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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

基本信息

批准号：
8239924
负责人：
Hongjie Dai
金额：
$ 31.91万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-12 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8239924
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

项目摘要

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偶联物，用于靶向成像，药物输送和癌症治疗。在这一提议中，我们计划开发新的单壁纳米管（SWNTs）功能化化学，以实现化疗药物的肿瘤特异性递送。我们还计划利用纳米管的固有光学性质（拉曼和光致发光）进行检测和成像，以监测和了解swnt -药物复合物的生物分布和治疗效果。由于碳纳米管独特的结构、化学和物理性质，我们希望充分展示将碳纳米管用于生物医学应用的新颖性，包括：(1)一维结构（直径~1nm，长度可调）和高表面积~1000m2/g，(2)无毒化学成分：碳，(3)用于拉曼标签的强拉曼光谱线，(4)近红外（NIR）带隙荧光或光致发光特性，用于荧光成像和检测。这些特性将swnt与其他各种纳米材料区分开来，使其非常适合于生物应用。我们已经有了很有希望的初步结果，表明单壁碳纳米管可以被功能化以在小鼠体内呈现生物相容性。高剂量静脉注射swnt是无毒的。纳米管保留在网状内皮系统（RES）中，并通过胆道和肾脏途径逐渐排出体外。我们的初步数据还表明，紫杉醇- SWNT缀合物优于cremoophor ELP溶解紫杉醇（PTX）治疗癌症。在本R01提案中，我们将扩展这些努力，并进行系统研究，以确定使用支链亲水分子的最佳纳米管功能化方案。然后，我们将通过可切割的酯键将紫杉醇附着在功能化纳米管上，用于肿瘤治疗，对正常器官的毒副作用低。我们将研究功能化swnt和swnt -药物偶联物的体内血液循环、生物分布、肿瘤摄取和肿瘤内分布，以了解治疗效果，并确定具有最佳肿瘤治疗效果和最低副作用毒性的最佳SWNT-PTX偶联物。我们将通过被动靶向研究SWNT-PTX在小鼠异种移植肿瘤模型中的治疗效果，并与Cremophor ELP和Abraxane进行比较。我们还将使用与RGD肽共功能化的SWNT-PTX偶联物进行特异性整合素识别和与肿瘤结合的靶向药物递送，以实现高效的肿瘤杀伤。最后，我们将热休克蛋白90 （heat-shock protein 90, Hsp90）抑制与SWNT-PTX治疗相结合，探讨Hsp90抑制剂是否能增强紫杉醇肿瘤的治疗效果。