PMID- 11356938
OWN - NLM
STAT- MEDLINE
DCOM- 20010614
LR  - 20161124
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 297
IP  - 3
DP  - 2001 Jun
TI  - In vivo delivery of antisense oligonucleotides in pH-sensitive liposomes inhibits 
      lipopolysaccharide-induced production of tumor necrosis factor-alpha in rats.
PG  - 1129-36
AB  - Kupffer cells play an important role in the pathogenesis of liver diseases. 
      During endotoxemia and alcohol-induced liver disease, tissue injury is preceded 
      by an excessive release of cytokines by these macrophages. Tumor necrosis 
      factor-alpha (TNF-alpha) is one of the key cytokines associated with liver 
      injury. Pre-exposure of animals to TNF-alpha antibodies has been shown to prevent 
      macrophage-mediated liver injury in experimental animals. In this article, we 
      describe a method to encapsulate in pH-sensitive liposomes and to deliver an 
      antisense phosphorothioate oligonucleotide (TJU-2755) against TNF-alpha. We 
      describe the efficacy of this formulation in inhibiting endotoxin-mediated 
      production of TNF-alpha. The liposomes prepared were stable for over 4 weeks at 
      pH 7.4, but readily released their contents when exposed to an acidic environment 
      below pH 6, similar to the pH that exists in early endosomes. Male Sprague-Dawley 
      rats were administered (i.v.) liposome-encapsulated TJU-2755 (1-2 mg/kg body 
      wt.). Empty liposomes served as controls. Forty-eight hours postinjection, the 
      animals were administered a single dose of lipopolysaccharide (50 microg/kg body 
      wt.) and were sacrificed 90 min later. The TNF-alpha produced by excised liver 
      incubated ex vivo and the levels of plasma TNF-alpha were determined. After a 
      single administration of liposome-encapsulated antisense TJU-2755, a 30% 
      reduction in TNF-alpha produced by liver slices was observed. Two daily doses of 
      the antisense oligonucleotide inhibited TNF-alpha production by 50%. This was 
      associated with a 65 to 70% reduction in plasma levels of TNF-alpha, compared 
      with controls. These results indicate that oligonucleotide TJU-2755 encapsulated 
      in pH-sensitive liposomes can be used to effectively reduce endotoxin-mediated 
      production of TNF-alpha in macrophages in vivo and thus may be of value in 
      attenuating or preventing macrophage-mediated liver injury.
FAU - Ponnappa, B C
AU  - Ponnappa BC
AD  - Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, 
      Philadelphia, Pennsylvania, USA. biddanda.ponnappa@mail.tju.edu
FAU - Dey, I
AU  - Dey I
FAU - Tu, G C
AU  - Tu GC
FAU - Zhou, F
AU  - Zhou F
FAU - Aini, M
AU  - Aini M
FAU - Cao, Q N
AU  - Cao QN
FAU - Israel, Y
AU  - Israel Y
LA  - eng
GR  - AA07186/AA/NIAAA NIH HHS/United States
GR  - AA10967/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Liposomes)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (Organothiophosphorus Compounds)
RN  - 0 (Phosphorothioate Oligonucleotides)
RN  - 0 (RNA, Messenger)
RN  - 0 (TJU 2755)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Chemical and Drug Induced Liver Injury
MH  - Dose-Response Relationship, Drug
MH  - Drug Delivery Systems/*methods
MH  - Drug Stability
MH  - Endosomes
MH  - Hydrogen-Ion Concentration
MH  - In Vitro Techniques
MH  - Injections, Intravenous
MH  - Lipopolysaccharides/*pharmacology
MH  - Liposomes
MH  - Liver/drug effects/metabolism
MH  - Liver Diseases/metabolism/prevention & control
MH  - Male
MH  - Oligonucleotides, Antisense/*administration & dosage/metabolism
MH  - Organothiophosphorus Compounds/*administration & dosage/metabolism
MH  - Phosphorothioate Oligonucleotides
MH  - RNA, Messenger/antagonists & inhibitors/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Spleen/metabolism
MH  - Tissue Distribution
MH  - Treatment Outcome
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/genetics/metabolism
EDAT- 2001/05/18 10:00
MHDA- 2001/06/23 10:01
CRDT- 2001/05/18 10:00
PHST- 2001/05/18 10:00 [pubmed]
PHST- 2001/06/23 10:01 [medline]
PHST- 2001/05/18 10:00 [entrez]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2001 Jun;297(3):1129-36.