A hepatic pDNA delivery system based on an intracellular environment sensitive vitamin E-scaffold lipid-like material with the aid of an anti-inflammatory drug

作者：Togashi Ryohei; Tanaka Hiroki; Nakamura Sakiko; Yokota Hideo; Tange Kota; Nakai Yuta; Yoshioka Hiroki; Harashima Hideyoshi; Akita Hidetaka

来源：Journal of Controlled Release, 2018, 279: 262-270.

DOI：10.1016/j.jconrel.2018.04.022

• Liver
• Lipid nano particle
• Plasmid DNA
• Innate immune response
• Dexamethasone

Non-viral vectors are considered to be an attractive approach for gene delivery, since an artificial material is less immunogenic and oncogenic compared to a viral vector. We previously reported on the hepatic delivery of plasmid DNA (pDNA) by using lipid-like material (an SS-cleavable and pH-activated lipid-like material: ssPalm) which mounts two hydrophobic scaffolds, proton-accepting motifs (tertiary amines), and a cleavable unit (disulfide bonding). In the present study, we report on an advanced hepatic gene delivery system that uses a new type of ssPalm derivative: ssPalmE-Paz4-C2. The hepatic transgene expression of the intravenously administrated lipid nanoparticle (LNP) that was formed with the ssPalmE-Paz4-C2 (LNPssPalmE-Paz4-C2) was significantly higher than that of conventional LNPs formed with a myristic acid-scaffold ssPalm (LNPssPalmM). However, the LNPssPalmE-Paz4-C2 particle induced a severe innate immune response that involved the production of the proinflammatory cytokines (IL-6 and TNF alpha), intracellular DNA sensor-related cytokine (IL-1 beta) and interferon (IFN beta), even when a pDNA free from CpG-motifs was encapsulated. The production of the pro-inflammatory cytokines and the DNA sensor-related cytokines is attributed to the combination of vitamin E scaffolds and encapsulated pDNA. The depletion of macrophages by chlodronate-encapsulating liposomes dramatically reduced inflammatory gene expression. Based on the above findings, we conclude that the use of a certain type of non-viral carrier that shows a robust gene expression activity is attended by a risk of eliciting an innate immune response. When a highly hydrophobic derivative of dexamethasone, an anti-inflammatory glucocorticoid compound, was co-loaded to the particle, this inflammatory response was relieved, and gene expression efficiency was enhanced. It is thus concluded that the co-delivery of dexamethasone and pDNA is a promising approach for reducing these risks.

• 出版日期2018-6-10
• 单位RIKEN