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

项目概述：在过去的十年中，金纳米颗粒材料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，通过单次偶联反应，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。通过共价附着的生物相容性树突壳，我们的方法应该比目前一些用于金纳米颗粒的涂层技术具有更好的生物相容性。首先，与传统的配体覆盖的金纳米颗粒相比，它们在生物流体中更能抵抗聚集。其次，在这些树突覆盖物的开放框架内而不是在涂层表面连接跟踪荧光团的能力应该会降低它们的细胞毒性。生物相容性荧光标记金纳米颗粒具有针对癌症特异性表面标记物的偶联抗体的发展可能提供一种机制，不仅可以可视化癌细胞，还可以通过非侵入性热疗法对目标细胞进行细胞特异性破坏。开发一种更简单和更安全的方法来检测和破坏特定的致病细胞表型被认为是生物技术和医学研究领域最优先考虑的领域之一。为了探索这些新型纳米颗粒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项目，包括一个由CSULB三个系的教师组成的合作团队：Young Shon博士（化学系）将合成生物相容性金纳米颗粒核树突大分子（NCDs）， Yohannes Abate博士（物理系）将使用最先进的无孔近场扫描光学显微镜表征这些NCDs的结构，而hongung - wei Tsai博士（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。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突的金非传染性细胞。2)将针对癌症特异性表面标记的靶向基团与金非传染性疾病结合。3)近场扫描光学显微镜表征功能化非传染性疾病。4)非传染性疾病在培养肿瘤细胞中的细胞毒性、细胞识别和分布评估。5)肿瘤细胞热疗。这个项目将促进一个多学科研究团队的发展，包括来自三个不同系（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移，并帮助PI和合作者发展基础和转化研究技能，成为多用途复合纳米结构研究、光学显微镜材料表征和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。通过注册现有的研究型课程，学生将有机会成为一个多学科团队的参与者，这个团队将在这个项目的各个方面进行合作——从开始，从基本的纳米颗粒材料合成开始，到完成，以及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，以进行有关新型纳米结构材料的合成，表征和生物学评估的基础研究，用于治疗疾病。他们还将培养批判性地分析现有信息的智力能力，以及培养分析、解释和呈现复杂数据集的熟练程度。

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.