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).

对于包括肺肿瘤/转移瘤在内的许多肺部疾病，需要基于 RNA 干扰 (RNAi) 的新型治疗策略，但需要有效递送小干扰 RNA (siRNA)。吸入式 siRNA 应用可提供直接接触、即时可用性，但全身性有限。扩散，因此在肺部的剂量更高，但遇到了重大挑战。基于聚合物或聚合物/脂质组合的纳米颗粒已用于探索体内 siRNA 递送，来自申请人和公司的初步数据。其他小组表明，聚（乙烯）亚胺（PEI）和其他多胺，以及对确定的生物降解性和改善的 NP 稳定性的特定修饰，可能会允许新型可吸入 siRNA 制剂除了功效之外，毒性评估将关键地确定肺部输送的最佳 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。致癌基因特异性 siRNA，用于通过吸入直接应用，这包括生成非常明确的新型修饰的小聚胺系统，特别是酪氨酸修饰的衍生物、可生物降解的衍生物及其组合，其特征通常涉及物理、物理化学、生物学和毒理学特性，并在肺转移小鼠模型中进行了关于 siRNA 递送、生物分布和治疗效果的体内测试（来自不同雾化策略的 NP）。除了 siRNA 之外，还将探索微环质粒 DNA 和 CRISPR-Cas9（即 sgRNA + Cas9 质粒）。最佳纳米颗粒的生成、吸入应用的最佳配方及其生物学评估依赖于 DE 和 PL 之间的高度相互作用，双方都贡献了自己的核心在迭代过程中，基于新型聚合物（DE）的纳米颗粒的生物功效（DE、PL）和生物相容性/毒性（PL）结果影响聚合物改性（DE）和纳米颗粒生成（DE、PL）的进一步细化。