DNA-linked dendrimer nanoparticle systems for diagnosis

用于诊断的 DNA 连接树枝状聚合物纳米颗粒系统

• 批准号: 7127295
• 负责人: JAMES R. BAKER
• 金额: $ 48.39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7127295
• 关键词: SCID mouse; atomic force microscopy; calorimetry; chelating agents; chemical conjugate; chemical synthesis; circular dichroism; cisplatin; complementary DNA; cytotoxicity; diagnosis design /evaluation; doxorubicin; fluorescent dye /probe; folate; gadolinium; high performance liquid chromatography; mass spectrometry; methotrexate; nanotechnology; neoplasm /cancer chemotherapy; neoplasm /cancer diagnosis; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; oligonucleotides; paclitaxel; pharmacokinetics; polymers; surface plasmon resonance; therapy design /development

DESCRIPTION (provided by applicant): Targeted dendrimer-based nanodevices have shown excellent promise in both in vitro cell culture and in vivo animal studies as cancer therapeutics. However, each device must be custom synthesized for a particular set of targeting molecules, imaging agents, and desired therapeutics. We propose a unique solution to this limitation by developing single function dendrimer modules linked by complementary oligonucleotides. This allows targeting, imaging, and therapeutic dendrimers to be combined into multifunctional therapeutics simply by heating mixtures of these agents above the annealing temperature of the oligonucleotide duplex. The project will consist of five specific aims. Specific Aim 1 will involve the design and synthesis of complementary oligonucleotides conjugated to poly(amido)amine dendrimers or dendrons to achieve the desired structural topologies. The ability to construct complex devices will be assessed using well-defined targeting molecules (folic acid, her2 antibodies and RGD peptides), drugs (methotrexate, Taxol, cis-platin and doxorubicin), imaging agents (Gadolinium chelators and fluorescent dyes). Specific Aim 2 will characterize the self-assembled nanodevices using techniques including PAGE, HPLC, CE, Mass Spectroscopy, NMR, AFM, and NSOM. Specific Aim 3 involves testing the DNA-linked nanodevices for binding and internalization in vitro; the avidity and specificity of binding will be examined using CD, differential calorimetry and Biacore analyses. Devices carrying therapeutics will be tested for effectiveness at inducing cell death, and all devices will also be tested for inherent cytotoxicity. Specific Aim 4 employs animal models to assess the effectiveness of the dendrimer linked therapeutics to treat tumors in vivo. In addition, the biodistribution of the therapeutics will be assessed using radiolabeled material and a novel fiber optic probe that uses two-photon excitation with femto-second pulses. Finally, under Specific Aim 5 we will work with the NCI nanoparticle characterization lab in Frederick to make the materials developed in this program available to other investigators. This platform has the potential to revolutionize cancer therapeutics and facilitate "personalized medicine." Lay description: We are designing a method and the tools for developing targeted cancer drugs that can be tailored to the needs of an individual patient. The physician can select various components and the components are then linked together like "tinker toys" to make a personalized medicine. This medicine would selectively target only the cancer, thereby avoiding the nausea, hair loss and illness caused by regular cancer chemotherapy.

描述（由申请人提供）： 靶向树枝状聚合物的纳米构造在体外细胞培养和体内动物研究中都表现出极好的希望。但是，必须自定义每个设备，以定制一组靶向分子，成像剂和所需的治疗剂。我们通过开发由互补寡核苷酸连接的单个功能树枝状聚合物模块，提出了一个独特的解决方案。这样一来，仅通过在寡核苷酸双工的退火温度上加热这些药物的混合物，就可以将靶向，成像和治疗性树枝状聚合物合并为多功能治疗剂。该项目将包括五个具体目标。具体的目标1将涉及与聚（amido）胺树突聚合物或树突偶联的互补寡核苷酸的设计和合成，以实现所需的结构拓扑。将使用明确定义的靶向分子（叶酸，HER2抗体和RGD肽），药物（甲氨蝶呤，紫杉醇，顺式 - 铂和阿霉素），成像剂（Gadolinium Chelators and Chelators and Cluorescentens）来评估构造复杂设备的能力。特定的目标2将使用PAGE，HPLC，CE，质谱，NMR，AFM和NSOM在内的技术来表征自组装的纳米版票。特定的目标3涉及测试DNA连接的纳米台词以在体外结合和内在化；结合的亲和力和特异性将使用CD，差异量热法和Biacore分析进行检查。携带治疗剂的设备将在诱导细胞死亡时的有效性进行测试，并且所有设备也将进行固有的细胞毒性测试。特定目标4采用动物模型来评估树突聚合物连接的治疗疗法治疗体内肿瘤的有效性。此外，将使用放射性标记的材料和一种新型的纤维光学探针评估治疗剂的生物分布，该探针使用具有FEMTO秒脉冲的两光子激发。最后，在特定目标5下，我们将与弗雷德里克（Frederick）的NCI纳米颗粒表征实验室合作，以使该计划中的材料可供其他研究人员使用。该平台有可能彻底改变癌症治疗疗法并促进“个性化医学”。 外表描述：我们正在设计一种方法和开发靶向癌症药物的工具，这些药物可以根据个人患者的需求量身定制。医师可以选择各种组件，然后将组件链接在一起，例如“修补玩具”以制作个性化药物。该药物将仅选择性地靶向癌症，从而避免因常规癌症化疗引起的恶心，脱发和疾病。