Synthesis of Gold Nanoparticle-Cored Dendrimers Linked with Fluorophores and Anti

描述（由申请人提供）：与荧光团和抗体连接的金纳米颗粒核树枝状聚合物的合成：用于癌症治疗的智能生物标志物项目摘要在过去十年中，金纳米颗粒材料已越来越多地用于各种生物和医学应用，从光学生物标志物到用于癌症诊断和治疗的纳米载体。使用这些材料治疗的主要问题之一是临床生物相容性。最近，我们的团队开发了一种方法，通过单一偶联反应在金纳米颗粒核心周围有效地构建特定尺寸和组成的树枝状框架。与共价连接的生物相容性树枝状壳，我们的方法应赋予上级生物相容性超过目前的一些涂层技术与金纳米粒子。首先，它们应该比更传统的配体覆盖的金纳米颗粒更好地抵抗生物流体中的聚集。其次，在这些树枝状覆盖物的开放框架内而不是在涂层表面上连接跟踪荧光团的能力应该降低它们的细胞毒性。具有针对癌症特异性表面标记物的缀合抗体的生物相容性荧光标记的金纳米颗粒的开发可以提供不仅使癌细胞可视化而且还允许通过非侵入性热疗法对靶细胞进行细胞特异性破坏的机制。开发一种更简单和更安全的方法来检测和破坏特定的病原细胞表型被认为是生物技术和医学研究领域的最高优先领域之一。 为了探索这些新型纳米粒子在生物医学研究中的潜在用途和应用，我们提出了一个跨学科的研究计划，涉及来自CSULB三个部门的教师合作团队：扬·肖恩医生，（化学系）将合成生物相容性金纳米粒子核树枝状聚合物（NCD），博士约翰尼斯阿巴特，（物理系）将使用最先进的无孔近场扫描光学显微镜来表征这些非传染性疾病的结构，（生物科学系）将帮助评估它们在体外光学标记和热破坏培养的癌细胞的潜力。Tsi博士和Abate博士同意作为合作者参与拟议的研究项目。 本工作主要包括五个方面的工作：1）合成具有不同核尺寸和生物相容性树枝状基元的金NCD。2)荧光团的并入和针对癌症特异性表面标记物的靶向基团与金NCD的连接。3)使用近场扫描光学显微镜表征官能化NCD。4)评价细胞毒性、细胞识别和NCD在培养的肿瘤细胞中的分布。5)肿瘤细胞的热疗。 该项目将促进一个多学科研究团队的发展，包括来自三个独立部门（化学，生物和物理）的科学家。该研究计划将允许实验室间的技术转让，并帮助PI和合作者发展基本和转化研究技能，成为多用途复合纳米结构研究，光学显微镜材料表征以及癌症检测和治疗的独立研究者。同时，该计划将为研究生和本科生提供独特和令人兴奋的纳米技术研究机会。通过在现有的研究为基础的类招生，学生将有机会成为一个多学科的团队，将在这个项目的各个方面合作的参与者-从开始，从基本的纳米颗粒材料合成开始-完成，与这些材料的生物医学性能的最终评估。学生将获得实践经验和技术实验室技能，需要进行有关的合成，表征和生物学评价的新型纳米结构材料的基础研究，用于治疗疾病的治疗。他们还将开发批判性分析现有信息的智力能力，并开发复杂数据集的分析，解释和演示的熟练程度。 公共卫生相关性：纳米科学和技术的进步极大地促进了现代医学中各种癌症治疗新系统的快速发展。理想的纳米颗粒平台应具有靶向、成像和治疗功能，其允许靶向、成像和杀死癌细胞。纳米核树枝状聚合物（NCD）是一类新型的高度支化的合成大分子，具有纳米核和明确的树枝状楔形。非传染性疾病的独特结构特性使其成为诊断和治疗癌症的多功能平台的理想候选物。拟议研究的标志物是与荧光团和癌症特异性抗体相关的金NCD。 该建议特别设计用于证明使用这种新型多功能复合纳米材料作为荧光图像增强剂和热疗指南的可行性。由于其能够准确地将能量聚焦到目标区域（肿瘤部位），热疗一直吸引着人们的兴趣。使用热疗最重要的优点是它的副作用少，不像目前癌症治疗中使用的化疗。

DESCRIPTION (provided by applicant): Synthesis of Gold Nanoparticle-Cored Dendrimers Linked with Fluorophores and Antibodies: Smart Biomarkers for Cancer Treatments Project Summary Within the last decade, gold nanoparticulate materials have been used increasingly for diverse biological and medical applications ranging from optical biomarkers to nanocarriers for cancer diagnosis and therapy. One of the major problems with using these materials therapeutically has been clinical biocompatibility. Recently, our group has developed a process to efficiently build dendritic frameworks of specific size and composition around a gold nanoparticle core by single coupling reaction. With covalently attached biocompatible dendron shells, our method should confer superior biocompatibility over some of the current coating technologies used with gold nanoparticles. First, they should resist aggregation better in biological fluids than the more conventional ligand-capped gold nanoparticles. Second, the ability to link tracking fluorophores within the open framework of these dendritic coverings rather than on the surface of the coating should lower their cellular toxicity. The development of biocompatible fluorescently labeled gold nanoparticles having conjugated antibodies against cancer-specific surface markers may provide a mechanism to not only visualize cancerous cells but also allow cell-specific destruction of the targeted cells through non-invasive thermal therapy. The development of a simpler and safer way to detect and destroy specific pathogenic cellular phenotypes is considered to be one of the highest priority areas in the field of biotechnology and medical research. To explore the potential use and applications of these novel nanoparticles in biomedical research, we are proposing an interdisciplinary research program involving a collaborative team of faculty from three Departments at CSULB: Dr. Young Shon, (Department of Chemistry) will synthesize biocompatible gold nanoparticle-cored dendrimers (NCDs), Dr Yohannes Abate, (Department of Physics) will characterize the structure of these NCDs using state-of-the art apertureless near-field scanning optical microscopy while Dr Houng-Wei Tsai, (Department of Biological Sciences) will help evaluating their potential to both optically mark as well as thermally destroy cultured cancerous cells in vitro. Dr. Tsi and Dr. Abate agreed to participate in the proposed research projects as collaborators. The work involves five major tasks: 1) Synthesis of gold NCDs with various core sizes and biocompatible dendrons. 2) Incorporation of fluorophore and linkage of targeting groups against cancer-specific surface markers to gold NCDs. 3) Characterization of functionalized NCDs using near-field scanning optical microscopy. 4) Evaluation of cytotoxicity, cell recognition, and distribution of NCDs in cultured tumor cells. 5) Hyperthermia treatments in tumor cells. This project will foster the development of a multidisciplinary research team involving scientist from three separate Departments (Chemistry, Biology, and Physics). This research plan will allow inter-laboratory technology transfer and help the PI and collaborators to develop the basic and translational research skills to become independent investigators in multi-purpose composite nanostructure research, optical microscopy materials characterization, and cancer detection and therapy. Simultaneously, this program will provide graduate and undergraduate students with unique and exciting research opportunities in nanotechnology. Through enrollment in existing research-based classes, students will be offered the opportunity to be participants in a multidisciplinary team that will collaborate on all aspects of this project - from inception, starting with basic nanoparticulate material synthesis - to completion, with the ultimate evaluation of the biomedical performance of these materials. Students will acquire hands-on experience and technical laboratory skills needed to conduct basic research regarding the synthesis, characterization and biological evaluation of novel nanostructured materials for the therapeutic treatment of diseases. They will also develop the intellectual capacity to critically analyze existing information as well as develop proficiency in the analysis, interpretation and presentation of complex data sets. PUBLIC HEALTH RELEVANCE: The advances in nanoscience and nanotechnology greatly promote the rapid development of various new systems for cancer therapy in current medicine. An ideal nanoparticle platform should be endowed with targeting, imaging, and therapeutic functionalities, which allow for targeting, imaging, and killing of cancer cells. Nanoparticle-cored dendrimers (NCDs) are a new class of highly branched, synthetic macromolecules with a nanoparticle core and well-defined dendritic wedges. The unique structural properties of NCDs make them ideal candidates for use as a multifunctional platform for the diagnostic and treatment of cancer. The markers for the proposed study are gold NCDs, which are linked with fluorophores and cancer-specific antibodies. This proposal is particularly designed to prove the feasibility of using this novel, multifunctional composite nanomaterial as a fluorescence image enhancer and hyperthermia guide. Due to its capability of accurately focusing energy to the targeted areas (the site of the tumor), hyperthermia has been attracting much interest. The most important advantage of using hyperthermia is its few side effects, unlike the chemotherapy used for the current cancer treatment.