The effect of intracellular delivery of catalase and antisense oligonucleotides to NF-kappaB using albumin microcapsules in the endotoxic shock model.
Microencapsulated (MC) catalase has been shown to inhibit H(2)O(2) and tumor necrosis factor (TNF) in vitro after endotoxin stimulation. It is the purpose of this study to determine whether MC catalase improves pro-inflammatory cytokine inhibition and mortality in an endotoxic shock model in vivo. We also examined whether MC catalase and antisense oligonucleotides (ASO) to nuclear factor kappaB (NF-kappaB) together improved survival by inhibiting pro-inflammatory cytokines using different mechanisms.


METHODS
Albumin microcapsules containing catalase and ASO to NF-kappaB were prepared 2-7 microm in size by using a Büchi spray dryer. Progressively increasing doses of MC catalase, MC ASO to NF-kappaB, and the combination were given to rats before the administration of Escherichia coli endotoxin. Results demonstrated 60% survival in rats given 15 mg/kg MC catalase, 70% survival with 20 mg/kg MC ASO NF-kappaB, and 80% survival with the combination. TNF was inhibited by 53% in the MC catalase group 4 h after endotoxin administration, 43% in the ASO NF-kappaB group, and 78% in the combination group compared to controls. In conclusion, this study demonstrates the effectiveness of MC intracellular delivery of the naturally occurring antioxidant catalase in improving animal survival. The addition of ASO to NF-kappaB improved both cytokine inhibition and animal survival in endotoxic shock.
Siwale
Rodney C
RC
Mercer University College of Pharmacy and Health Sciences, Atlanta, GA 30341, USA.
Oettinger
Carl W
CW
Addo
Richard
R
Siddig
Aladin
A
D'Souza
Martin J
MJ
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D002374:Catalase / Q000008:administration & dosage / Q000494:pharmacology*; D002417:Cattle; D003131:Combined Modality Therapy; D016207:Cytokines / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry; D004731:Endotoxins; D008863:Microspheres; D016328:NF-kappa B / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000737:chemistry; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D015996:Survival Rate
D000975:Antioxidants; D016207:Cytokines; D004337:Drug Carriers; D004731:Endotoxins; D016328:NF-kappa B; D020319:Oligodeoxyribonucleotides, Antisense; D012710:Serum Albumin, Bovine; C044101:endotoxin, Escherichia coli; D002374:Catalase