Tailoring liposomal spherical nucleic acid nanoparticles for biological and therapeutic potency

定制脂质体球形核酸纳米颗粒以获得生物和治疗效力

基本信息

批准号：
9126899
负责人：
Jennifer Rachel Ferrer
金额：
$ 3.75万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9126899
关键词：
Adaptor Signaling Protein Address Advanced Development Affinity Animals Architecture Attenuated Autoimmune Diseases Binding Biological Biological Markers Biological Process Biological Response Modifier Therapy Biology Cell Line Cells Chemicals Chemistry Complex DNA DNA Sequence Alteration Development Diagnostic Disease Drug Delivery Systems Elements Encapsulated Engineering Future Gene Expression Regulation Goals Gold Health Heavy Metals Histology Host Defense Human Hyperactive behavior In Vitro Individual Inflammation Inflammatory Inflammatory Response Injury Ischemia Lead Ligands Lipid A Lipids Liposomes Location Lymphocyte Mediating Mediator of activation protein Membrane Methods Modeling Molecular Molecular Probes Molecular Target Motion Mus Oligonucleotide Probes Oligonucleotides Organ Donor Organ Survival Organ Transplantation Outcome Measure Pathologic Pathway interactions Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Production Property Proteomics Receptor Activation Receptor Inhibition Receptor Signaling Reperfusion Injury Reperfusion Therapy Reporter Research Resistance Rodent Model Role Science Sepsis Shapes Signal Pathway Specificity Spherical Nucleic Acids Sterility Surface System TLR4 gene Therapeutic Time Toll-Like Receptor Pathway Toll-like receptors Toxic effect Transplantation Vertebral column base chemical property clinical efficacy cytokine density design emergency service responder immune activation immune function improved in vitro testing in vivo in vivo Model inflammatory marker inhibitor/antagonist innovation liposomal delivery mRNA Expression nanomaterials nanoparticle novel novel therapeutics nuclease particle pathogen pre-clinical protein expression public health relevance receptor receptor binding receptor downregulation response small molecule tool training opportunity treatment response uptake

项目摘要

DESCRIPTION (provided by applicant): Hyperactivation of toll-like receptors (TLRs) leads to inflammatory conditions and disease states, both pathogenic and sterile, such as sepsis, autoimmune disorders and ischemia reperfusion injury during organ transplantation. This proposal is centered on the use of a newly developed liposomal spherical nucleic acid nanoparticle (LSNA) carrying TLR antagonists to probe the molecular mechanism of immune activation by TLRs and to advance the development of a novel therapeutic platform for potential treatment of inflammation. LSNAs are novel nanomaterials that withstand degradation, lead to higher receptor binding affinities and have enhanced potency due to their 3D architecture and oligonucleotide arrangement around a lipid core that confers enhanced biological properties beyond their individual components alone. The elements of the LSNA nanoparticle, specifically the chemistry governing the liposomal core and the oligonucleotide shell, provide a platform for integrating target specificity into the design of the delivery system and payload delivery that permits potent inhibition of TLR activation. This design allows for inhibition of multiple, yet distinct, receptor subtypes. This proposal investigates the biological function of a dual TLR-inhibitory LSNA, which has been previously synthesized and validated, to inhibit distinct TLR ligands that differ in cellular location, but are jointly involved in propagating injury from tissu ischemia and reperfusion. The central goal of this transdisciplinary and collaborative project is t explore the chemical properties of LSNAs that govern biological efficacy and specificity in modulating downstream TLR signaling pathways. Aim 1 probes the oligonucleotide backbone chemistry and specific sequence alterations with the goal of correlating chemical composition with potency of TLR inhibition and immune activation using cellular tools, such as engineered cell lines and primary human lymphocytes. Aim 2 investigates novel methods to minimize ischemia reperfusion injury using LSNAs in an in vivo model of organ transplantation. The use of targeting nanoparticles with the potential to selectively inhibit more than one receptor is an innovative approach because TLR co-stimulation and pathway crosstalk is implicated in multiple diseases and pathologic states. If effective, there are widespread possibilities to applying this nanoparticle for therapeutic applications to other inflammatory diseases in which TLR hyperactivity has been implicated.

描述（由适用提供）：通风样受体（TLR）的过度激活导致炎症状况和疾病状态，包括致病性和无菌性，例如脓毒症，自身免疫性疾病和器官移植期间的缺血再融化损伤。该建议集中在使用新开发的脂质体球形核酸纳米颗粒（LSNA），该核酸纳米粒子（LSNA）带有TLR拮抗剂，以探测TLR通过TLRS探测免疫激活的分子机制，并促进用于炎症潜在治疗的新型治疗平台的开发。 LSNA是应受降解的新型纳米材料，导致受体结合亲和力较高，并且由于其3D结构和脂质核周围的寡核苷酸排列而具有增强的效力，从而使其赋予了更高的生物学特性，从而增强了其单独成分的生物学特性。 LSNA纳米颗粒的元素，特别是管理脂质体核心和寡核苷酸外壳的化学，为将目标特异性集成到递送系统的设计和有效载荷递送的设计中提供了一个平台，从而允许潜在的TLR激活抑制。该设计允许抑制多种但不同的接收器亚型。该提案研究了以前已合成和验证的双重TLR抑制性LSNA的生物学功能，以抑制在细胞位置不同的不同TLR配体，但共同参与了从Tissu Ischemia造成的损伤和再灌注。这个跨学科和协作项目的核心目标是探索在调节下游TLR信号通路时控制生物学有效性和特异性的LSNA的化学特性。 AIM 1问题是寡核苷酸主链化学和特定序列改变与将化学成分与TLR抑制效力相关联和使用细胞工具（例如工程细胞系和原发性人类淋巴细胞）相关的目标。 AIM 2研究了在器官移植的体内模型中使用LSNA最小化缺血再灌注损伤的新方法。靶向纳米颗粒具有选择性抑制多种受体的潜力是一种创新方法，因为TLR共刺激和途径串扰在多种疾病和病理状态下实施。如果有效，将这种纳米颗粒应用于其他炎症性疾病的治疗应用可能性宽度可能性。