The effect of the cholesterol content of small unilamellar liposomes on the fate of their lipid components (original) (raw)
Related papers
Biochemical Journal, 1980
Small unilamellar neutral, negatively and positively charged liposomes composed of egg phosphatidylcholine, various amounts of cholesterol and, when appropriate, phosphatidic acid or stearylamine and containing 6-carboxyfluorescein were injected into mice, incubated with mouse whole blood, plasma or serum or stored at 4°C. Liposomal stability, i.e. the extent to which 6-carboxyfluorescein is retained by liposomes, was dependent on their cholesterol content. (1) Cholesterol-rich (egg phosphatidylcholine/ cholesterol, 7: 7 molar ratio) liposomes, regardless of surface charge, remained stable in the blood of intravenously injected animals for up to at least 400 min. In addition, stability of cholesterol-rich liposomes was largely maintained in vitro in the presence of whole blood, plasma or serum for at least 90 min. (2) Cholesterol-poor (egg phosphatidylcholine/cholesterol, 7 :2 molar ratio) or cholesterol-free (egg phosphatidylcholine) liposomes lost very rapidly (at most within 2 min) much of their stability after intravenous injection or upon contact with whole blood, plasma or serum. Whole blood and to some extent plasma were less detrimental to stability than was serum. (3) After intraperitoneal injection, neutral cholesterol-rich liposomes survived in the peritoneal cavity to enter the blood circulation in their intact form. Liposomes injected intramuscularly also entered the circulation, although with somewhat diminished stability. (4) Stability of neutral and negatively charged cholesterol-rich liposomes stored at 4°C was maintained for several days, and by 53 days it had declined only moderately. Stored liposomes retained their unilamellar structure and their ability to remain stable in the blood after intravenous injection.
Liposome disposition in vivo. III. Dose and vesicle-size effects
Biochimica et biophysica acta, 1981
The effect of lipid dose (4,3-512.8 mumol total lipid/kg body weight), administered intravenously as liposomes encapsulating radioactive inulin, upon the ability of mouse organs to bind and/or take-up the radioactive label has been studied in vivo. Three different liposome diameters were investigated: 0.46 micrometers (L), 0.16 micrometers (M) and 0.058 micrometers(S). All liposomes were negatively charged with lipid composition of phosphatidylcholine/phosphatidic acid/cholesterol/alpha-tocopherol in the molar ration 4 : 1 : 5 : 0.1 or 4 : 1 : 1 : 0.05. Overall radioactive label disposition after 2 h was consistent with localization predominantly in the reticuloendothelial system. A saturation of liver with increasing lipid dose was demonstrated for all three sizes, together with a corresponding increase in blood levels. Spleen radioactivity increased with increasing dose of L- and M-liposomes, but decreased for increasing doses of S-liposomes. Levels in residual carcass exhibited n...
Effect of cholesterol concentration on size of liposome
IOSR Journal of Pharmacy and Biological Sciences, 2012
In this article information about effect of cholesterol concentration on vesicle size of liposome. The advantages and disadvantages of the methods have been described in terms of size distribution and encapsulation efficiency. The reduction of the size of the multilamellar vesicles (MLVs) to small unilamellar vesicles (SUVs) so as to increase their plasma lifetime and consequently increase the possibility of achieving greater tissue localisation.
Biochimica et Biophysica Acta (BBA) - General Subjects, 1983
The effect of high density lipoproteins (HDL) ~ on the stability and clearance of injected liposomes was investigated under conditions of abnormal lipoprotein metabolism in vivo. Small unilamellar liposomes composed of phosphatidylcholine and containing quenched carboxyfluorescein were injected intravenously or intraperitoneally into normal mice or mice previously made lipoprotein deficient with 4-aminopyrazolo[3,4d]pyrimidine (4-APP). As evidenced from quenched carboxyfluorescein values in the blood, levels of stable iiposomes in the circulation were increased and clearance rates reduced considerably in lipoprotein-deficient animals indicating increased bilayer integrity. This was confirmed by the demonstration that transfer of liposomal phosphatidylcholine to HDL, occurring in the presence of normal mouse plasma, was virtually abolished in the presence of plasma from lipoprotein deficient mice. The role of other lipoprotein species in destabilizing liposomes was also investigated. Plasma from lipoprotein-deficient mice was supplemented with increasing amounts of HDL, LDL + IDL or VLDL (to cover the physiological range of lipoprotein concentrations in mouse blood) prior to the addition of phosphatidylcholine liposomes, and incubated at 37°C. It was shown that among the lipoprotein species studied only HDL was detrimental to liposomal stability under the conditions employed. Our results indicate that use of liposomal drugs in the treatment of patients must take into account HDL fluctuations in their blood as these could after liposomal membrane permeability to the drugs and thus upset therapeutic efficiency.
Modulation of pharmacokinetic behavior of liposomes
Advanced Drug Delivery Reviews, 1997
The authors's recent work on matters pertinent to the in vivo processing of systemically administered liposomes is reviewed. Particular emphasis is given to factors influencing blood clearance rates, hepatic and splenic uptake and intrahepatic as well as intrasplenic distribution. In addition to size, liposomal composition plays a crucial role in determining these parameters as was shown by comparing the fate of liposomes composed of egg phosphatidylcholine (eggPC), cholesterol (Chol) and either phosphatidylglycerol (PG) or different molar fractions of phosphatidylserine (PS) as negatively charged components. Neutral eggPC/Chol liposomes with and without lipid-anchored poly(ethylene glycol) were also compared. The experimental approach included the measurement of radiolabel distribution from [ 'Hlcholesterylether-labeled liposomes in blood, liver and spleen and in isolated hepatic cell fractions as well as morphological observations on colloidal gold containing liposomes at the light-and electronmicroscopical level. Evidence is presented that apolipoprotein-E plays an important role in the clearance and hepatic uptake and processing of some liposomes but not of others.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 1989
Many of the applications of liposomes drag-delivery systems have been limited by their short circulation half-lives as a result of rapid uptake into the retieuloendothelial (mononudear phagocyte) system. We have recently described li~ formulations with long circulation half-lives in mice (Allen, T.M. and Chonn, A. (1987) FEBS Lett. 223, 42-46), A study of the principal factors important to the attainment of liposomes with prolonged circulation half-lives is Wesented in this manuscript. Liposomes with the longest circulation half-lives, in mice, had compositions which mimkked the outer leaflet of red blood cell membranes (egg phosphatidyleholine/sphingomyelin/cholesterol/ gangUoside GMa , molar ratio 1 : I : 1:0.1,1). Several other gangliosides and 81ycolipids were examined, but none could substitute for GMt in their ability to prolong circulation half-lives. However, other negatively charged lipids with bulky headllmUl~ i.e., sulfatides and i~lmsphatldyli~itol, had some effect in prolonging circulation half-lives, but GM! was clearly superior in this regard. Bilayer ril0dity, imparted by sphingomyelin or other high-phase-transition lipids, acted synergistically with the negatively charged components, especially GMt , in extending circulation times. Circulation half-Uves of Iiimsemes increased with decreasing size, but even larger (0.2-0.4 pro) liposomes of the optimum formulations had significantly prolonged half-lives in circulation. Uptake of liposomes into tissues other than liver and spleen increased with increasing circulation times of the liposomes for i.v. and for i.p. injections. Liposornes appeared to move from the ¢irodation into the carcass between 6 and 24 h post-injection. Our ability to achieve significant prolongation in eireulation times of liposomes makes possible a number of therapeutic applications of liposomes which, until now, have not been achievable.
Lipids and Liposomes in the Enhancement of Health and Treatment of Disease
The discovery of liposomes initially came from studies by Bangham and Horne who observed by electron microscopy the self-association of the lipid phosphatidylcholine (mixed with or without cholesterol) in water formed ‘spherulites’ of varying sizes which had not a recognizable lamellar shell comprising a lipid bilayer [1]. The self-assembling ‘spherulites’, subsequently named liposomes from the greek lipo (fat) and soma (body), were recognised to be functionally analogous to studied biological membrane systems due to the similar rates of diffusion of ions [2]. However only when an ionophore, valinomycin, was utilised demonstrating selective diffusion of K+ over Na+ from liposomes containing equal concentrations of the ions, could liposomes be confirmed as entirely sealed membrane vesicles [3]. Furthermore Papahadjopoulos and Watkins showed the differential permeability to anions and cations could be significantly altered with liposomes of different phospholipid compositions [4]. Natural liposomes have bilayers composed of phospholipids and/or cholesterol and as such are poorly antigenic, typically non-toxic and physiologically inert. Liposomes can vary in size from 25 nm to 2.5 µm and are classified within three broad categories [5]: Multilamellar vesicles (MLV), which structurally resemble an onion with multiple concentric phospholipid bilayers separated by aqueous layers,large unilamellar vesicles (LUV) and small unilamellar vesicles (SUV) which have a single lipid bilayer surrounding the aqueous core. Typically multiple unilamellar vesicles of differing sizes can form inside of each other generating multilamellar structures. The concept of liposomes as drug-carriers to aid in selectivity was explored in the early nineteen seventies predominantly through the work of drug-transport scientists such as Gregoriadis who initially looked at the fate of protein-containing liposomes delivered into animals [6]. The theory that liposomes stay intact and circulate in the bloodstream before accumulating in specific tissues where they release their molecules into cells was confirmed using radiolabelled proteins entrapped in liposomes. The radioactive signal from the proteins was barely detected in the bloodstream, but predominantly in the lysosomes of cells of the liver and spleen, showing the liposomes stayed intact prior to the radiolabelled proteins being taken up by the cells. This and related studies revealed the physiological behaviour of liposomes such as their integrity and long life span in the mammalian bloodstream. It was only through the use of cell culture it was confirmed that cargo carried by liposomes was directly delivered through endocytosis into the lysosomes and thus into the intracellular environment of cells [7]. These initial studies demonstrated the huge potential for liposomes as model systems, and a number of various applications were subsequently explored as listed here: The effect of surface charge on ion permeability [8]; their susceptibility to phospholipase hydrolysis [9]; the function of integral membrane ion transporters [10]; the delivery of active enzymes to functionally deficient cells [11]; their use as immunological adjuvants [12]; as stimulants of interferon production [13]; their interaction with polyene antibiotics [14]; their incorporation of local and general anaesthetics [15]; the inclusion and presentation of virus surface proteins [16]. Since those early experiments, there has been a continued interest in the use of liposomes and currently there are applications in a wide variety of scientific fields. In this chapter we will focus on the use of lipids and liposomes in the enhancement of a number of health related areas and cover the development of new synthetic molecules, which have great potential in advancing improvements in health and the treatment of disease.