Trimetallic Nitride Templated Endohedral Metallofullerenes as Dual Imaging and Mu

描述(申请人提供)：该项目的目标是研究一种名为三金属氮化物模板内面金属富勒烯(TNT EMF)的新型富勒烯，作为激光癌症治疗的双重成像和多模式治疗剂。我们将独立地和以豆荚排列(单壁碳纳米管中的Gd3N@C80分子)形式研究TNT电磁场在癌症激光诱导热疗中的疗效。这些颗粒以前已经被证明是特殊的磁共振成像造影剂，因为它们比Gd具有更好的弛豫度和更低的扩散和消除速率。因此，需要较低浓度的造影剂，从而减少潜在的毒性。虽然Gd3N@C80已被证明是一种优良的显像剂，但它们也具有巨大的治疗潜力，值得探索。Gd3N@C80在红外光谱中有一个大约1050 nm的吸收峰，在这个波长上已经发现了其他TNT电动势和碳纳米管吸收光和产生热。富勒烯和金属富勒烯暴露在红外线辐射下时也会产生单线态氧，从而允许靶向细胞细胞毒性(5)。这项建议将通过测量激光激发后Gd3N@C80颗粒的热增强(产热能力)和光毒性(产生活性氧物种)来评估这些颗粒在激光治疗中的治疗潜力。如果指导得当，这两种机制都可能导致细胞毒性。Gd3N@C80的热敏化效应将通过以下方式确定：1)测量含有Gd3N@C80-Peapod的激光照射细胞后的热传递、细胞死亡和HSP表达；2)表征光和热性质、温度、细胞损伤和HSP表达分布随Gd3N@C80-Peapod属性、浓度和组织代表性模体分布的变化。通过测量激光激发细胞后产生的活性氧(ROS)、单线态氧(1O2)、超氧化物(O2-.)和羟基自由基(.oh)的生成，研究了Gd3N@C80豆荚的光毒性。这项研究的完成将使人们能够确定Gd3N@C80豆荚在癌症治疗中的治疗效用，并允许优化它们的性能和激光参数，以实现最大限度的肿瘤破坏。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药物，可以极大地改善患者的预后。本项目的目标是探索一种名为三金属氮化物模板内面金属富勒烯(TNT EMF)的新型富勒烯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电磁场与激光加热相结合，可以使用更低的热剂量，实现更有选择性的加热，从而可以更精确地控制热能传递，最终实现有效的肿瘤根除，同时将健康组织破坏降至最低。

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.