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、生化和生物质工程项目共同资助。本项目旨在研究通过肺途径给药治疗药物，从而显著提高患者依从性，降低多种疾病的药物相关全身毒性。传统吸入性药物存在呼吸分数低、呼出分数高、被肺泡巨噬细胞清除、靶向不特异性等问题。该项目提出了一种独特的纳米颗粒-微颗粒配方，包括可膨胀的肽交联微凝胶载体，包封多糖小干扰RNA （siRNA）纳米颗粒，通过肺部途径有效地在细胞内递送药物。这些可吸入载体设计用于：(i)有效的空气动力学输送到深肺气道上皮细胞；（ii）由于原位肿胀（体积大）和隐身特性，肺泡巨噬细胞增加肺沉积和避免吞噬；（iii）病理生理触发的载药纳米颗粒从病变组织中的微凝胶释放；（iv）使用基于多糖的纳米颗粒增强治疗性siRNA的细胞内递送。这一项目对科学和教育的重大影响超出了拟议的目标。所收集的知识将为在肺部治疗中应用多阶段、纳米颗粒-微颗粒型递送概念的可行性提供新的见解。该项目本质上是跨学科的，将为研究生、本科生和高中生提供一个独特而有益的教育和培训环境，包括那些来自工程专业中代表性不足的群体的学生。这些研究的结果和前沿概念也将直接受益于一些研究生和本科课程。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。虽然已经确定了几种非常有前途的药物，但由于无法将这些药物安全有效地输送到肺部的靶细胞，因此没有一种药物能够转化为临床治疗。因此，重要的是要投入大量的研究工作，寻找改进的肺部治疗药物载体，克服当前给药系统的局限性。最先进的概念是使用聚合物或基于脂质的纳米颗粒来输送这种药物。然而，众所周知，这些纳米颗粒并不具有最佳的空气动力学特性，无法有效地分布到肺部深处。这导致低疗效和增加药物相关的副作用和毒性。在这里，我们建议开发一种新型的递送系统，该系统由包裹在可降解的多孔聚合物微凝胶中的纳米颗粒组成，该微凝胶将为肺部运输提供理想的性能，并为疾病组织提供高效的细胞内药物递送。这些载体的设计也使得药物只在需要的时候和地方被递送，从而大大减少了副作用并提高了生物功效。该研究将为肺部药物输送系统提供新的方向，最终可能导致下一代吸入治疗。该项目还包括重要的教育组成部分，以培训下一代科学家，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中代表性不足的群体的学生。作为她们经验的一部分，研究生将接受最先进和最尖端技术的培训，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德克萨斯州奥斯汀地区的高中生，以培养兴趣并鼓励追求STEM职业。

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.