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

描述(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。在这项计划中，我们计划为单壁纳米管(SWNTs)开发新的功能化化学，以实现肿瘤特异性化疗药物的输送。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，以监测和了解单壁碳纳米管-药物复合体的生物分布和治疗效果。我们希望充分展示由于碳纳米管独特的结构、化学和物理特性而将其用于生物医学应用的新颖性，这些特性包括：(1)一维结构(直径~1 nm，可调长度)和高比表面积~1000m2/g，(2)无毒的化学成分：碳，(3)用于拉曼标签的强拉曼光谱线，以及(4)用于荧光成像和检测的近红外(NIR)的带隙荧光或光致发光特性。这些都将单壁碳纳米管与其他各种纳米材料区分开来，使其非常适合于生物应用。我们有很有希望的初步结果表明，单壁碳纳米管可以功能化，在小鼠体内实现生物相容性。当高剂量静脉注射时，单壁碳纳米管是无毒的。纳米管保留在网状内皮系统(RES)中，并通过胆道和肾脏逐渐排出体外。我们的初步数据还表明，紫杉醇-SWNT结合物在癌症治疗方面优于Cremophor ELP可溶性紫杉醇(PTX)。在这份R01提案中，我们将扩大这些努力，并进行系统研究，以确定使用支化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连接到功能化的纳米管上，用于肿瘤治疗，对正常器官的副作用较低。我们将对功能化的SWNTs和SWNT-药物结合物的体内血液循环、生物分布、肿瘤摄取和在肿瘤内的分布进行研究，以了解治疗结果，并确定最佳的SWNT-PTX结合物，具有最佳的肿瘤治疗效果和最低的毒副作用。我们将通过被动靶向研究SWNT-PTX对肿瘤的治疗效果，并与Cremophor ELP和Abraxane在小鼠移植瘤模型中进行比较。我们还将利用与RGD多肽共官能化的SWNT-PTX结合物进行靶向药物输送，以实现高效的肿瘤杀伤，以识别和结合肿瘤。最后，我们将结合热休克蛋白90(Hsp90)抑制剂和SWNT-PTX治疗来研究Hsp90抑制剂是否能增强紫杉醇肿瘤的治疗效果。 与公共健康相关：该项目将使用一种新型的一维分子--单壁碳纳米管(SWNT)，用于癌症药物的输送和利用其固有的光学特性进行癌症成像。这些纳米技术的进步将导致紫杉醇等化疗药物的新配方，提供比目前FDA批准的紫杉醇和亚伯拉索更高的癌症治疗效率和更低的毒副作用，为医生提供更好的利用纳米技术对抗癌症的药物。

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.