Depot characteristics and biodistribution of interleukin-2 liposomes: importance of route of administration.
Due to rapid clearance of interleukin-2 (IL-2), it has had limited effective use as an in vivo immunostimulant. Current experimental and clinical protocols generally must utilize large doses, multiple injections, or continuous infusions of IL-2 in order to achieve significant immunostimulation, often at the expense of systemic toxicity. Therefore, the pharmacodynamics of IL-2 liposomes were investigated. IL-2 liposome incorporation efficiency was 80.4% (SD 5.5); vesicle diameter was 1.65 microns (SD 0.09) as determined by fluorescence-activated cell sorting (FACS). Both formulation (free cytokine vs. IL-2 liposomes) and route of administration were important variables in determination of the biodistribution and pharmacokinetic characteristics of IL-2. When free [125I]IL-2 was given i.v. to mice, only 6.5% was in the blood and 3% in liver and spleen 2 h after injection; on the other hand, at 2 h greater than 70% of i.v. [125I]IL-2 liposomes were detected in the blood, liver, spleen, and lungs. Mean i.v. elimination t1/2 from the blood of rats given 20 x 10(6) U/kg free cytokine or IL-2 liposomes was 41 versus 102 min, respectively, as measured by bioassay and 59 and 119 min as measured by enzyme immunoassay (EIA). After i.v. administration, the estimated Vd of IL-2 liposomes was 13-fold smaller than the free cytokine. Intrathoracic (i.tx.), i.p., and s.c. administration of [125I]IL-2 to mice also demonstrated significant depot effects when IL-2 was incorporated into liposomes. These data suggest IL-2 liposomes may provide in vivo immunostimulation superior to the free cytokine due to biodistribution and depot characteristics.
Anderson
P M
PM
Department of Pediatrics, University of Minnesota, Minneapolis 55455.
Katsanis
E
E
Sencer
S F
SF
Hasz
D
D
Ochoa
A C
AC
Bostrom
B
B
D000818:Animals; D002460:Cell Line; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005260:Female; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D013909:Thorax; D014018:Tissue Distribution / Q000502:physiology
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007376:Interleukin-2; D007457:Iodine Radioisotopes; D008081:Liposomes; D011994:Recombinant Proteins