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.

Autor: Togashi R; Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan., Tanaka H; Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Science, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-Shi, Chiba 260-0865, Japan., Nakamura S; Image Processing Research Team, RIKEN Center for Advanced Photonics, RIKEN, Wako, Saitama, Japan., Yokota H; Image Processing Research Team, RIKEN Center for Advanced Photonics, RIKEN, Wako, Saitama, Japan., Tange K; NOF Corporation, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-0865, Japan., Nakai Y; NOF Corporation, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-0865, Japan., Yoshioka H; NOF Corporation, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-0865, Japan., Harashima H; Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan., Akita H; Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Science, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-Shi, Chiba 260-0865, Japan. Electronic address: akitahide@chiba-u.jp.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2018 Jun 10; Vol. 279, pp. 262-270. Date of Electronic Publication: 2018 Apr 17.
DOI: 10.1016/j.jconrel.2018.04.022
Abstrakt: 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 (LNP ssPalmE-Paz4-C2 ) was significantly higher than that of conventional LNPs formed with a myristic acid-scaffold ssPalm (LNP ssPalmM ). However, the LNP ssPalmE-Paz4-C2 particle induced a severe innate immune response that involved the production of the pro-inflammatory cytokines (IL-6 and TNFα), intracellular DNA sensor-related cytokine (IL-1β) and interferon (IFNβ), 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.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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