Toxicity and Biodistribution of Liposomes of the Main Phospholipid from the Archaebacterium<i>Thermoplasma Acidophilum</i>in Mice

Freisleben, Hans-Joachim; Bormann, Joachim; Litzinger, David C.; Lehr, F.; Rudolph, Petra; Schatton, Wolfgang; Huang, Leaf

doi:10.3109/08982109509039918

Cited by 28 publications

(22 citation statements)

References 13 publications

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“…Archaeosomes, administered through intravenous, intranasal, oral, and subcutaneous routes, do not exhibit any significant toxicity in mice (Freisleben et al, 1993(Freisleben et al, , 1995bOmri et al, 2003;Patel and Sprott, 1999;Patel et al, 2008). In addition, archaeal BTL liposomes are remarkably stable against oxidative and mechanical stress, temperature variations, alkaline pH, membrane fusion, autoclaving, as well as the attacks of various lipases (discussed earlier) (Kanichay et al, 2003;Patel and Sprott, 1999;Relini et al, 1994Relini et al, , 1996Patel et al, 2000;Brown et al, 2009).…”

Section: Applications Of Btl Membranesmentioning

confidence: 95%

“…Upon intravenous injection into mice, the liposomes of the main phospholipids (MPL, mainly tetraethers) from T. acidophilum were rapidly cleared from the blood and accumulated mainly in the liver (85%) and the spleen (7%) after 0.25-2.5 h (Freisleben et al, 1995b). Using the liposomes made of the total polar lipids (TPL, mainly diethers) from Methanosurcina mazei, Omri et al (2000) compared the biodistributions of orally and intravenously administered archaeosomes in mice for archaeosomes containing either coenzyme Q10 (archaeosome-CoQ10), polyethylene glycol (archaeosome-PEG), or PEG plus CoQ10 (archaeosome-PEG-CoQ10).…”

Section: Applications Of Btl Membranesmentioning

confidence: 99%

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Archaebacterial bipolar tetraether lipids: Physico-chemical and membrane properties

Chong

2010

Chemistry and Physics of Lipids

124

117

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Section: Applications Of Btl Membranesmentioning

confidence: 95%

Section: Applications Of Btl Membranesmentioning

confidence: 99%

Archaebacterial bipolar tetraether lipids: Physico-chemical and membrane properties

Chong

2010

Chemistry and Physics of Lipids

124

117

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“…A lack of toxicity may stem from the eukaryote-like lipid structures, which bear phytanyl alkyl chains, as do fat-soluble vitamins. Indeed, a detailed study of mice with archaeosomes composed of the main polar lipid of T. acidophilum has indicated no toxicity (13).…”

Section: Discussionmentioning

confidence: 99%

Archaeosome Vaccine Adjuvants Induce Strong Humoral, Cell-Mediated, and Memory Responses: Comparison to Conventional Liposomes and Alum

et al. 2000

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Ether glycerolipids extracted from various archaeobacteria were formulated into liposomes (archaeosomes) possessing strong adjuvant properties. Mice of varying genetic backgrounds, immunized by different parenteral routes with bovine serum albumin (BSA) entrapped in archaeosomes (ϳ200-nm vesicles), demonstrated markedly enhanced serum anti-BSA antibody titers. These titers were often comparable to those achieved with Freund's adjuvant and considerably more than those with alum or conventional liposomes (phosphatidylcholine-phosphatidylglycerol-cholesterol, 1.8:0.2:1.5 molar ratio). Furthermore, antigen-specific immunoglobulin G1 (IgG1), IgG2a, and IgG2b isotype antibodies were all induced. Association of BSA with the lipid vesicles was required for induction of a strong response, and >80% of the protein was internalized within most archaeosome types, suggesting efficient release of antigen in vivo. Encapsulation of ovalbumin and hen egg lysozyme within archaeosomes showed similar immune responses. Antigen-archaeosome immunizations also induced a strong cell-mediated immune response: antigen-dependent proliferation and substantial production of cytokines gamma interferon (Th1) and interleukin-4 (IL-4) (Th2) by spleen cells in vitro. In contrast, conventional liposomes induced little cell-mediated immunity, whereas alum stimulated only an IL-4 response. In contrast to alum and Freund's adjuvant, archaeosomes composed of Thermoplasma acidophilum lipids evoked a dramatic memory antibody response to the encapsulated protein (at ϳ300 days) after only two initial immunizations (days 0 and 14). This correlated with increased antigen-specific cell cycling of CD4 ؉ T cells: increase in synthetic (S) and mitotic (G 2 /M) and decrease in resting (G 1 ) phases. Thus, archaeosomes may be potent vaccine carriers capable of facilitating strong primary and memory humoral, and cell-mediated immune responses to the entrapped antigen.

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“…It should be noted that compared to the IV route of administration used in the current study, the appearance of intact liposomes from the intraperitoneal injection site into circulatory blood would be expected to be delayed by several hours as noted with ester liposomes (Allen 1993). It has been suggested that increased CNS activity such as the nonspecific excitation observed with MPL vesicles could be a consequence of lipophilicity, similar to that seen with many lipophilic compounds and pharmaceuticals (Freisleben et al 1995). Because very little of negatively charged liposomal lipid can enter brain tissue after IV administration (Jonah, Cerny, and Rahman 1975), severe CNS-related toxicity with negatively charged ester liposomes or the archaeosomes is not expected.…”

Section: Figurementioning

confidence: 97%

Short-Term Repeated-Dose Toxicity Profile of Archaeosomes Administered to Mice via Intravenous and Oral Routes

2003

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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.

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Toxicity and Biodistribution of Liposomes of the Main Phospholipid from the ArchaebacteriumThermoplasma Acidophilumin Mice

Cited by 28 publications

References 13 publications

Archaebacterial bipolar tetraether lipids: Physico-chemical and membrane properties

Archaebacterial bipolar tetraether lipids: Physico-chemical and membrane properties

Archaeosome Vaccine Adjuvants Induce Strong Humoral, Cell-Mediated, and Memory Responses: Comparison to Conventional Liposomes and Alum

Short-Term Repeated-Dose Toxicity Profile of Archaeosomes Administered to Mice via Intravenous and Oral Routes

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