A Polymer-Based, Disease-Responsive, Nanoparticle-in-Microparticle System for Pulmonary Delivery of siRNA

该奖项授予德克萨斯大学奥斯汀分校，由材料研究部的生物材料项目和化学，生物工程，环境和运输系统部的生物技术，生物化学和生物质工程项目共同资助。该项目旨在研究通过肺部途径输送治疗药物，从而显著提高患者的依从性，并减少各种疾病的药物相关全身毒性。用于吸入的传统药物具有低的可吸入分数和高的呼出分数、肺泡巨噬细胞的清除率和靶点非特异性。该项目提出了一种独特的纳米微粒中的微粒制剂，该制剂由可溶胀的肽交联微凝胶载体组成，该微凝胶载体封装多糖-小干扰RNA（siRNA）纳米颗粒，用于通过肺部途径有效地细胞内递送药物。这些可吸入的载体被设计用于：（i）有效的空气动力学递送至肺深部的气道上皮细胞;（ii）增加肺沉积和避免由于原位膨胀而引起的肺泡巨噬细胞的吞噬作用（iii）病理生理触发的载药纳米颗粒从患病组织中的微凝胶释放;和（iv）使用基于多糖的纳米颗粒增强治疗性siRNA的细胞内递送。该项目在科学和教育方面产生了重大影响，超出了拟议的目标。所收集的知识将提供关于将多阶段、纳米微粒中微粒类型递送概念应用于肺部治疗的可行性的新见解。该项目本质上是跨学科的，将为研究生、本科生和高中生，包括来自工程专业代表性不足群体的学生提供一个独特的、有益的教育和培训环境。这些研究的结果和前沿概念也将直接惠及多个研究生和本科生课程。基于RNA的药物在成功治疗各种复杂疾病方面具有巨大的前景，包括肺部疾病，如哮喘、慢性阻塞性肺病和肺癌。虽然已经鉴定出几种非常有前途的药物，但没有一种药物转化为临床治疗，主要是由于无法将这些药物安全有效地递送到肺部的靶细胞。因此，重要的研究工作在于找到克服当前递送系统的局限性的用于肺部治疗的改进的药物载体。递送此类药物的最先进概念使用聚合物或基于脂质的纳米颗粒。然而，众所周知，这些纳米颗粒不具有最佳的空气动力学特性，无法有效地分布到肺深处。这导致低治疗功效和增加的药物相关副作用和毒性。在这里，我们建议开发一种新的递送系统，包括纳米颗粒内可降解的，多孔的聚合物微凝胶，将提供理想的性能肺运输以及高效的，细胞内的药物递送到患病组织。这些载体也被设计成使得药物仅在需要的时候和需要的地方被递送，从而大大减少副作用并提高生物功效。这项研究将为肺部给药系统提供新的方向，最终可能导致下一代吸入治疗。该项目还纳入了重要的教育内容，以培养下一代科学家，包括研究生和本科生以及高中生，特别是那些来自工程专业代表性不足群体的学生。作为他们经验的一部分，研究生将接受最先进和尖端技术的培训，并指导本科女工程师从事研究型职业。研究实习机会也将提供给来自得克萨斯州奥斯汀地区的高中生，以培养兴趣和鼓励追求干事业。

This award to University of Texas at Austin is funded jointly by the Biomaterials program in the Division of Materials Research, and the Biotechnology, Biochemical, and Biomass Engineering program in the Division of Chemical, Bioengineering, Environmental, and Transport Systems. This project is to study the delivery of therapeutic agents through the pulmonary route that could provide significant improvement in patient compliance and reduce drug-related systemic toxicity for a variety of diseases. Traditional drugs for inhalation suffer from low respirable fractions and high exhaled fractions, clearance by alveolar macrophages, and target non-specificity. This project proposes a unique nanoparticle-in-microparticle formulation comprising of swellable, peptide-crosslinked microgel-carriers encapsulating polysaccharide-small interfering RNA (siRNA) nanoparticles for efficient, intracellular delivery of drugs through the pulmonary route. These inhalable carriers are designed for: (i) efficient aerodynamic delivery to airway epithelial cells of the deep lung; (ii) increased lung deposition and avoidance of phagocytosis by alveolar macrophages due to in-situ swelling (large size) and stealth properties; (iii) pathophysiologically-triggered release of drug-loaded nanoparticles from microgels in the diseased tissue; and (iv) enhanced intracellular delivery of therapeutic siRNA using polysaccharide-based nanoparticles. There are significant scientific as well as educational impacts of this project that reaches beyond the proposed aims. The knowledge gathered would provide new insights on the feasibility of applying multi-stage, nanoparticle-in-microparticle type delivery concepts for pulmonary therapies. The project is inherently interdisciplinary and will provide a unique and rewarding educational and training environment for graduate, undergraduate and high school students, including those from under-represented groups in engineering professions. The results and cutting-edge concepts developed by these studies would also directly benefit several graduate and undergraduate courses.RNA-based drugs hold tremendous promise in successfully treating a wide variety of complex diseases, including pulmonary diseases, e.g. asthma, chronic obstructive pulmonary disease and lung cancers. Although several highly promising drugs have been identified, none has translated into clinical therapy primarily due to the inability to deliver these drugs safely and efficiently to the target cells in the lungs. It is therefore critical that significant research effort is vested on finding improved drug carriers for pulmonary therapeutics that overcomes the limitations of current delivery systems. The state-of-the-art concept to deliver such drugs uses polymer or lipid-based nanoparticles. However, it is well understood that these nanoparticles do not possess optimal aerodynamic properties for efficient distribution deep into the lung. This leads to low therapeutic efficacy and increased drug-associated side effects and toxicity. Here, we propose to develop a novel delivery system comprising of nanoparticles entrapped inside degradable, porous polymer microgels that would provide ideal properties for lung transport as well as highly efficient, intra-cellular delivery of drugs to diseased tissues. These carriers are also designed such that the drug is delivered only when and where it is needed, thereby greatly reducing side-effects and enhancing biological efficacy. The proposed research would provide new directions in pulmonary drug delivery system that could eventually lead to the next generation of inhaled therapeutics. The project also incorporates significant educational components to train the next generation of scientists, including graduate and undergraduate students as well as high school students especially those from under-represented groups in engineering professions. As part of their experience, graduate students will be trained in state-of-the-art and cutting edge techniques as well as on mentoring undergraduate women engineers for a research-based career. Research internship opportunities will also be offered to high school students from the Austin, Texas area to foster interest and encourage pursuit of STEM careers.