Incorporation of all-trans retinoic acid into lipoplexes inhibits nuclear factor kappaB activation mediated liver injury induced by lipoplexes in mice.
BACKGROUND
All-trans retinoic acid (ATRA) is a natural derivative of vitamin A, which is well known to suppress inflammatory cytokine production. To date, there have been few reports about the systemic use of ATRA for inflammation because of acute resistance and the highly lipophilic nature of ATRA.


METHODS
ATRA-lipoplexes were prepared by mixing CMV-Luc plasmid DNA with ATRA-incorporated 1,2-dioleoyl-3-trimethylammoniopropane (DOTAP)/cholesterol liposome. After intravenous injection, tissue accumulation, transfection efficacy, NFkappaB activation, cytokine production, and hepatic toxicity of ATRA-lipoplexes were evaluated and compared with lipoplexes lacking ATRA.


RESULTS
The particle size and zeta potential of ATRA-lipoplexes were similar to those of lipoplexes. After intravenous injection of ATRA-lipoplexes, tissue accumulation in liver and gene expression in liver and lung were similar to those of lipoplexes, supporting the hypothesis that ATRA incorporation did not affect the delivery and gene transfection efficacy. In addition, ATRA incorporated in ATRA-lipoplexes was delivered to liver in a manner similar to that for ATRA incorporated in liposomes. In addition, intravenous injection of ATRA-lipoplexes inhibited the activation of NFkappaB in liver, and subsequently suppressed the serum levels of tumor necrosis factor-alpha (TNF-alpha) and alanine aminotransferase (ALT) compared with lipoplexes. Liver histology data also demonstrated a low degree of liver injury produced by ATRA-lipoplexes compared with lipoplexes.


CONCLUSIONS
ATRA-incorporated lipoplexes effectively suppress NFkappaB activation, cytokine response and liver injury induced by lipoplexes without affecting gene delivery and transfection efficacy in vivo.
Charoensit
Pensri
P
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. hashidam@pharm.kyoto-uac.jp
Kawakami
Shigeru
S
Higuchi
Yuriko
Y
Hashida
Mitsuru
M
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D004247:DNA / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000097:blood; D008081:Liposomes; D008107:Liver Diseases / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism*; D009928:Organ Specificity / Q000187:drug effects; D010316:Particle Size; D010761:Phosphorus Radioisotopes; D014212:Tretinoin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D014316:Tritium; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D015850:Interleukin-6; D008081:Liposomes; D016328:NF-kappa B; D010761:Phosphorus Radioisotopes; D014409:Tumor Necrosis Factor-alpha; D014316:Tritium; D014212:Tretinoin; D004247:DNA; D000410:Alanine Transaminase