Aptamer-siRNA Chimera/Nanoparticle Conjugates for MRI Guided Cancer Therapy

用于 MRI 引导癌症治疗的适体-siRNA 嵌合体/纳米颗粒缀合物

• 批准号: 7644393
• 负责人: Konstantin V Sokolov
• 金额: $ 19.81万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644393
• 关键词: Achievement; Adverse effects; Affect; Animals; Antibodies; Berlex brand of ferumoxides; Binding; Biochemistry; Biodistribution; Biological; Biological Markers; Cancerous; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Chimera organism; Complex; Contrast Media; DNA Sequence; Development; Diagnostic; Diffuse; Diffusion; Down-Regulation; Drug Monitoring; Electrical Engineering; Engineering; Ensure; Excision; Feedback; Fluorescence; Gadopentetate Dimeglumine; Gene Expression; Gene Silencing; Genes; Genetic; Glutamate Carboxypeptidase II; Goals; Gold; Green Fluorescent Proteins; Hand; Heating; Human; Hybrids; Image; Injection of therapeutic agent; International; Investigation; Lead; Left; Legal patent; Life; Light; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Malignant neoplasm of prostate; Manuscripts; Medicine; Membrane; Messenger RNA; Metabolism; Methods; MicroRNAs; Modern Medicine; Molecular; Molecular Biology; Molecular Target; Monitor; Mus; Nanotechnology; Normal tissue morphology; Nucleic Acids; Nucleotides; Oligonucleotides; Operative Surgical Procedures; Optics; PC3 cell line; Pathology; Permeability; Pharmaceutical Preparations; Polymers; Process; Prodrugs; Protocols documentation; Publishing; RNA; Radioactive; Research; Signal Transduction; Site; Small Interfering RNA; Specificity; Stimulus; Structure; Surface; System; Technology; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Weight; Work; Xenograft Model; aptamer; cancer cell; cancer therapy; carcinogenesis; cellular imaging; design; experience; human DICER1 protein; image processing; improved; in vivo; interest; iron oxide; irradiation; meetings; melting; member; nanocarrier; nanomaterials; nanoparticle; novel; novel strategies; particle; programs; receptor; research study; response; technology development; therapeutic gene; treatment site; tumor

DESCRIPTION (provided by applicant): One of the major challenges of modern medicine is the development of novel approaches for the efficient delivery of therapeutics and molecular specific treatment of pathology that can be carried out under imaging guidance and monitoring. Recent advances in nanotechnology, biochemistry and molecular biology give an opportunity to combine all these capabilities in a single entity. In this research program we will use recent achievements in nanotechnology and biochemistry to engineer a nanomaterial with both therapeutic and MRI contrast enhancing capabilities. This material will provide the optimized combination of: efficient delivery of a deactivated therapeutic compound, selective activation of the prodrug using external stimuli, molecular specific therapeutic effect upon activation and MRI monitoring and guidance. The nanomaterial will consist of a gold-coated iron oxide nanoparticle carrier with attached oligonucleotide handles that interact with fluorinated aptamer-siRNA chimera molecules through complementary nucleotides. The aptamer portion of the chimera will be specific for a cancer biomarker and the siRNA portion will be used to down-regulate expression of genes that are essential for cancer cell survival. The oligonucleotide handle will be designed to interact with and reversibly deactivate the aptamer portion of the chimera; this will ensure that the particles do not spontaneously bind to their target especially in normal tissue. These bioconjugated nanoparticles will be delivered in cancerous tissue under T2 weighted MRI monitoring of their accumulation and biodistribution. Then, near infrared (NIR) irradiation will be delivered to the treatment site that will lead to the local heating of the gold layer, melting of the double stranded helix between oligonucleotide handles and the aptamer portion of chimera molecules, and release of the chimeras which will then diffuse deep into the cancerous tissue. We hypothesize that release and diffusion of chimera molecules can be imaged by 19F MRI. The aptamer portion will refold and regain molecular specificity, delivering the therapeutic siRNA inside cancer cells thereby inducing cell death. The nanoparticle carrier will improve delivery, reduce non-specific toxicity, and enable monitoring of accumulation and activation of molecular specific cancer therapy. Initial tests with cell cultures and mouse xenograft models will demonstrate its efficacy. The main objective of this program is to develop and initially test a new, nontoxic nanomaterial that can be activated via NIR light irradiation to release a targeted molecular compound that can be selectively internalized by cancer cells and induce a therapeutic gene-silencing response. The nanoparticle carrier will improve delivery, reduce non-specific toxicity, and enable monitoring of accumulation and activation of molecular specific cancer therapy. Initial tests with mouse xenograft models will demonstrate its efficacy. Successful completion of this project will make an important advance toward realization of one of the ultimate goals of cancer medicine, a material that can be used to simultaneously detect and treat cancer.

描述（由申请人提供）：现代医学的主要挑战之一是开发新的方法来有效地提供治疗药物和病理分子特异性治疗，这些方法可以在成像指导和监测下进行。纳米技术、生物化学和分子生物学的最新进展为将所有这些能力结合在一起提供了机会。在这个研究项目中，我们将利用纳米技术和生物化学的最新成果来设计一种具有治疗和MRI对比度增强能力的纳米材料。该材料将提供以下优化组合：失活治疗化合物的有效递送，使用外部刺激选择性激活前药，激活后的分子特异性治疗效果以及MRI监测和指导。该纳米材料将由一个镀金的氧化铁纳米颗粒载体组成，其上附着寡核苷酸把手，通过互补的核苷酸与氟化适配体- sirna嵌合体分子相互作用。嵌合体的适体部分将对癌症生物标志物具有特异性，siRNA部分将用于下调对癌细胞存活至关重要的基因的表达。寡核苷酸手柄将被设计成与嵌合体的适体部分相互作用并可逆地使其失活；这将确保颗粒不会自发地与目标结合，特别是在正常组织中。在T2加权MRI监测其积累和生物分布的情况下，这些生物共轭纳米颗粒将被递送到癌组织中。然后，将近红外（NIR）照射到治疗部位，这将导致金层的局部加热，熔化在寡核苷酸柄和嵌合体分子的适配体部分之间的双链螺旋，并释放嵌合体，然后扩散到癌组织深处。我们假设嵌合体分子的释放和扩散可以通过19F MRI成像。适体部分将重新折叠并重新获得分子特异性，在癌细胞内传递治疗性siRNA，从而诱导细胞死亡。纳米颗粒载体将改善递送，减少非特异性毒性，并能够监测分子特异性癌症治疗的积累和激活。细胞培养和小鼠异种移植模型的初步试验将证明其有效性。该项目的主要目标是开发并初步测试一种新的无毒纳米材料，这种材料可以通过近红外光照射激活，释放出一种靶向分子化合物，这种化合物可以被癌细胞选择性地内化，并诱导治疗性基因沉默反应。纳米颗粒载体将改善递送，减少非特异性毒性，并能够监测分子特异性癌症治疗的积累和激活。小鼠异种移植模型的初步试验将证明其有效性。该项目的成功完成将为实现癌症医学的终极目标之一——一种可用于同时检测和治疗癌症的材料——迈出重要的一步。