Liposome dependent delivery of S-adenosyl Methionine to cells by liposomes: A potential treatment for liver disease
Schools of Pharmacy and Veterinary Medicine, University of Wisconsin Madison, Madison, Wisconsin 53705-222, USA.Journal of Pharmaceutical Sciences (Impact Factor: 2.59). 02/2009; 98(2):573-82. DOI: 10.1002/jps.21460
The present study demonstrates that the nutritional supplement S-adenosyl methionine (SAMe), the primary methyl donor in mammalian cells, is delivered selectively to cells by anionic liposomes, and is, therefore, a liposome dependent drug. Contrary to our expectations, free SAMe chloride was growth inhibitory in cultured cells. The growth inhibitory potency of SAMe chloride in anionic liposomes composed of distearoylphosphatidylglycerol/cholesterol 2:1 was fivefold greater than that of free SAMe. Neutral liposomes composed of distearoylphosphatidylcholine and cholesterol did not increase the potency of the drug. An improved anionic liposome SAMe formulation was produced by use of the 1,4-butanedisulfonate salt (SD4), adding a metal chelator (EDTA), and lowering the buffer pH from pH 7.0 to pH 4.0. This formulation was 15-fold more potent than free SD4, and was active after more than 28 days at 4 degrees C. SAMe and its potential degradation products were screened for toxicity. Formaldehyde was determined to have potency similar to that of free SAMe chloride in CV1-P cells, suggesting that the growth inhibitory effects of SAMe may partly arise from the formation of formaldehyde. The cytotoxic effects of formaldehyde and the less stable forms of SAMe, (SAMe chloride and SAMe tosylate) were decreased in the presence of 3 mM GSH (IC(50) approximately 0.44 mM). The cytotoxic effects of SD4 were not reduced by GSH, suggesting that this more stable form of SAMe is not toxic through the production of formaldehyde. SD4 in anionic DSPG liposomes stimulated murine IL-6 production in RAW 264 cells at concentrations 25- to 30-fold lower than free drug. This increase in potency for IL-6 production was in keeping with the increase in potency observed in our growth inhibition experiments. These results suggest that SD4 in liposomes may be a potential treatment for acute or chronic liver failure.
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ABSTRACT: We have used a murine model of Acetaminophen induced hepatoxicity to determine if S-adenosyl methionine 1,4 butanedisulfonate (SD4) in liposomes can prevent liver injury when administered immediately prior to acetaminophen, as judged by serum aspartate aminotransferase and alanine aminotransferase levels, and histological evidence of liver necrosis. No protection was observed when mice received 1 g/kg unencapsulated SD4. Partial protection was observed with 5 or 0.5 mg/kg SD4 in unextruded distearoylphosphatidylglycerol (DSPG) liposomes. Protection comparable to that seen in mice receiving encapsulated SD4 is achieved when mice received lipid alone in equivalent amounts, suggesting that the contribution of encapsulated SD4 to the efficacy of the liposomes may be minimal. Unextruded distearoylphosphatidylcholine (DSPC) liposomes show only slight effects even at 50 mg/kg SD4. This is likely caused by the size of unextruded DSPC lipsomes, because extruded DSPC liposomes, whose size is smaller, are of comparable efficacy to unextruded DSPG liposomes.Journal of Pharmaceutical Sciences 01/2009; 99(4):1800-9. DOI:10.1002/jps.21950 · 2.59 Impact Factor
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ABSTRACT: Abstract Liposomes are artificially-prepared bilayered phospholipid vesicles. Since their discovery, they have emerged as a promising vehicle for the efficient delivery of active biological compounds. They can be loaded with hydrophilic drugs in their aqueous interior and/or hydrophobic drugs in the lipid membrane while simultaneously protecting the incorporated drug from degradation or inactivation and changing drug pharmacokinetics and bio-distribution in a favorable fashion. The coating of the liposome surface with polyethylene glycol (PEG) gave rise to long-circulating liposomes. This coating helps prevent liposomal uptake by the mononuclear phagocyte system. Longer circulation times allow for an increased concentration of the liposomes in the blood and when combined with active targeting through the attachment of targeting ligands, lead to efficient liposomal delivery to the target sites increasing thus drug concentration in the required zone and decreasing toxicity. This chapter aims to provide the reader with a clear understanding of the advantages and limitations of different types of liposomes and bring to light the recent advances in the use of liposomes in the field of drug delivery.Advanced Biomaterials and Biodevices, Edited by Ashutosh Tiwari and Anis Nordin, 07/2014: chapter Recent Advances with Liposomes as Drug Carriers: pages 79-119; John Wiley & Sons, Inc.
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