficacy for irreversible electroporation in immunocompetent versus immunodeficient mice.

• DOI: 10.1371/journal.pone.0064559
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Neal RE 2nd;Rossmeisl JH Jr;Robertson JL;Arena CB;Davis EM;Singh RN;Stallings J;Davalos RV
• 通讯作者: Davalos RV