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

项目摘要 该一期STTR项目的目的是开发用于组合递送的靶向纳米颗粒， 核酸和小分子药物作为治疗剂。我们以前开发了一个小说库， 能够同时递送核酸和小分子的氨基糖苷类衍生的聚合物纳米颗粒 分子药物或成像剂进入哺乳动物细胞。纳米颗粒平台的功效 组合核酸和药物递送将被证明用于治疗缓慢愈合/慢性 伤口，将用作本STTR的测试用例。愈合缓慢/慢性伤口，包括糖尿病 伤口不能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年将翻一番。慢性 所有糖尿病患者中有15 - 25%发生伤口，如果不适当治疗，会造成截肢的高风险。 这些伤口的特征在于长时间的炎症、持续感染、ECM降解、细胞外基质（ECM）的增加、细胞外基质（ECM）的降解。 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 局部敷料和抗微生物剂用于治疗慢性伤口，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，用于治疗性质粒DNA和小分子的靶向共递送。 真皮细胞中转基因表达的分子增强剂。我们先前的工作表明， 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，用于靶向递送质粒DNA货物， 特定细胞类型。在拟议的项目中，我们将开发一种针对缓慢愈合伤口的纳米颗粒库 并评估这些纳米颗粒在体外和体内共同递送质粒DNA和小分子药物的情况。 vivo.伤口大小，屏障功能，组织生物力学恢复，炎症，胶原含量，再- 将在糖尿病患者中评价上皮形成、肉芽形成、血糖和胰岛素水平以及血管生成。 小鼠模型拟议的靶向聚合物技术，能够针对特定的细胞类型的网站- 质粒DNA货物和小分子增强子特异性递送具有高翻译潜力， 在几种疾病中产生治疗益处。

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.