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

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用于靶向成像、药物递送和癌症治疗的高度生物相容性碳纳米管生物缀合物。在这项提案中，我们计划开发新的单壁纳米管（SWNTs）的功能化化学，以实现肿瘤特异性化疗药物的递送。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，以监测和了解SWNT-药物复合物的生物分布和治疗效果。由于单壁碳纳米管具有独特的结构、化学和物理性质，我们希望充分展示碳纳米管在生物医学应用中的新奇，包括：（1）一维结构（直径~ 1 nm，长度可调）和高比表面积~ 1000 m2/g，（2）无毒化学组成：碳，（3）用于拉曼标记的强拉曼光谱线和（4）用于荧光成像和检测的近红外（NIR）中的带隙荧光或光致发光性质。这些将SWNT与各种其他纳米材料区分开来，使其非常适合生物应用。我们有希望的初步结果表明，单壁碳纳米管可以在小鼠体内功能化，使生物相容性。当以高剂量静脉内施用时，SWNT无毒。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缀合物对于癌症治疗上级Cremophor ELP增溶的紫杉醇（PTX）。在这个R 01提案中，我们将扩展这些努力，并进行系统的研究，以确定使用支链亲水分子的最佳纳米管功能化方案。然后，我们将通过可裂解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。我们将研究功能化单壁碳纳米管和单壁碳纳米管-药物缀合物的体内血液循环、生物分布、肿瘤摄取和肿瘤内分布，以了解治疗结果并确定具有最佳肿瘤治疗功效和最低副作用毒性的最佳单壁碳纳米管-PTX缀合物。我们将通过被动靶向研究SWNT-PTX的肿瘤治疗效果，并与Cremophor ELP和Abraxane在小鼠异种移植瘤模型中进行比较。我们还将使用与RGD肽共功能化的SWNT-PTX缀合物进行靶向药物递送，以高效杀死肿瘤，从而特异性识别整合素并与肿瘤结合。最后，我们将结合联合收割机热休克蛋白90（Hsp 90）抑制剂和SWNT-PTX治疗，以研究Hsp 90抑制剂是否能增强紫杉醇肿瘤治疗效果。 公共卫生相关性：该项目将使用一种新的一维分子，单壁碳纳米管（SWNT）用于癌症药物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化疗药物的新配方，如紫杉醇，以提供比目前FDA批准的紫杉醇和Abraxane更高的癌症治疗效果和更低的毒副作用，为医生提供更好的药物来对抗癌症使用纳米技术。

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.