Carbon Nanotubes as Multi-functional Spectroscopic Markers and Delivery Agents fo

碳纳米管作为多功能光谱标记物和递送剂

• 批准号: 8066348
• 负责人: Hongjie Dai
• 金额: $ 31.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-12 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066348
• 关键词: Abraxane; Adverse effects; Albumins; Antineoplastic Agents; Area; Behavior; Biliary; Binding; Biocompatible; Biodistribution; Biological; Blood; Blood Chemical Analysis; Blood Circulation; Brain Neoplasms; Caliber; Carbon; Carbon Nanotubes; Cellular Stress; Chemicals; Chemistry; Chemotherapy-Oncologic Procedure; Client; Clinic; Combined Modality Therapy; Complex; Cremophor; Data; Detection; Dextrans; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Ensure; Esters; Ethylene Glycols; Excretory function; Exhibits; Exposure to; FDA approved; Fluorescence; Glean; HSP 90 inhibition; Half-Life; Heat shock proteins; Heat-Shock Proteins 90; Heat-Shock Response; Homeostasis; Image; In Situ Nick-End Labeling; Integrins; Kidney; Label; Lead; Length; Libraries; Ligands; Liver; Location; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Measures; Mediating; Modeling; Molecular Chaperones; Monitor; Mus; Nanotechnology; Nanotubes; Neoplasm Metastasis; Optics; Organ; PI3K/AKT; Paclitaxel; Pathway interactions; Permeability; Pharmaceutical Preparations; Phospholipids; Play; Polyethylene Glycols; Positron-Emission Tomography; Process; Property; Proteins; RGD (sequence); Radiolabeled; Relative (related person); Reticuloendothelial System; Role; Scheme; Shapes; Side; Signal Transduction; Signal Transduction Pathway; Staining method; Stains; Structure; Surface; Testing; Tissues; Toxic effect; Treatment Efficacy; Tumor Angiogenesis; Water; base; biological research; biomaterial compatibility; cancer cell; cancer imaging; cancer therapy; chemical property; chemotherapy; cytotoxic; dextran; drug distribution; ethylene glycol; fluorescence imaging; imaging modality; in vivo; inhibitor/antagonist; killings; malignant breast neoplasm; molecular imaging; mouse model; nano; nanobiotechnology; nanomaterials; neoplastic cell; novel; overexpression; particle; physical property; polyglycerol; polypeptide; protein expression; protein protein interaction; public health relevance; radiotracer; response; single walled carbon nanotube; targeted delivery; tool; tumor; tumor xenograft; uptake

DESCRIPTION (provided by applicant): One of our long-term objectives in the nano-biotechnology area is to develop highly biocompatible carbon nanotube biological conjugates for targeted imaging, drug delivery and cancer therapy. In this proposal, we plan to develop new functionalization chemistry for single-walled nanotubes (SWNTs) to achieve tumor specific delivery of chemotherapeutics. We also plan to utilize the intrinsic optical properties (Raman & photoluminescence) of nanotubes for detection and imaging for monitoring and understanding the biodistribution and treatment efficacy of SWNT-drug complexes. We hope to fully demonstrate the novelty of using carbon nanotubes for biomedical applications owing to the unique structural, chemical and physical properties of SWNTs including, (1) one-dimensional structure (diameter ~1nm, tunable length) and high surface area ~1000m2/g, (2) non-toxic chemical composition: carbon, (3) strong Raman spectroscopic lines for raman tags and (4) band-gap fluorescence or photoluminescence properties in the near IR (NIR) for fluorescence imaging and detection. These distinguish SWNTs from various other nanomaterials and make them ideally suited for biological applications. We have promising preliminary results showing that SWNTs can be functionalized to render biocompatibility in vivo in mice. SWNTs are non-toxic when administered intravenously at high doses. Nanotubes retained in the reticuloendothelial system (RES) and are gradually excreted out of the body via the biliary and renal pathways. Our preliminary data also indicate that paclitaxel- SWNT conjugate is superior to the Cremophor ELP solubilized paclitaxel (PTX) for cancer therapy. In this R01 proposal we will extend such efforts and perform systematic studies to identify an optimal nanotube functionalization scheme using branched hydrophilic molecules. We will then attach paclitaxel via cleavable ester bonds to the functionalized nanotubes for tumor treatment with low side toxicity effects to normal organs. We will investigate in vivo blood circulation, biodistribution, tumor uptake, and distribution within tumor for functionalized SWNTs and SWNT-drug conjugates, for understanding the treatment results and identifying the best SWNT-PTX conjugate with the optimal tumor treatment efficacy and lowest side effect toxicity. We will investigate the tumor treatment efficacy of SWNT-PTX by passive targeting and compare with Cremophor ELP and Abraxane in mice xenograft tumor models. We will also carry out targeted drug delivery for highly efficient tumor killing using SWNT-PTX conjugates co-functionalized with RGD peptide for specific integrin recognition and binding to tumors. Finally, we will combine heat-shock protein 90 (Hsp90) inhibitions and SWNT-PTX treatment to investigate if Hsp90 inhibitor affords enhancement of paclitaxel tumor treatment efficacy. PUBLIC HEALTH RELEVANCE: This project will use a novel one-dimensional molecule, single-walled carbon nanotube (SWNT) for cancer drug delivery and for cancer imaging using their intrinsic optical properties. These nano-technological advances will lead to new formulations for chemotherapy drugs such as paclitaxel to afford higher cancer treatment efficacy and lower toxic side effects than currently FDA approved Taxol and Abraxane, providing doctors with better drugs to battle cancer using nanotechnology.

描述（由申请人提供）：我们在纳米生物技术领域的长期目标之一是开发高度生物相容性的碳纳米管生物结合物，用于靶向成像，药物递送和癌症治疗。在此提案中，我们计划为单壁纳米管（SWNT）开发新的功能化化学，以实现肿瘤特异性化学治疗剂的递送。我们还计划利用纳米管的固有光学特性（拉曼和光致发光）进行检测和成像，以监测和理解SWNT-rug-Complexes的生物分布和治疗功效。我们希望完全证明，由于SWNT的独特结构，化学和物理特性，使用碳纳米管进行生物医学应用的新颖性，包括（1）一维结构（直径〜1NM，可调长度，可调长度）和高表面积和高表面积面积〜1000m2/g，〜1000m2/g，〜1000m2/g，（2）非毒性化学分组：2）carbon and carbon for Ramans Spectr SpectRosc SpectRosc SpectRosc Spect（3）强（3）强（3）强（3）强（3）近红外（NIR）中的荧光或光致发光特性，用于荧光成像和检测。这些区别于SWNT与其他各种纳米材料，使它们非常适合生物应用。我们已经有希望的初步结果表明，SWNT可以在小鼠体内功能化以在体内实现生物相容性。当高剂量静脉内给药时，SWNT是无毒的。保留在网状内皮系统（RES）中的纳米管，并通过胆道和肾脏途径逐渐排出体内。我们的初步数据还表明，用于癌症治疗的紫杉醇SWNT结合物优于Cremophor ELP ELP溶解的紫杉醇（PTX）。在此R01提案中，我们将扩大此类努力并进行系统研究，以使用分支的亲水分子来识别最佳的纳米管功能化方案。然后，我们将通过可裂解的酯键将紫杉醇连接到功能化的纳米管上，以进行肿瘤治疗，对正常器官的侧毒性效应低。我们将研究功能化的SWNT和SWNT-Crug共轭物中的体内血液循环，生物分布，肿瘤摄取和分布，以理解治疗结果并鉴定与最佳的SWNT-PTX结合与最佳的最佳肿瘤治疗效果和最低的副作用毒性。我们将通过被动靶向研究SWNT-PTX的肿瘤治疗功效，并与小鼠异种移植肿瘤模型中的Cremophor ELP和Abraxane进行比较。我们还将使用SWNT-PTX共轭物与RGD肽共同功能进行特定的整联蛋白识别并与肿瘤结合，以进行高效的肿瘤杀死靶向药物。最后，我们将结合热冲蛋白90（HSP90）抑制作用和SWNT-PTX治疗，以研究HSP90抑制剂是否提供了紫杉醇肿瘤治疗功效的增强。 公共卫生相关性：该项目将使用一种新型的一维分子，单壁碳纳米管（SWNT）进行癌症药物输送，并使用其内在的光学特性进行癌症成像。这些纳米技术的进步将为化学疗法药物（例如紫杉醇）提供新的制剂，以提供更高的癌症治疗功效和毒性较低的副作用，比目前获得FDA认可的紫杉醇和Abraxane的毒性较低，从而为医生提供了使用纳米技术来对抗癌症的更好的药物。