Activation of the human complement system by cholesterol-rich and PEGylated liposomes-modulation of cholesterol-rich liposome-mediated complement activation by elevated serum LDL and HDL levels

Intravenously infused liposomes may induce cardiopulmonary distress in some human subjects, which is a manifestation of "complement activation-related pseudoallergy." We have now examined liposome-mediated complement activation in human sera with elevated lipoprotein (LDL and HDL) levels, since abnormal or racial differences in serum lipid profiles seem to modulate the extent of complement activation and associated adverse responses. In accordance with our earlier observations, cholesterol-rich (45 mol% cholesterol) liposomes activated human complement, as reflected by a significant rise in serum level of S-protein-bound form of the terminal complex (SC5b-9). However, liposome-induced rise of SC5b-9 was significantly suppressed when serum HDL cholesterol levels increased by 30%. Increase of serum LDL to levels similar to that observed in heterozygous familial hypercholesterolemia also suppressed liposome-mediated SC5b-9 generation considerably. While intravenous injection of cholesterol-rich liposomes into pigs was associated with an immediate circulatory collapse, the drop in systemic arterial pressure following injection of liposomes preincubated with human lipoproteins was slow and extended. Therefore, surface-associated lipoprotein particles (or apolipoproteins) seem to lessen liposome-induced adverse haemodynamic changes, possibly as a consequence of suppressed complement activation in vivo. PEGylated liposomes were also capable of activating the human complement system, and the presence of surface projected methoxypoly(ethylene glycol) chains did not interfere with generation of C3 opsonic fragments. We also show that poly(ethylene glycol) is not responsible for PEGylated liposome-mediated complement activation. The net anionic charge on the phosphate moiety of the phospholipid-mPEG conjugate seemed to play a critical role in activation of both the classical and alternative pathways of the complement system.     

Effect of prebiotic mannan oligosaccharide on hematological and blood serum biochemical parameters of cultured juvenile great sturgeon (Huso huso Linnaeus, 1754)

The nutritional effects of prebiotic mannan oligosaccharide were evaluated using hematological and blood serum biochemical parameters in cultured juvenile great sturgeon (Huso huso). Fish were offered formulated diets containing two levels of prebiotic mannan oligosaccharide (2 and 4 g kg^?1); a basal diet with no prebiotics was used as control. The experiment lasted for 46 days. Blood samples were collected from the caudal veins of 18 apparently healthy fish (average weight 217.77 ± 29.8 g) at the end of the trial. No significant differences were found in the serum enzyme activity levels between treatments (P > 0.05). However, adding mannan oligosaccharide as a supplement to the basal diet resulted in significant differences in lymphocytes and eosinophils between the control and the 2 g kg^?1 treatment (P < 0.05) as well as a significant difference in the creatinine factor in the 2 g kg^?1 mannan oligosaccharide treatment (P < 0.05). The results show that it would be advantageous to add 2 g kg^?1 mannan oligosaccharide to the diets of juvenile great beluga sturgeon (Huso huso).     

Non-phagocytic uptake of intravenously injected microspheres in rat spleen: influence of particle size and hydrophilic coating

A recent development in prolonging the circulation time of drug carriers, such as liposomes and microspheres, has been to minimize their removal by macrophages of the reticuloendothelial system by covering their surface with hydrophilic polymers such as poloxamers, poloxamines and poly(ethyleneglycols). Here we demonstrate that this strategy may not necessarily prolong the circulatory half-life of drug carriers in all animal models. In rats, as opposed to rabbits, a non-phagocytic mechanism in the spleen may be triggered to remove efficiently from the blood drug carriers coated with hydrophilic coatings. Both the size of particle and its hydrophilic coating may act synergistically to trigger this non-phagocytic mechanism. In rats, a remarkable log to log relationship between particle size and spleen uptake was observed for both uncoated and polymeric coated microspheres. The potential implication of these observations in site-specific delivery of drug carriers is discussed.