Nanoparticle-induced gene-silencing for the suppression of inflammation in mouse models (edema, scleroderma, sepsis)

纳米颗粒诱导的基因沉默可抑制小鼠模型中的炎症（水肿、硬皮病、脓毒症）

• 批准号: 382633364
• 负责人: Professor Dr. Matthias Epple
• 金额: --
• 依托单位: Arbeitsgruppe Experimentelle Radiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/382633364?language=en
• 关键词: Nanoparticle; induced; gene; silencing; suppression

A multifunctional nanoparticle-based system for local and/or systemic inhibition of NF-[kappa]B p65-mediated transcription of pro-inflammatory cytokines/chemokines in acute and chronic inflammatory diseases will be synthesized and examined. If it is successful, it will be widely applicable to patients who demonstrate a high risk of inflammation, e.g. during surgical operations. This therapeutic system can also be prophylactically applied in patients, especially with regard to the alarming problem of antibiotic resistance. Moreover, it could be also helpful in patients who are incompatible with conventional therapies. NF-[kappa]B is an intracellular protein that cannot be addressed by conventional antibody therapies, therefore nanoparticulate carriers for siRNA will be developed in this project. For this purpose, multi-shell siRNA-loaded calcium phosphate nanoparticles will be developed. They will be functionalized with appropriate cell-targeting molecules, i.e. antibodies and peptides. After near-infrared dye conjugation, they will also be detectable in vivo. As alternative system, siRNA-loaded calcium phosphate nanoparticles will be incorporated into polylactic acid nanoparticles in order to obtain a higher degree of siRNA protection from nucleases. The efficiency of the multifunctional nanoparticle-based system will be studied first in defined target cells, i.e. T-cells, B-cells, monocytes/macrophages, and endothelial cells, under controlled culture conditions, and second in vivo in living animals. Regarding the in vivo study, the ability of the nanoparticles to treat an acute localized (e.g. edema), an acute systemic (sepsis) and a chronic (scleroderma) inflammation will be studied. In all these cases, NF-[kappa]B plays an important role in the course of the disease.

将合成并检查用于局部和/或全身抑制急性和慢性炎性疾病中NF-[κ]B p65介导的促炎细胞因子/趋化因子转录的基于多功能纳米颗粒的系统。如果成功，它将广泛适用于那些表现出高炎症风险的患者，例如在外科手术期间。这种治疗系统也可以应用于患者，特别是关于抗生素耐药性的惊人问题。此外，它也可能有助于与传统疗法不相容的患者。NF-[kappa]B是一种细胞内蛋白质，无法通过常规抗体疗法解决，因此本项目将开发用于SiRNA的纳米颗粒载体。为此，将开发多壳siRNA负载的磷酸钙纳米颗粒。它们将用适当的细胞靶向分子（即抗体和肽）功能化。在近红外染料缀合后，它们也将在体内可检测。作为替代系统，将负载siRNA的磷酸钙纳米颗粒掺入聚乳酸纳米颗粒中，以获得更高程度的siRNA保护免受核酸酶的侵害。基于多功能纳米颗粒的系统的效率将首先在受控培养条件下在限定的靶细胞（即T细胞、B细胞、单核细胞/巨噬细胞和内皮细胞）中进行研究，然后在活体动物中进行体内研究。关于体内研究，将研究纳米颗粒治疗急性局部（例如水肿）、急性全身性（败血症）和慢性（硬皮病）炎症的能力。在所有这些情况下，NF-[kappa]B在疾病过程中起重要作用。