Novel polymeric nanoparticles for pulmonary nucleic acid therapy - synthesis, toxicological analysis and biological / therapeutic assessment

用于肺核酸治疗的新型聚合物纳米粒子 - 合成、毒理学分析和生物/治疗评估

• 批准号: 426524608
• 负责人: Professor Dr. Achim Aigner
• 金额: --
• 依托单位: Rudolf-Boehm-Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/426524608?language=en
• 关键词: Novel; polymeric; nanoparticles; pulmonary; nucleic

For many pulmonary diseases including lung tumors / metastases, novel treatment strategies are needed. Therapeutics based on RNA interference (RNAi) are advantageous but require efficient delivery of small interfering RNAs (siRNAs). Inhalative siRNA application offers direct contact, immediate availability, limited systemic spread and thus higher doses in the lung, but meets major challenges.Nanoparticles based on polymers or polymer/lipid combinations have been explored for siRNA delivery in vivo. Initial data from the applicants’ and other groups indicate that poly(ethylene) imines (PEIs) and other polyamines, and specific modifications for defined biodegradability and improved NP stability, may allow for novel inhalable siRNA formulations. Beyond efficacy, the assessment of toxicity will critically determine optimal NPs for lung delivery. Additionally, the development of inhalable formulations, e.g. based on nebulizers or dry powder inhalers, is crucial for clinical applications. This project will develop polymeric NPs as a platform for the delivery of oncogene-specific siRNAs, for direct application via inhalation. This includes generating a library of very defined, novel modified small polyamine systems, esp. tyrosine-modified derivatives, biodegradable derivatives and combinations thereof. Novel NPs will be extensively characterized regarding physical, physicochemical, biological and toxicological properties, and tested in vivo in lung metastasis mouse models regarding siRNA delivery, biodistribution and therapeutic efficacy. Different nebulization strategies (NPs from aqueous solution or dry powder, lyophilized or spray-dried upon NP embedding into hydrogels) will be explored. Beyond siRNA, the systems developed will be extended towards minicircle plasmid DNA and CRISPR-Cas9 (i.e., sgRNA + Cas9 plasmid).The definition and generation of optimal NPs, their optimal formulation for inhalative application and their biological assessment rely on the high degree of interaction between DE and PL, with both sides contributing their core competences. In an iterative process, results on biological efficacy (DE, PL) and biocompatibility/toxicity (PL) of NPs based on novel polymers (DE) influence further refinement of polymer modifications (DE) and NP generation (DE, PL).

对于许多肺部疾病，包括肺肿瘤/转移，需要新的治疗策略。基于RNA干扰（RNAi）的治疗是有利的，但需要有效递送小干扰RNA（siRNA）。吸入性siRNA应用提供了直接接触、立即可用性、有限的全身扩散和因此在肺中的较高剂量，但遇到了主要挑战。来自申请人和其他小组的初始数据表明，聚（亚乙基）亚胺（PEI）和其他聚胺，以及用于限定的生物降解性和改善的NP稳定性的特定修饰，可以允许新的可吸入siRNA制剂。除了功效之外，毒性的评估将关键地确定用于肺递送的最佳NP。此外，可吸入制剂（例如基于雾化器或干粉吸入器）的开发对于临床应用至关重要。该项目将开发聚合物NP作为递送癌基因特异性siRNA的平台，用于通过吸入直接应用。这包括产生非常明确的、新颖的改性的小聚胺系统，特别是酪氨酸改性的衍生物、生物可降解的衍生物及其组合的文库。新型NP将在物理、物理化学、生物学和毒理学性质方面进行广泛表征，并在肺转移小鼠模型中就siRNA递送、生物分布和治疗功效进行体内测试。将探索不同的雾化策略（NP来自水溶液或干粉，在NP包埋到水凝胶中后冻干或喷雾干燥）。除了siRNA，开发的系统将扩展到小环质粒DNA和CRISPR-Cas9（即，最佳NP的定义和产生、其用于吸入应用的最佳制剂及其生物学评估依赖于DE和PL之间的高度相互作用，双方都贡献了其核心能力。在迭代过程中，基于新型聚合物（DE）的NP的生物学功效（DE，PL）和生物相容性/毒性（PL）的结果影响聚合物改性（DE）和NP生成（DE，PL）的进一步细化。