Size-dependent specific targeting and efficient gene silencing in peritoneal macrophages using a pH-sensitive cationic liposomal siRNA carrier

• Published in: International journal of pharmaceutics Vol. 495; no. 1; pp. 171 - 178
• Main Authors: Matsui, Hideki, Sato, Yusuke, Hatakeyama, Hiroto, Akita, Hidetaka, Harashima, Hideyoshi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.11.2015
• Subjects: Administration route; Animals; Cations; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Carriers - chemistry; Gene Expression; HeLa Cells; Humans; Hydrogen-Ion Concentration; Lipids - chemistry; Macrophages, Peritoneal - drug effects; Mice; Multifunctional envelope-type nano device; Nanoparticles - chemistry; Peritoneal macrophages; pH-Sensitive cationic lipid; Piperidines - chemistry; Polyethylene Glycols - chemistry; RNA Interference; RNA, Small Interfering - administration & dosage; Short interference RNA; Size; RNAi; pH-Sensitive cationic lipid; Short interference RNA; Size; PLK1; Peritoneal macrophages; t-BuOH; MEND; siRNA; chol; LNP; PEG; PEM; Administration route; Multifunctional envelope-type nano device; DC; DMG
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2015.08.044

[Display omitted] Macrophages are key contributors to various inflammatory diseases. Therefore, the development of an efficient in vivo short interference RNA (siRNA) system that can be delivered to macrophages represents a novel treatment strategy for addressing these disorders. It was recently revealed that peritoneal macrophages (PEMs) are involved in several diseases including ovarian cancer, and are now recognized as a promising drug target. We report herein on the use of pH-sensitive cationic YSK05-MENDs as siRNA carriers and on the impact of both the size of the YSK05-MENDs and their administration routes for the efficient targeting PEMs to achieve a high level of gene silencing activity. The size of the YSK05-MENDs had a dramatic effect on their specificity for PEMs when administered intravenously, but not for intraperitoneal injection. Also, significant gene silencing was achieved by an intraperitoneal administration of the YSK05-MEND at a dose in the single digit μg/kg range. To our knowledge, this is the most efficacious method for siRNA delivery for gene silencing in PEMs in vivo reported to date. These findings enabled us to investigate the complex function of PEMs through several gene silencing simultaneously.