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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.