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）：