Trimetallic Nitride Templated Endohedral Metallofullerenes as Dual Imaging and Mu

描述（由申请人提供）：该项目的目标是研究一类新的富勒烯，称为三金属氮化物模板内嵌金属富勒烯（TNT EMF），作为激光癌症治疗的双重成像和多模式治疗剂。我们将独立地研究形式为Gd3N@C80的TNT EMF的治疗有效性，以及在被表示为Gd3N@C80-peapod的peapod排列（单壁碳纳米管内的Gd3N@C80分子）中的TNT EMF在癌症激光诱导的热疗中的治疗有效性。这些颗粒先前已被证明是特殊的磁共振成像造影剂，因为与钆相比，它们具有上级弛豫性和较低的扩散和消除速率。因此，需要较低浓度的造影剂，从而降低潜在的毒性。虽然Gd_3N@C_（80）已被证明是上级显像剂，但它们也具有巨大的治疗潜力，值得探索。Gd3N@C80在红外光谱内在大约1050 nm处具有吸收峰，已经发现在该波长处其他TNT EMF和碳纳米管吸收光并产生热。富勒烯和金属富勒烯在暴露于允许靶向细胞毒性的红外辐射时也产生单线态氧（5）。该提案将通过测量激光激发后这些颗粒的热增强（产生热量的能力）和光毒性（产生活性氧）来评估Gd3N@C80在激光治疗中的治疗潜力。这两种机制，如果指导得当，可导致细胞毒性。Gd3N@C80的热敏化效应将通过以下方式确定：1）测量激光照射包含Gd3N@C80-peapod的细胞后的热传递、细胞死亡和HSP表达，和2）表征光学和热性质、温度、细胞损伤和HSP表达分布的变化对Gd3N@C80-peapod性质、浓度、并在组织代表性体模中分布。通过测定Gd_3N@C_80-豆荚的活性氧（ROS）、单线态氧（1O_2）、超氧阴离子（O_2 ~-）、和羟基自由基（.OH）。这项研究的完成将允许确定Gd3N@C80-peapods在癌症治疗中的治疗效用，并允许优化其特性和激光参数，以最大限度地破坏肿瘤。开发具有高敏感性、高选择性和低毒性的癌症双重诊断和治疗剂可以大大改善患有这种疾病的患者的预后。该项目的目标是探索采用一类新的富勒烯称为三金属氮化物模板内嵌金属富勒烯（TNT EMF）作为癌症激光治疗中的双重成像和多模式治疗剂的可行性。通过将TNT EMF与激光加热相结合，可以采用较低的热剂量并实现更有选择性的加热，从而允许更精确地控制热能输送，最终允许有效的肿瘤根除，同时最小化健康组织的破坏。

DESCRIPTION (provided by applicant): The project objective is to investigate a novel class of fullerenes called trimetallic nitride templated endohedral metallofullerenes (TNT EMFs) as dual imaging and multimodal therapeutic agents for laser cancer therapy. We will investigate the therapeutic effectiveness of TNT EMFs of the form Gd3N@C80 independently and in a peapod arrangement (Gd3N@C80 molecules within single- walled carbon nanotubes) denoted as Gd3N@C80-peapods in cancer laser induced hyperthermia therapy. These particles have been previously demonstrated as exceptional magnetic resonance imaging contrast agents due to their superior relaxivity and lower diffusion and elimination rates as compared to gadolinium. Therefore, lower concentrations of contrast agent are required thereby reducing potential toxicity. Although Gd3N@C80 have been shown to be superior imaging agents, they also have tremendous therapeutic potential which merits exploration. Gd3N@C80 possesses an absorption peak within the infrared spectrum at approximately 1050 nm at which wavelength other TNT EMFs and carbon nanotubes have been found to absorb light and generate heat. Fullerenes and metallofullerenes also generate singlet oxygen when exposed to infrared radiation permitting targeted cell cytotoxicity (5). This proposal will evaluate the therapeutic potential of Gd3N@C80 in laser therapy by measuring the thermal enhancing (ability to generate heat) and photo-toxicity (generation of reactive oxygen species) of these particles following laser excitation. Both mechanisms if directed properly can lead to cytotoxicity. The thermal sensitizing effect of Gd3N@C80 will be determined by 1) measuring heat delivery, cell death, and HSP expression following laser irradiation of cells with inclusion of Gd3N@C80-peapods and 2) characterizing the change in optical and thermal properties, temperature, cellular injury, and HSP expression distribution dependence on Gd3N@C80-peapod properties, concentration, and distribution in tissue representative phantoms. The photo-toxicity of Gd3N@C80-peapods by measuring generation of reactive oxygen species (ROS), singlet oxygen (1O2), superoxide (O2-.), and hydroxyl radical (.OH) following laser excitation of cells. Completion of this research will permit determination of the therapeutic utility of Gd3N@C80-peapods in cancer therapy and permit optimization of their properties and laser parameters to permit maximum tumor destruction. Development of dual diagnostic and therapeutic agents for cancer with heightened sensitivity, selectivity, and lower toxicity could greatly enhance the prognosis of patients suffering from this disease. The goal of this project is to explore the feasibility of employing a novel class of fullerenes called trimetallic nitride templated endohedral metallofullerenes (TNT EMFs) as dual imaging and multimodal therapeutic agents in cancer laser therapy. By integrating TNT EMFs with laser heating, lower thermal doses can be employed and more selective heating achieved, thereby permitting more precise control of the thermal energy delivery ultimately permitting effective tumor eradication while minimizing healthy tissue destruction.