Development of nanomedicine system based the control of intracellular pharmacokinetics.

基于DNA或RNA寡核苷酸的治疗剂（例如，反义DNA寡核苷酸、小干扰RNA）需要调节它们在细胞质中的动力学以在治疗期间维持最佳浓度。在这方面，含有药物的功能性纳米颗粒递送到细胞质中被认为具有细胞溶质控制基因释放的潜力。在本研究中，我们建立了一种将纳米颗粒包裹到脂质体中的方法，并将其与紫外线灭活的仙台病毒融合，制成融合脂质体。当纳米颗粒被封装在常规脂质体中时，观察到内吞介导的纳米颗粒的无效摄取。与此相反，纳米颗粒直接和有效地通过融合脂质体，这是由一个融合依赖，但不依赖于内吞介导的途径传递到细胞质。此外，融合脂质体显示出将含有DNA寡核苷酸的纳米颗粒递送到细胞质中的高能力，其中寡核苷酸从纳米颗粒中逐渐释放。这些结果表明，这种融合脂质体和纳米粒的组合纳米技术是用于调控基因药物的细胞内药代动力学的有价值的系统。

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.