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: 9367787
• 负责人: Yupeng Chen
• 金额: $ 35.42万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9367787
• 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; Nobel Prize; Outcome; Penetration; Peptide Hydrolases; Pharmaceutical Preparations; Process; Public Health; RNA; 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; disability; functional group; improved; in vivo; innovation; insight; intermolecular interaction; joint destruction; joint injury; nano; nanomaterials; nanorod; prevent; residence; self assembly; 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（例如运动相关的关节损伤）引起的，是关节的常见原因。 退化和残疾每年影响 560 万美国人。 修饰药物以阻止 PTOA 进展 作为诺贝尔奖获奖发现，小干扰 RNA。 (siRNA) 提供了特异性抑制疾病基因表达的巨大治疗潜力。 传递带负电的 siRNA 来穿透无血管、致密、带负电的区域极具挑战性 此外，关节囊中的治疗剂通常会被迅速清除，从而限制了它们的停留。 时间短至 1-5 小时，为了克服这些障碍，我们开发了一种非共价 Janus 基纳米 - 名为 Nanopiece (NP) 的运载工具具有定制的尺寸和表面特性，这使得 封装的siRNA渗透到关节软骨组织中并通过与软骨细胞结合。 细胞外基质 (ECM)，NP 在软骨中保留较长的半衰期，将屏障转化为载体。 该提案的目标是确定调节纳米颗粒尺寸和表面性质的因素， 1) 确定有效渗入软骨的纳米粒子的最佳尺寸 2) 制定； 结合软骨基质以保留组织的纳米颗粒的表面特性，以及 3) 评估治疗能力 NPs 在 DMM 模型中抑制 PTOA 进展的根本原理是完成 该提案将1）增进我们对非共价纳米递送载体自组装的理解 及其与组织 ECM 分子的相互作用；2) 实现 siRNA 递送技术平台 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) 为开发第一个针对 PTOA 的疾病修饰 RNA 疗法奠定基础。 所提出的研究具有创新性，因为：1）NP是新一代药物输送载体，具有独特的 尺寸的多功能性、对 ECM 分子的亲和力以及优异的生物降解性等优点 2）我们根据以下方面描述了输送载体和软骨ECM之间的相互作用。 车辆的尺寸和表面特性，然后确定成功内软骨的关键因素 3）这项技术突破启发了一种通过递送siRNA来治疗PTOA的治疗方法。 完成具体目标后，我们期望：1）增进对非 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、 持久地将 siRNA 递送到软骨中，以及 3) 通过 siRNA/NP 抑制 DMM 模型中的 PTOA 进展 这些结果将对开发特定的药物输送载体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 PTOA 等关节疾病的治疗。