Microencapsulation of tumor necrosis factor oligomers: a new approach to proinflammatory cytokine inhibition.
Antisense oligonucleotides offer great therapeutic potential provided adequate intracellular penetration can be achieved. In this study, we evaluated the effectiveness of microencapsulating antisense oligonucleotides to tumor necrosis factor (TNF) in suppressing TNF release in vitro and in vivo. Microencapsulation of TNF oligomers was performed using albumin to produce microcapsules 0.6-1.0 mum in size that target phagocytic cells. Albumin microcapsules containing fluoresceinated TNF oligomers were incubated with U-937 cells to observe uptake. Microcapsules were added to whole blood and stimulated with Escherichia coli endotoxin. Endotoxin was given intravenously (i.v.) to rats along with 100 mug microencapsulated TNF oligomers to determine TNF inhibition and animal survival. E. coli was given intraperitoneally (i.p.) along with gentamicin and microencapsulated TNF oligomers to assess TNF inhibition and animal survival. The duration of microencapsulated antisense TNF oligomers was also determined in vivo. The results demonstrated rapid uptake of the microcapsules by macrophages after 2 h and 4 h incubation. There was improvement in TNF inhibition in vitro and improved animal survival by microencapsulated antisense in both endotoxin (100% survival) and peritonitis models (70% survival) compared with free antisense oligomers in solution. Microencapsulation extended the duration of action of the oligomers to 72 h. Intracellular targeting of macrophages with antisense oligomers to TNF by microencapsules as a delivery system improves TNF inhibition using the models of whole blood endotoxin stimulation and endotoxic shock and peritonitis in rats.
Oettinger
Carl
C
828 W. Peachtree Street, Atlanta, GA 30308, USA. coettinger@aol.com
D'Souza
Martin
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004339:Drug Compounding / Q000379:methods; D007249:Inflammation / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D008863:Microspheres; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010538:Peritonitis / Q000188:drug therapy; D051381:Rats; D011916:Rats, Inbred F344; D012772:Shock, Septic / Q000188:drug therapy; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha