Pharmacological disposition of negatively charged phospholipid vesicles in rats

Kao, Yin J.; Loo, Ti Li

doi:10.1002/jps.2600691126

Cited by 10 publications

(4 citation statements)

References 18 publications

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“…PI-containing liposomes have been reported as potential drug delivery vehicles that provide long circulating properties [3–5, 43] as well as the capability to reduce immunogenicity [5]. As the in vivo behavior of liposomes depends on the fundamental physical characteristics of the bilayer, it is important to understand the structure and dynamic properties of PI-containing lipid bilayer organization.…”

Section: Discussionmentioning

confidence: 99%

“…The role of phosphatidylinositol (PI) in liposomes for drug delivery applications has been extensively investigated [3–5]. The pharmacological disposition of PI-containing liposomes showed reduced uptake by the reticuloendothelial system (RES) which resulted in prolonged circulation time in rats and mice compared with other liposome formulations.…”

Section: Introductionmentioning

confidence: 99%

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Phosphatidylinositol induces fluid phase formation and packing defects in phosphatidylcholine model membranes

Peng

Pisal

Doty

et al. 2012

Chemistry and Physics of Lipids

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Liposomes consisted of phosphatidylinositol (PI) and phosphatidylcholine (PC) have been utilized as delivery vehicle for drugs and proteins. In the present work, we studied the effect of soy PI on physical properties of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes such as phase state of lipid bilayer, lipid packing and phase properties using multiple orthogonal biophysical techniques. The 6-dodecanoyl-2-dimethylamino naphthalene (Laurdan) fluorescence studies showed that presence of PI induces the formation of fluid phases in DMPC. Differential scanning calorimetry (DSC), temperature dependent fluorescence anisotropy measurements, and generalized polarization values for Laurdan showed that the presence of as low as 10 mol% of PI induces substantial broadening and shift to lower temperature of phase transition of DMPC. The fluorescence emission intensity of DPH labeled, PI containing DMPC lipid bilayer decreased possibly due to deeper penetration of water molecules in lipid bilayer. In order to further delineate the effect of PI on the physico chemical properties of DMPC is due to either significant hydrophobic mismatch between the acyl chains of the DMPC and that of soy PI or due to the inositol head group, we systematically replaced soy PI with PC species of similar acyl chain composition (DPPC and 18:2 (Cis) PC) or with diacylglycerol (DAG) respectively. The anisotropy of PC membrane containing soy PI showed largest fluidity change compared to other compositions. The data suggests that addition of PI alters structure and dynamics of DMPC bilayer in that it promotes deeper water penetration in the bilayer, induces fluid phase characteristics and causes lipid packing defects that involve its inositol head group.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol induces fluid phase formation and packing defects in phosphatidylcholine model membranes

Peng

Pisal

Doty

et al. 2012

Chemistry and Physics of Lipids

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“…(iii) The inclusion of certain gangliosides, which confer to the liposome surface a negative charge and increased hydrophilicity, synergizes with Chol to enhance liposome stability in plasma (23) and prolongs liposome half-life in blood with a concomitant decrease in liver and spleen uptake (24). In addition, inclusion of phosphatidylinositol (Ptdlns) in liposomes (25), or hydrophilic coating of polystyrene particles with polymeric glycols (26) results in significantly enhanced blood half-lives. (iv) Small unilamellar liposomes exhibit a slower clearance from the circulation when compared to larger multilamellar ones of the same composition (22,27).…”

mentioning

confidence: 99%

Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.

Gabizón

Papahadjopoulos

1988

Proc. Natl. Acad. Sci. U.S.A.

1,005

488

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The rapid clearance of circulating liposomes from the bloodstream, coupled with their high uptake by liver and spleen, has thus far been an obstacle to any attempts at targeting to tumors. We have assessed the impact of liposome composition on their clearance from the circulation in normal and tumor-bearing mice and on their uptake by tumors and various normal tissues. By selective changes in lipid composition, while maintaining a mean particle diameter of '100 nm, we have achieved up to a 60-fold increase in the fraction of recovered dose present in blood 24 hr after i.v. i 'ection. Concomitantly, there was a decrease by a factor of 4 of the recovered dose localizing in the liver and spleen, the major organs of the reticuloendothelial system. Parallel experiments in tumor-bearing mice demonstrated a 25-fold increase of the liposome concentration in the tumor when formulations with long and short blood residence time were compared. The most favorable results were obtained with liposomes containing a small molar fraction of a negatively charged glycolipid, such as monosialoganglioside or phosphatidylinositol, and a solidphase neutral phospholipid as the bulk component. The biodistribution of such formulations is of considerable therapeutic potential in cancer for increasing the concentration of cytotoxic agents in tumors while minimizLing the likelihood of toxicity to the reticuloendothelial system. Liposome encapsulation has been proven useful for reducing the toxicity of certain drugs (1-6) as well as for enhancing the efficacy of macrophage-activating factors (7,8) and drugs directed against parasites residing within the reticuloendothelial system (RES) (9)(10)(11)(12). The propensity of the RES to remove liposomes from the circulation has thus far limited the prospect oftargeting liposomes to tissues other than liver, spleen, and lung (13-15).Designing liposomes with prolonged circulation time would require a reduction of the rate of their clearance by the RES and of the leakage of liposome contents in the bloodstream. Our strategy to achieve these goals was based on the following prior observations. (i) The inclusion of cholesterol (Chol) and solid-phase phospholipids such as sphingomyelin and distearoyl phosphatidylcholine has been shown to increase liposome stability in plasma as determined by the degree of retention of various liposome-encapsulated markers in vitro (16-18). (ii) The same solid-phase phospholipids (sphingomyelin or distearoyl phosphatidylcholine) in the form of small sonicated liposomes are cleared more slowly after intravenous injection than those made with fluid phospholipids such as egg yolk phosphatidylcholine (PtdCho) (19)(20)(21)(22). (iii) The inclusion of certain gangliosides, which confer to the liposome surface a negative charge and increased hydrophilicity, synergizes with Chol to enhance liposome stability in plasma (23) and prolongs liposome half-life in blood with a concomitant decrease in liver and spleen uptake (24). In addition, inclusion of phosphatidylinositol (P...

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“…(Stein & Stein, 1966 Stamp, 1975;Patel & Ryman, 1981). With PS-containing lipo-!r Spleen somes, however, the disappearance from plasma has been rat 2 rat I rat 2 shown to be independent of the vesicle size (Juliano & Stamp, 1975 (Juliano & Stamp, 1975;Kao & Loo, 1980 lOOmgkg-1) far higher than those employed in this study (2mgkg-'). In the case of PS, saturation at this dose would imply a very low capacity uptake by the macrophage scavenger receptor that is expected to mediate the endocytosis of vesicles containing this phospholipid (Nishikawa et al, 1990).…”

Section: Discussionmentioning

confidence: 57%

Pharmacokinetic characterization of phosphatidylserine liposomes in the rat

Palatini

Viola

Bigon

et al. 1991

British J Pharmacology

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1 The plasma decay, tissue uptake and biotransformation of radiolabelled phosphatidylserine (PS) liposomes have been investigated in rats following bolus i.v. injection (2 mg kg-1). 2 PS plasma concentration showed a biexponential decay with half-lives of 0.85 and 40min. The following interpretation of the biphasic decay is proposed: (1) The rapid initial decline is due to the irreversible uptake of PS liposomes by the mononuclear phagocyte system, as demonstrated by the almost exclusive accumulation of PS in liver and spleen. (2) The slow decay phase reflects the elimination of that fraction of PS that has been incorporated into high density plasma lipoproteins (HDL). A kinetic model has been developed to describe these phenomena and a good agreement has been observed between experimental data and theoretical values. 3 Evidence has been obtained that a large fraction of PS is hydrolyzed at the injection site, probably by phospholipase A2 and other hydrolytic enzymes released by platelets. Hydrolysis at the injection site has also been observed following intraperitoneal and intramuscular injections. 4 As shown by the comparative analysis of the biotransformation products found in tissues after administration of either [3H]-glycerol-PS or ["4C]-serine-PS, parenterally administered PS follows two distinct metabolic pathways: (1) decarboxylation to phosphatidylethanolamine and (2) extensive hydrolytic degradation with release of the individual components of the molecule. These pathways probably reflect the two main mechanisms of PS uptake, incorporation into the plasma membrane and internalization by endocytosis, respectively.

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Pharmacological disposition of negatively charged phospholipid vesicles in rats

Cited by 10 publications

References 18 publications

Phosphatidylinositol induces fluid phase formation and packing defects in phosphatidylcholine model membranes

Phosphatidylinositol induces fluid phase formation and packing defects in phosphatidylcholine model membranes

Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.

Pharmacokinetic characterization of phosphatidylserine liposomes in the rat

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