Iontophoresis-mediated direct delivery of nucleic acid therapeutics, without use of carriers, to internal organs via non-blood circulatory pathways
Iontophoresis-mediated direct delivery of nucleic acid therapeutics, without use of carriers, to internal organs via non-blood circulatory pathways
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DOI：
10.1016/j.jconrel.2022.01.052
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发表时间：
2022-02-09
影响因子：
10.8
通讯作者：
Kogure, Kentaro
中科院分区：
文献类型：
--
作者：
Hasan, Mahadi;Fukuta, Tatsuya;Kogure, Kentaro
纳米颗粒药物载体已被用于实现核酸治疗剂（包括小干扰RNA（siRNA））的全身递送;然而，非特异性分布和免疫相关事件通常引起不期望的不良反应。因此，需要一种能够将核酸治疗剂特异性递送至所需位点的新技术。我们证明了使用弱电流（0.3-0.5 mA/cm（2））的离子电渗（IP）作为局部药物递送技术的实用性。我们以前的研究表明，IP允许通过诱导由Ca 2+流入介导的细胞信号传导激活引发的细胞间连接裂解，以及随后通过皮肤和其他细胞中的独特内吞过程的细胞质递送来透皮渗透核酸治疗剂。基于这些发现，我们假设IP可以使核酸治疗剂能够通过非血液循环途径直接递送至内部器官，而不使用递送载体。在两个器官中均观察到通过IP施用至肝脏和胰腺表面的荧光标记核酸的渗透，但局部施用未观察到。IP介导的siRNA局部递送到肝脏和胰腺中显著抑制每个器官中的靶mRNA表达。此外，IP施用针对负责肝脏脂肪变性和纤维化的分子的治疗性siRNA显著抑制了个体模型小鼠中的脂质积累和纤维化肝损伤。这些发现表明，IP可能是一种有用的技术，可以直接将核酸治疗剂递送到内部器官，而不使用药物递送载体，通过非血液循环途径。
Nanoparticle drug carriers have been employed to achieve systemic delivery of nucleic acid therapeutics, including small interfering RNA (siRNA); however, non-specific distribution and immune-related events often cause undesired adverse effects. Thus, there is a need for a new technology capable of specifically delivering nucleic acid therapeutics to desired sites. We demonstrated the utility of iontophoresis (IP) using weak electric current (0.3-0.5 mA/cm(2)) as a local drug delivery technology. Our previous studies revealed that IP allows for transdermal permeation of nucleic acid therapeutics via induction of intercellular junction cleavage initiated by Ca2+ influx-mediated cellular signaling activation, and subsequent cytoplasmic delivery through a unique endocytosis process in both skin and other cells. Based on these findings, we hypothesized that IP may enable direct delivery of nucleic acid therapeutics to internal organs through non-blood circulatory pathways without the use of delivery carriers. Permeation of fluorescent-labeled nucleic acids administered via IP applied to the surface of the liver and pancreas was observed in both organs, but not with topical application. IP-mediated local delivery of siRNA into the liver and pancreas significantly suppressed target mRNA expression in each organ. Moreover, IP administration of therapeutic siRNA against the molecules responsible for liver steatosis and fibrosis significantly inhibited lipid accumulation and fibrotic hepatic damage in individual model mice. These findings suggest that IP may be a useful technology to directly deliver nucleic acid therapeutics to internal organs without use of drug delivery carriers via non-blood circulatory pathways.