Developing Nanomaterial Platform for Intra-Cartilage Delivery of RNA Therapeutics against Joint Diseases

开发用于软骨内递送 RNA 治疗关节疾病的纳米材料平台

• 批准号: 10379302
• 负责人: Yupeng Chen
• 金额: $ 35.07万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379302
• 关键词: Affect; Affinity; American; Architecture; Binding; Cartilage; Cartilage Matrix; Charge; Chemicals; Chondrocytes; Custom; Degenerative polyarthritis; Development; Dimensions; Disease; Drug Delivery Systems; Encapsulated; Ensure; Extracellular Matrix; Foundations; Gene Expression; Generations; Goals; Half-Life; Health; Hour; Human; Intra-Articular Injections; Joint Capsule; Length; Medial meniscus structure; Mediating; Mission; Modeling; Morphology; Mus; Names; Nano delivery; Nobel Prize; Outcome; Penetration; Peptide Hydrolases; Pharmaceutical Preparations; Process; Public Health; RNA delivery; Research; Small Interfering RNA; Sonication; Sports; Surface; Surface Properties; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Trauma; Treatment Efficacy; United States National Institutes of Health; Width; arthropathies; articular cartilage; base; cartilage degradation; delivery vehicle; disability; functional group; improved; in vivo; innovation; insight; intermolecular interaction; joint destruction; joint injury; nanomaterials; nanorod; prevent; residence; self assembly; therapeutic RNA; therapy outcome

Abstract PTOA is caused by physical trauma such as sports related joint injuries. It is a common cause of joint degeneration and disability, affecting 5.6 millions of Americans every year. Currently, there is no disease- modifying drug to prevent PTOA progression. As a Nobel-prize winning discovery, small interfering RNA (siRNA) provides great therapeutic potential to specifically inhibit disease gene expression. However, it is extremely challenging to deliver negatively-charged siRNA to penetrate avascular, dense, negatively-charged cartilage matrix. Moreover, therapeutics in the joint capsule is usually cleared rapidly, limiting their residence times to as short as 1-5 hours. To overcome these obstacles, we developed a non-covalent Janus-base nano- delivery vehicle named Nanopiece (NP) with customized dimensions and surface properties, which enable the encapsulated siRNA to penetrate into articular cartilage tissue and enter chondrocytes. Through binding with extracellular matrix (ECM), NP is retained in cartilage for a long half-life, converting a barrier to carrier. The goal of this proposal is to determine the factors regulating the dimensions and surface properties of NPs, thereby 1) identifying the optimal dimensions of NPs that penetrate into cartilage effectively; 2) formulating surface properties of NPs that bind cartilage matrix for tissue retention, and 3) evaluating the therapeutic ability of the NPs to inhibit PTOA progression in the DMM model. The underlying rationale is that the completion of this proposal will 1) advance our understanding on the self-assembly of non-covalent nano-delivery vehicles and their interactions with tissue ECM molecules; 2) realize a platform siRNA delivery technology that penetrating cartilage and other matrix-rich tissues with customized dimensions and surface properties; and 3) lay the foundation for the development of the first disease-modifying RNA therapeutic against PTOA. The proposed research is innovative because: 1) NP is a new generation drug delivery vehicle with unique advantages such as the versatility in dimensions, affinity to ECM molecules and excellent biodegradability and non-toxicity. 2) We delineate the interactions between delivery vehicles and cartilage ECM in terms of the vehicles’ dimension and surface property, and then determine the key factors for successful intra-cartilage delivery. 3) The technology breakthrough enlightens a therapeutic approach to deliver siRNA to treat PTOA. After accomplishing the specific aims, we expect to 1) advance fundamental understandings of the non- covalent nanomaterial self-assembly and its interactions with tissue matrix, 2) achieve highly effective and long-lasting siRNA delivery into cartilage, and 3) inhibit PTOA progression in the DMM model via the siRNA/NP therapy. These outcomes will have important positive impact on developing specific drug delivery vehicles for cartilage or other matrix-rich tissues, and improving treatment of joint diseases such as PTOA.

抽象的 PTOA是由身体创伤引起的，例如与运动相关的关节损伤。这是关节的常见原因 退化和残疾，每年影响5600万美国人。目前，没有疾病 - 修饰药物以防止PTOA进展。作为诺贝尔奖的获奖发现，小小的干扰RNA （siRNA）为特异性抑制疾病基因表达提供了巨大的治疗潜力。但是，是 交付负电荷的siRNA极为挑战 软骨矩阵。此外，关节囊中的治疗通常会迅速清除，从而限制了他们的住所 时间短达1-5小时。为了克服这些障碍，我们开发了一种非共价janus-base纳米 - 具有自定义尺寸和表面特性的纳米胶质（NP）的送货车辆，这使得 封装的siRNA渗透到关节软骨组织中并进入软骨细胞。通过结合 细胞外基质（ECM），NP保留在软骨中，以延长半衰期，将障碍物转换为载体。这 该建议的目标是确定调查NPS的维度和表面特性的因素， 1）识别有效渗透到软骨的NP的最佳尺寸； 2）制定 结合软骨基质以进行组织的NP的表面特性，3）评估治疗能力 NP抑制DMM模型中的PTOA进展。基本的理由是完成 该提议将1）提高我们对非共价纳米交付车辆自组装的理解 它们与组织ECM分子的相互作用； 2）实现平台siRNA传递技术 具有定制尺寸和表面特性的穿透软骨和其他富含基质的组织； 3） 为针对PTOA的第一种疾病改良RNA疗法的开发奠定了基础。这 拟议的研究具有创新性，因为：1）NP是一种新一代药物，具有独特的 优点，例如维度的多功能性，对ECM分子的亲和力以及出色的生物降解性和 无毒。 2）我们从 车辆的尺寸和表面特性，然后确定成功内部的关键因素 送货。 3）技术突破启发了一种治疗方法来提供siRNA来治疗PTOA。 完成具体目标后，我们希望1）提前对非 - 共价纳米材料自组装及其与组织基质的相互作用，2）实现高效和 持久的siRNA递送到软骨中，3）通过siRNA/NP抑制DMM模型中的PTOA进展 治疗。这些结果将对开发特定药物输送工具产生重要的积极影响 用于软骨或其他富含基质的组织，并改善关节疾病（例如PTOA）的治疗。