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

项目总结 这个第一阶段STTR项目的目的是开发用于联合给药的靶向纳米粒 作为治疗药物的核酸和小分子药物。我们之前已经建立了一个小说图书馆 氨基糖苷类聚合物纳米粒可同时输送核酸和小分子 分子药物或显像剂进入哺乳动物细胞。纳米颗粒平台的疗效 将展示组合核酸和药物输送用于治疗慢愈/慢性 Wentures，它将被用作此STTR的测试用例。愈合缓慢/慢性伤口，包括糖尿病 创伤，不能通过正常的修复机制愈合，给医学领域带来了巨大的挑战。糖尿病 2018年，全球超过4.25亿成年人受到影响，预计未来20年将翻一番。慢性 在所有糖尿病患者中，伤口的发生率为15%-25%，如果治疗不当，有很高的截肢风险。 这些伤口的特点是长期炎症，持续感染，细胞外基质降解，增加 蛋白水解酶、衰老细胞、血管生成和干细胞减少。尽管伤口护理选项包括 外用敷料和抗菌剂，用于治疗慢性创面，这些治疗的有效性 是不一致的。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 生物相容聚合物纳米粒文库用于靶向共传递治疗性质粒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 这些纳米颗粒用于在不同细胞类型中组合输送质粒DNA和治疗药物。 我们还开发了小分子-聚合物结合物，用于将质粒DNA货物定向递送到 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粒子库 并评价这些纳米粒子在体外和体内对质粒DNA和小分子药物的共传递作用。 活着。创面大小，屏障功能，组织生物力学恢复，炎症，胶原含量，恢复 将评估糖尿病患者的上皮化、肉芽形成、血糖和胰岛素水平以及血管生成。 老鼠模型。拟议的靶向聚合物技术，能够针对现场的特定细胞类型- 特异性递送质粒DNA货物和小分子增强剂，具有高翻译潜力，并可以 对几种疾病有治疗作用。

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.