Short-term repeated-dose toxicity profile of archaeosomes administered to mice via intravenous and oral routes.
Archaeosomes, liposomes made from polar ether lipids of archaea, show promise for vaccine and drug delivery applications. The potential toxicity of intravenously (14, 70, or 140 mg/kg/day for 5 consecutive days) and orally (gavaged at 55, 275, or 550 mg/kg/day for 10 consecutive days) administered unilamellar archaeosomes, prepared from the total polar lipids (TPLs) extracted from several species of archaea, was assessed in female BALB/c mice. Liposomes prepared from an ester phospholipid composition were included for comparative purposes. Control groups of mice were administered 0.1 ml phosphate-buffered saline (PBS) by either route. Animals were monitored at least once daily for temperature, body weight, and clinical signs of adverse reactions. One day after the last dose, the mice were sacrificed. Blood was collected for selected biochemical/enzyme analyses, and the major organs (heart, lungs, liver, spleen, kidneys) were weighed and examined macroscopically. In addition, the spleens were examined histologically. At the two lower dosages of intravenously administered vesicles, there were no significant indications of toxicity, as compared with the PBS-administered control group. At the highest intravenous dose of 140 mg/kg/day, archaeosomes prepared from the TPL of the extreme halophiles, Halobacterium salinarum and Natronobacterium magadii, indicated potential toxicity, as evidenced by clinical signs (hyperactivity and/or piloerection), drop in body temperature, and loss in body weight. Spleens from mice administered some archaeosomes types, primarily at the highest intravenous dose tested, were enlarged, had increased organ weight, and microscopic examination revealed mild to moderate expansion of the red pulp with increased numbers of hematopoietic cells, but no changes in the white pulp. There were similar clinical signs at one or more of the higher oral doses of the ester liposomes and some of the archaeosome types; however, no other apparent toxicity was observed. Based on this limited mouse study, archaeosomes were generally well tolerated after intravenous or oral delivery at the dosages so indicated in this study.
Omri
Abdelwahab
A
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada.
Agnew
Brian J
BJ
Patel
Girishchandra B
GB
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001105:Archaea / Q000737:chemistry*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects; D008055:Lipids / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D008081:Liposomes / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D013696:Temperature; D013997:Time Factors
D001786:Blood Glucose; D008055:Lipids; D008081:Liposomes; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase