Nanomedicine technology for drug delivery in Rheumatoid Arthritis using a synovium-specific targeting peptide

使用滑膜特异性靶向肽治疗类风湿关节炎的纳米医学技术

• 批准号: 1955149
• 金额: --
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1955149
• 关键词: Nanomedicine; technology; drug; delivery; Rheumatoid

Despite the availability of numerous effective therapeutic agents for the treatment of rheumatoid arthritis (RA), a sizable group of patients (approximately 30-40%) do not respond to current medication. In addition, the risk/benefit ratio profile of current therapies, requires improvement due to systemic exposure leading to potential immune suppression and issues related to off-target adverse effects. One way to combat this is to exploit tissue specific addressin molecules, known to be present in both normal and disease tissues, as targets to deliver/concentrate drugs at the disease tissue site (Ferrari et al., 2016). This has been shown in other conditions such as cancer, to be a powerful tool for drug delivery systems allowing more specific disease tissue targeting, a reduced drug dosage requirement and improved safety profile. In the case of RA, the Pitzalis' group, using in vivo phage display selection in severe combined immunodeficient (SCID) mice transplanted with human synovium, has identified a distinct target for such disease tissue recognised by a cyclic epta-peptide KSTHDRL, known as peptide 3.1 (Lee et al., 2002) constrained by two terminal cysteines that form a disulphide bond. Previous published work from the same group, has also demonstrated the capability of peptide 3.1 to effectively fuse to and deliver the anti-inflammatory cytokine IL-4, directly to RA synovium transplanted into SCID mice and functionally inhibit inflammation in the grafted tissue (Wythe et al., 2013). The distinct synovial targeting potential of this peptide was also tested by Professor Macor's group (University of Trieste) who conjugated it to a neutralising antibody for C5 or TNF, and tested it in vivo using the antigen-induced arthritis rat model (AIA), further supporting the notion that peptide 3.1 can be feasibly used for drug delivery specifically to the diseased joints (Macor et al., 2012; Colombo et al., 2016)The same group also developed a nanomedicine approach arming biodegradable nanoparticles with peptide 3.1 in order to deliver drugs such as Methotrexate (MTX) to diseased joints. Nanoparticle-3.1 was shown to specifically bind its target both in vitro and in vivo and increase MTX efficacy by requiring a lower therapeutic drug dose in order to achieve a similar effect to free-MTX. In addition, they demonstrated by following the distribution of Nanoparticle-3.1 in vivo by immunofluorescence, that it is possible to use this approach for chronic long-term drug delivery and as a diagnostic tool for early detection of inflammation in the joints of potential patients (Colombo et al., 2016). However, these armed nanoparticles have only been tested in animal models such as the AIA rat model. Therefore, in order to translate the development of novel specific therapeutic agents for the treatment of human RA, we propose to use the human-RA/SCID mouse model that has been routinely run in our laboratory for over 17 years (Wahid et al., 2000) to test the capacity of Nanoparticle-3.1 to deliver cargo (e.g. MTX) preferentially to human synovial tissue over skin tissue (control). In order to achieve this, we have established a collaboration with the Macor group (University of Trieste) and the Cruz group (Leiden University Medical Centre) who have produced Nanoparticle-3.1 and successfully used it in conventional animal models e.g AIA. This project's main objectives are to optimise the pharmokinectics of this nanoparticle armed with peptide 3.1 while loaded with an RA drug (e.g. MTX) and establish its in vivo biodistribution in the human-RA/SCID transplantation model and its efficiency delivering and releasing the therapeutic drug to its specific target in inflamed tissue in order to identify its potential for clinical use. Skills Priority Alignment: Advanced Therapeutics, Quantitative Biology, Whole Organism

尽管有许多有效的治疗药物可用于治疗类风湿性关节炎（RA），但相当大的一组患者（约30-40%）对目前的药物治疗无反应。此外，由于全身暴露导致潜在的免疫抑制和与脱靶不良反应相关的问题，目前治疗的风险/获益比特征需要改善。对抗这种情况的一种方法是利用已知存在于正常组织和疾病组织中的组织特异性地址素分子作为靶点以在疾病组织部位递送/浓缩药物（Ferrari等人，2016年）。这已在其他病症如癌症中显示为药物递送系统的有力工具，其允许更特异性的疾病组织靶向、降低的药物剂量要求和改善的安全性。在RA的情况下，Pitzalis的小组在移植有人滑膜的严重联合免疫缺陷（SCID）小鼠中使用体内噬菌体展示选择，已经鉴定了由称为肽3.1的环状肽KSTHDRL识别的这种疾病组织的不同靶标（Lee等人，2002）被形成二硫键的两个末端半胱氨酸限制。来自同一组的先前发表的工作也已经证明了肽3.1有效融合并直接递送抗炎细胞因子IL-4至移植到SCID小鼠中的RA滑膜并在移植组织中功能性抑制炎症的能力（Wythe等人，2013年）。Macor教授的小组（的里雅斯特大学）也测试了这种肽的独特的滑膜靶向潜力，该小组将其与C5或TNF的中和抗体缀合，并使用抗原诱导的关节炎大鼠模型（AIA）在体内测试，进一步支持肽3.1可以可行地用于特异性地向患病关节的药物递送的观点（Macor等人，2012;科隆博等人，2016)同一个小组还开发了一种纳米医学方法，用肽3.1武装可生物降解的纳米颗粒，以便将甲氨蝶呤（MTX）等药物输送到患病的关节。纳米颗粒-3.1显示出在体外和体内特异性结合其靶标，并通过需要较低的治疗药物剂量来增加MTX功效，以实现与游离MTX相似的效果。此外，他们通过免疫荧光跟踪纳米颗粒-3.1在体内的分布证明，可以将这种方法用于慢性长期药物递送，并作为早期检测潜在患者关节炎症的诊断工具（科隆博等人，2016年）。然而，这些武装的纳米颗粒仅在动物模型中进行了测试，例如AIA大鼠模型。因此，为了转化用于治疗人RA的新型特异性治疗剂的开发，我们提出使用在我们的实验室中常规运行超过17年的人-RA/SCID小鼠模型（Wahid等人，2000）以测试纳米颗粒-3.1相对于皮肤组织（对照）优先向人滑膜组织递送货物（例如MTX）的能力。为了实现这一目标，我们与Macor集团（的里雅斯特大学）和Cruz集团（莱顿大学医学中心）建立了合作，他们生产了Nanoparticle-3.1并成功地将其用于传统的动物模型，例如AIA。该项目的主要目标是优化这种装载有RA药物（例如MTX）的肽3.1的纳米颗粒的药代动力学，并建立其在人RA/SCID移植模型中的体内生物分布及其将治疗药物递送和释放到炎症组织中的特定靶点的效率，以确定其临床应用的潜力。技能优先级调整：高级治疗学，定量生物学，整体生物学