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Chronic liposome administration in mice: effects on reticuloendothelial function and tissue distribution
Abstract:
Liposomes have a pronounced tendency to localize in the reticuloendothelial (RE) system, a major host defense system. We have examined, in mice, the effect of chronic i.v. administration of low to moderate liposome doses on drug metabolism, phagocytic index and spleen and liver size. Little effect on the rate of pentobarbital metabolism was noted, except when mice received 80 mg/kg of sphingomyelin-containing liposomes in a series of 10 injections over 3.5 weeks. Impairment of RE phagocytic function was found to be related to liposome size and composition, size and frequency of liposome dose and the presence of lipid peroxides. The effects on tissue distribution of liposome-entrapped [14C]sucrose was also determined in mice receiving chronic liposome injections. In RE blockaded mice there was a consistent trend in favor of decreased liver uptake and increased spleen uptake. No significant uptake of liposome contents was seen in non-RE tissues even in mice with severe RE blockade, indicating that the induction of RE blockade by predosing with empty liposomes may not be a successful strategy for increasing liposome uptake to non-RE tissues. Liver to spleen ratios of [14C]sucrose appeared to be a sensitive method for quantitating RE blockade. Sphingomyelin-containing liposomes produced the greatest RE blockade, distearoylphosphatidylcholine-cholesterol liposomes were intermediate and egg phosphatidylcholine-cholesterol liposomes produced the least impairment in RE function. Liposomes which contained 1% vitamin E as an antioxidant had slightly less effect on RE function than liposomes not containing vitamin E.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Chronic liposome administration impacts the reticuloendothelial system, affecting drug metabolism and tissue distribution. Liposome composition, size, and dose influence these effects, with sphingomyelin-based liposomes causing the most significant reticuloendothelial blockade.
Area of Science:
- Pharmacology and Toxicology
- Nanomedicine
- Immunology
Background:
- Liposomes are frequently utilized drug delivery systems with a known tendency to accumulate in the reticuloendothelial (RE) system.
- Understanding the long-term effects of liposome administration on host defense mechanisms is crucial for optimizing therapeutic strategies.
Purpose of the Study:
- To investigate the impact of chronic, low-to-moderate dose liposome administration on drug metabolism, RE system phagocytic function, and organ size in mice.
- To evaluate how liposome characteristics (size, composition, lipid peroxides) and dosing regimens affect RE system blockade and tissue distribution of encapsulated drugs.
Main Methods:
- Chronic intravenous administration of varying liposome formulations to mice.
- Assessment of pentobarbital metabolism rates.
- Measurement of RE phagocytic index.
- Determination of spleen and liver sizes.
- Quantification of tissue distribution of liposome-entrapped [14C]sucrose.
Main Results:
- Chronic liposome dosing had minimal impact on pentobarbital metabolism, except for sphingomyelin liposomes at high doses.
- RE phagocytic function impairment correlated with liposome size, composition, dose frequency, and presence of lipid peroxides.
- Sphingomyelin liposomes caused the most significant RE blockade, followed by distearoylphosphatidylcholine-cholesterol, and then egg phosphatidylcholine-cholesterol liposomes.
- Liposomes with vitamin E showed slightly less RE function impairment.
- RE blockade led to decreased liver and increased spleen uptake of liposome contents, with no significant uptake in non-RE tissues.
Conclusions:
- Chronic liposome administration can modulate RE system function, with effects dependent on liposome properties and dosing.
- Sphingomyelin-containing liposomes are most effective at inducing RE blockade.
- Strategies aiming to increase non-RE tissue uptake by inducing RE blockade with empty liposomes may not be successful.
- Liver to spleen ratios of entrapped substances offer a sensitive measure of RE blockade.