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Development of nanomedicine system based the control of intracellular pharmacokinetics.

基于细胞内药代动力学控制的纳米医学系统的开发。

基本信息

批准号：
15310093
负责人：
NAKAGAWA Shinsaku
金额：
$ 8.38万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15310093/
关键词：
intracellular controlled release nanoparticles fusogenic liposomes drug delivery system oligonucleotide confocal laser microscope gene therapy FACS 共焦点レーザー顕微鏡

项目摘要

Therapeutic agents based on DNA or RNA oligonucleotides (e.g., antisense DNA oligonucleotide, small interfering RNA) require a regulation of their kinetics in cytoplasm to maintain an optimal concentration during the treatment period. In this respect, delivery of functional nanoparticles containing the drugs into cytoplasm is thought to have a potential for the cytosolic controlled gene release. In this study, we establish a protocol for the encapsulation of nanoparticles into liposome, which is further fused with ultra violet-inactivated Sendai virus to compose fusogenic liposomes. When nanoparticles were encapsulated in conventional liposomes, endocytosis-mediated inefficient uptake of nanoparticles was observed. In contrast, nanoparticles were delivered directly and effectively into the cytoplasm by fusogenic liposome, which was mediated by a fusion-dependent but endocytosis-independent pathway. Additionally, fusogenic liposome showed a high ability to deliver nanoparticles containing DNA oligonucleotides into cytoplasm, where the oligonucleotides were gradually released from the nanoparticles. These results indicate that this combinatorial nanotechnology using fusogenic liposome and nanoparticle is valuable system for regulating the intracellular pharmacokinetics of gene-based drugs.

以DNA或RNA寡核苷酸为基础的治疗药物(如反义DNA寡核苷酸、小干扰RNA)需要调节其在细胞质中的动力学，以在治疗期间保持最佳浓度。在这方面，将含有药物的功能纳米颗粒输送到细胞质中被认为有可能控制细胞内基因的释放。在这项研究中，我们建立了一种将纳米颗粒包裹到脂质体中的方案，并将其与紫外线灭活的仙台病毒进一步融合，以合成融合脂质体。当纳米颗粒被包裹在常规脂质体中时，观察到内吞作用介导的纳米颗粒的低效摄取。相反，纳米粒通过融合脂质体直接有效地进入细胞质，这是通过融合依赖但非内吞作用的途径介导的。此外，融合脂质体还能将含有DNA寡核苷酸的纳米颗粒输送到细胞质中，使寡核苷酸逐渐从纳米颗粒中释放出来。这些结果表明，这种融合脂质体和纳米颗粒的组合纳米技术是调节基因药物细胞内药代动力学的有价值的系统。