- 著者
- Yu Sakurai
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Biological and Pharmaceutical Bulletin (ISSN:09186158)
- 巻号頁・発行日
- vol.45, no.8, pp.972-977, 2022-08-01 (Released:2022-08-01)
- 参考文献数
- 40
- 被引用文献数
- 2
Nucleic acid drugs can control gene expression and function in a manner different from that of conventional compounds. On the other hand, nucleic acids can be easily degraded in the in vivo circumstances. In addition, nucleic acids cannot penetrate cell membranes. Therefore, a drug delivery system (DDS) is essential to protect nucleic acid molecules until they reach the target cell and to release them efficiently inside the cell. In order to apply nucleic acid drugs to new cancer therapeutic strategies, the author has been developing a DDS that enables functional control of vascular endothelial cells that consist of the tumor microenvironment. The aim of my study is to develop lipid nanoparticles (LNPs) were modified with functional molecules that control their pharmacokinetics in vivo and intracellular fate to delivered small interfering RNA (siRNA) to tumor vasculature. By imparting pH-responsive membrane fusion properties to lipid nanoparticles, I have developed a system that responds to acidification in endosomes within cells and subsequently efficiently releases siRNA into the cytoplasm via membrane fusion, where siRNA molecules exhibit their function. In addition, by developing a method for presenting functional molecules, such as peptides, saccharides and so on, that recognize target cells on the surface of LNPs, I succeeded in establishing LNPs which internalize more efficiently into specific cells than off-target cells. Finally, by integrating these technologies, I developed an in vivo siRNA DDS that enables in vivo control of genes of interest in tumor vascular endothelial cells and succeeded in cancer therapy by regulating vascular function.
- 著者
- Takashi Nakamura Yosuke Noma Yu Sakurai Hideyoshi Harashima
- 出版者
- 公益社団法人日本薬学会
- 雑誌
- Biological and Pharmaceutical Bulletin (ISSN:09186158)
- 巻号頁・発行日
- vol.40, no.2, pp.234-237, 2017-02-01 (Released:2017-02-01)
- 参考文献数
- 12
- 被引用文献数
- 17
Intravesical drug delivery by cationic liposomes (Cat-LPs) represents a potent nanotechnology for enhancing therapeutic effects against bladder disorders. However, preventing the aggregation of Cat-LPs in urine poses a significant barrier. We report on an examination of the effect of modifying liposomes with polyethylene glycol (PEG) lipids to prevent Cat-LPs from aggregating in human urine. Although Cat-LPs underwent significant aggregation in human urine, introducing 5 mol% of PEG2k lipid or 2 mol% of PEG5k lipid completely inhibited the aggregation of the Cat-LPs. When 2 mol% of PEG2k lipids were introduced, the lipid structures of 1,2-distearoly-sn-glycero-3-phosphoethanolamine (DSPE) and 1,2-distearoyl-sn-glycerol (DSG) greatly prevented aggregation compared with cholesterol. By contrast, when Cat-LPs, after incubation in urine, were exposed to bladder cancer cells, only introducing cholesteryl-PEG into the Cat-LPs showed a significant enhancement in cellular uptake. These results offer the potential for incorporating cholesteryl-PEG into Cat-LPs for achieving both stability in urine and effective cellular uptake.