Development of nanomedicine system based the control of intracellular pharmacokinetics.

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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.