Influence of poly(ethylene glycol) grafting density and polymer length on liposomes: Relating plasma circulation lifetimes to protein binding

Abstract

The incorporation of poly(ethylene glycol) (PEG)-conjugated lipids in lipid-based carriers substantially prolongs the circulation lifetime of liposomes. However, the mechanism(s) by which PEG-lipids achieve this have not been fully elucidated. It is believed that PEG-lipids mediate steric stabilization, ultimately reducing surface-surface interactions including the aggregation of liposomes and/or adsorption of plasma proteins. The purpose of the studies described here was to compare the effects of PEG-lipid incorporation in liposomes on protein binding, liposome-liposome aggregation and pharmacokinetics in mice. Cholesterol-free liposomes were chosen because of their increasing importance as liposomal delivery systems and their marked sensitivity to protein binding and aggregation. Specifically, liposomes containing various molecular weight PEG-lipids at a variety of molar proportions were analyzed for in vivo clearance, aggregation state (size exclusion chromatography, quasi-elastic light scattering, cryo-transmission and freeze fracture electron microscopy) as well as in vitro and in vivo protein binding. The results indicated that as little as 0.5 mol% of 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE) modified with PEG having a mean molecular weight of 2000 (DSPE-PEG(2000)) substantially increased plasma circulation longevity of liposomes prepared of 1,2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC). Optimal plasma circulation lifetimes could be achieved with 2 mol% DSPE-PEG(2000). At this proportion of DSPE-PEG(2000), the aggregation of DSPC-based liposomes was completely precluded. However, the total protein adsorption and the protein profile was not influenced by the level of DSPE-PEG(2000) in the membrane. These studies suggest that PEG-lipids reduce the in vivo clearance of cholesterol-free liposomal formulations primarily by inhibition of surface interactions, particularly liposome-liposome aggregation.

The Impact of Nanoparticle Protein Corona on Cytotoxicity, Immunotoxicity and Target Drug Delivery

“…On the other hand, the physicochemical characterization of bare NPs before exposure to body fluids remains crucial to reveal the correlations between the properties of NPs and PC composition (Figure 1). During the recent years, a large number of studies have been devoted to the characterization of NP-PC complexes [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Furthermore, the scientific community is now moving from the The impact of nanoparticle protein corona on cytotoxicity, immunotoxicity and target drug delivery The bare NP (synthetic identity) that has a specific shape, size and charge is injected into the body.…”

Fiber-optic triggered release of liposome in vivo: implication of personalized chemotherapy

“…Liposome-delivered anticancer agents, such as doxorubicin, have been proved to reduce side effects (cardiotoxicity, gastrointestinal toxicity, stomatitis, hair loss, etc) while exhibiting superior performance or preserving efficacy in clinical studies and maintaining an extended period of therapeutic concentration. [11][12][13] Considerable efforts have been devoted to extend the lifetime and integrity of liposomes in the bloodstream to periods on the order of days, raising the successful rate of transportation to the target location, 14,15 but the liposomes interfere with the passive drug release efficiency upon arriving at the destination and reduce clinical efficacy. [16][17][18][19] An active triggered mechanism is required to facilitate sufficient liposome content release in situ for optimal treatment effects, [16][17][18][19][20][21] and a non-invasive or minimally invasive monitoring method is required to adjust the topical release kinetics tailored for each subject in vivo by detecting drug-induced bio-events, with the goal of achieving and extending the therapeutic dosage period without exceeding toxic levels.…”

Impact of interfacial cholesterol-anchored polyethylene glycol on sterol-rich non-phospholipid liposomes

“…[8][9][10] This protective effect has been associated with the steric stabilization of liposomes that inhibits the uptake by MPS and prolongs the liposome circulation lifetime. 6,[8][9]11 The origin of this protection is still not fully understood but it has been proposed that the reduced binding of plasma proteins, including potential opsonizing factors, the limitation of direct interactions with cells of the reticuloendothelial system, and the inhibition of liposome-liposome aggregation could contribute to the reduced clearance of PEGylated liposomes [12][13][14][15][16][17][18] .…”

“…13,19 It was shown that improved circulation times of liposomes in the blood stream were obtained for liposomes with 2-10 mol% of interfacial PEG with a molecular weight between 350 and 2000 (anchored with distearoylphosphatidylethanolamine (DSPE) in these studies). 12,16 The protection of liposomes against phagocytosis was also improved with introducing PEG with a molecular weight of 2000 at its interface. 9 An increase of the PEG molecular weight to 5000 had no effect on half-life time of liposomes in the blood stream or, in some reports, slightly decreased it.…”