Kogure Kentaro, Fukuta Tatsuya
Graduate School of Biomedical Sciences, University of Tokushima.
Yakugaku Zasshi. 2020;140(5):611-615. doi: 10.1248/yakushi.19-00218-1.
Delivery of nucleic acid therapeutics to target body organs requires injection of nanocarriers into the bloodstream. However, as such nanocarriers would also be delivered to non-target organs, low delivery efficiency to target organs and risk of unexpected effects are clear limitations of this technology. We recently applied iontophoresis (IP) for direct delivery of nucleic acid therapeutics to various organs. IP relies on a weak electric current for noninvasive transdermal drug delivery. We found that IP can deliver hydrophilic macromolecules and nanoparticles into the skin. We previously succeeded in transdermal delivery of siRNA, and subsequent knockdown (70%) of target mRNA levels in the skin via IP of siRNA (Int. J. Pharm., 383, 2010, Kigasawa et al.). Moreover, we found that cell signal activation and cleavage of intercellular junctions are induced by IP (J. Biol. Chem., 289, 2014, Hama et al.). We hypothesized that this phenomenon should be observed in not only skin but also other organs, and subsequently carried out IP of nucleic acid therapeutics to various body organs including liver, pancreas and kidney. This technique resulted in delivery of nucleic acid therapeutics into the various target body organs, and subsequent knockdown of target genes. These results suggest that direct delivery to target body organs via non-blood circulatory pathway is possible. This technology may offer a solution to the various limitations associated with current drug delivery systems (DDS).
将核酸治疗剂递送至靶器官需要将纳米载体注射到血液中。然而，由于此类纳米载体也会被递送至非靶器官，因此对靶器官的递送效率较低以及存在意外效应风险是该技术的明显局限。我们最近应用离子电渗疗法（IP）将核酸治疗剂直接递送至各种器官。离子电渗疗法依靠弱电流进行非侵入性经皮给药。我们发现离子电渗疗法可以将亲水性大分子和纳米颗粒递送至皮肤。我们之前成功地通过离子电渗疗法实现了小干扰RNA（siRNA）的经皮递送，随后皮肤中靶mRNA水平降低了70%（《国际药学杂志》，第383卷，2010年，木泽等人）。此外，我们发现离子电渗疗法可诱导细胞信号激活和细胞间连接的裂解（《生物化学杂志》，第289卷，2014年，滨田等人）。我们推测这种现象不仅在皮肤中会出现，在其他器官中也会出现，随后我们对包括肝脏、胰腺和肾脏在内的各种身体器官进行了核酸治疗剂的离子电渗疗法。该技术实现了核酸治疗剂向各种靶器官的递送，随后靶基因被敲低。这些结果表明通过非血液循环途径直接递送至靶器官是可行的。这项技术可能为解决当前药物递送系统（DDS）相关的各种局限性提供一种方案。
