DEVELOPMENT OF NOVEL AMINOGLYCOSIDE POLYMERS AND NANOPARTICLES FOR NUCLEIC ACID DELIVERY IN CHRONIC WOUNDS

开发用于慢性伤口核酸输送的新型氨基糖苷聚合物和纳米颗粒

基本信息

批准号：
10009545
负责人：
Kaushal Rege
金额：
$ 32.5万
依托单位：
SYNERGYAN, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2023-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10009545
关键词：
Adult Affect Aminoglycosides Amputation Antibodies Area Arizona Biomechanics Biopsy Blood Circulation Blood Glucose CSF3 gene Caliber Cell Proliferation Cells Chromatin Chronic Collagen Cytoplasmic Granules DNA delivery Dermal Development Diabetes Mellitus Diabetic Foot Ulcer Diabetic mouse Disease Drug Controls Drug Delivery Systems Effectiveness Elastin Enhancers Enzymes Epithelial Epithelium Evaluation Extracellular Matrix Extracellular Matrix Degradation Fibroblasts Gelatinase A Gene Delivery Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Factor Health Professional Hematoxylin and Eosin Staining Method Hemostatic function Human Hydroxyproline IL1A gene IL2 gene IL4 gene IL6 gene Image Analysis In Vitro Inflammation Inflammatory Insulin Interferon Type II Interleukin-10 Interleukin-12 Interleukin-17 Laboratories Lead Libraries MMP2 gene Mammalian Cell Measures Mediating Medical Modeling Mus Nucleic Acids PECAM1 gene Patients Peptide Hydrolases Peptides Phagocytes Pharmaceutical Preparations Phase Plasmids Polymers Property Proteins Recovery Research Resistance Site Skin Small Business Technology Transfer Research Splint Device Stains Sterile coverings TNF gene Technology Tensile Strength Testing Therapeutic Thick Tissues Treatment Effectiveness Universities Water Western Blotting Work angiogenesis antimicrobial biocompatible polymer cell type chemokine chronic infection chronic wound combinatorial cost cytokine diabetic diabetic ulcer diabetic wound healing healing high risk imaging agent in vivo inhibitor/antagonist mouse model nanoparticle nanoparticle delivery novel nuclease nucleic acid delivery overexpression plasmid DNA repaired senescence small molecule small molecule inhibitor stem cells targeted delivery transgene expression wound wound bed wound care wound closure wound healing

项目摘要

PROJECT SUMMARY The purpose of this Phase I STTR project is to develop targeted nanoparticles for the combinatorial delivery of nucleic acids and small molecule drugs as therapeutics. We have previously developed a library of novel aminoglycoside-derived polymer nanoparticles capable of simultaneously delivering nucleic acids and small molecule drugs or imaging agents into mammalian cells. The efficacy of the nanoparticle platform for combinatorial nucleic acid and drug delivery will be demonstrated for the treatment of slow-healing / chronic wounds, which will be employed as a test case for this STTR. Slow healing / chronic wounds, including diabetic wounds, do not heal via normal repair mechanisms and present a great challenge to the medical field. Diabetes affected over 425 million adults worldwide in 2018 and is expected to double in the next 20 years. Chronic wounds occur in 15-25% of all patients with diabetes and pose a high risk of amputation if not properly treated. These wounds are characterized by prolonged inflammation, persistent infection, ECM degradation, increase in proteases, senescent cells, and decrease in angiogenesis and stem cells. Although wound care options including topical dressings and antimicrobials, exist for treatment of chronic wounds, the effectiveness of these treatments is inconsistent. In this STTR project, Synergyan, LLC and Arizona State University (ASU) will screen a novel biocompatible polymer nanoparticle library for the targeted co-delivery of therapeutic plasmid DNA and small- molecule enhancers of transgene expression in dermal cells. Our prior work has shown the effectiveness of these nanoparticles for the combinatorial delivery of plasmid DNA and therapeutic drugs in different cell types. We have also developed small-molecule-polymer conjugates for the targeted delivery of plasmid DNA cargo to specific cell types. In the proposed project, we will develop a nanoparticle library targeting slow healing wounds and evaluate these nanoparticles for the co-delivery of plasmid DNA and small molecule drugs in vitro and in vivo. Wound size, barrier function, tissue biomechanical recovery, inflammation, collagen content, re- epithelialization, granulation, blood glucose and insulin levels, and angiogenesis will be evaluated in the diabetic mouse model. The proposed targeted polymer technology, capable of targeting specific cell types for the site- specific delivery of plasmid DNA cargo and small-molecule enhancers, has high translational potential and can be lead to therapeutic benefit in several diseases.

项目概要 STTR 第一阶段项目的目的是开发用于组合递送的靶向纳米粒子核酸和小分子药物作为治疗剂。我们之前开发了一个小说库氨基糖苷衍生的聚合物纳米颗粒能够同时递送核酸和小分子分子药物或显像剂进入哺乳动物细胞。纳米颗粒平台的功效组合核酸和药物输送将被证明可用于治疗缓慢愈合/慢性疾病伤口，将用作此 STTR 的测试用例。愈合缓慢/慢性伤口，包括糖尿病患者伤口无法通过正常的修复机制愈合，这对医学领域提出了巨大的挑战。糖尿病 2018 年，全球有超过 4.25 亿成年人受到影响，预计未来 20 年将增加一倍。慢性的 15-25% 的糖尿病患者会出现伤口，如果治疗不当，截肢的风险很高。这些伤口的特点是长期炎症、持续感染、ECM 降解、蛋白酶、衰老细胞以及血管生成和干细胞减少。尽管伤口护理选项包括局部敷料和抗菌剂可用于治疗慢性伤口，这些治疗的有效性不一致。在这个 STTR 项目中，Synergyan, LLC 和亚利桑那州立大学 (ASU) 将放映一部小说生物相容性聚合物纳米颗粒库，用于靶向共同递送治疗性质粒 DNA 和小分子真皮细胞中转基因表达的分子增强剂。我们之前的工作已经证明了以下方法的有效性这些纳米颗粒用于在不同细胞类型中组合递送质粒 DNA 和治疗药物。我们还开发了小分子聚合物缀合物，用于将质粒 DNA 货物靶向递送至特定的细胞类型。在拟议的项目中，我们将开发一个针对缓慢愈合伤口的纳米颗粒库并评估这些纳米粒子在体外和体内共同递送质粒 DNA 和小分子药物的情况体内。伤口大小、屏障功能、组织生物力学恢复、炎症、胶原蛋白含量、再将评估糖尿病患者的上皮形成、肉芽形成、血糖和胰岛素水平以及血管生成鼠标模型。所提出的靶向聚合物技术，能够针对该位点的特定细胞类型质粒 DNA 货物和小分子增强剂的特异性递送，具有很高的翻译潜力，并且可以对多种疾病产生治疗效果。