Effects of Poly(ethylene glycol) (PEG) Concentration on the Permeability of PEG-Grafted Liposomes

Abstract

Liposomal drug delivery systems (DDS) have been widely researched for use in drug toxicity reduction and/or drug targeting to desired target tissues.1) However, liposomes are rapidly removed from the circulation following their intravenous administration primarily by Kupffer cells in the liver and fixed macrophages in the spleen. Thus, it is important to develop modified liposomes that are able to avoid uptake by the reticuloendothelial system (RES) and extend their circulation half-life in vivo. Many studies have reported that the conjugation of amphipathic polyethylene glycol (PEG) with liposomes (PEG-liposomes) significantly increases the blood circulation liposome half-life compared with those without PEG. [2][3][4][5] In our previous studies, 6,7) we reported on the effect of PEG-lipid PEG chain length on the membrane characteristics of liposomes. The addition of PEG-lipid to liposomes caused lateral phase separation in the gel and liquid-crystalline states, and the fluidity in the interfacial region of liposomal bilayer membranes was markedly increased by the addition of PEG-lipids. In addition, the permeability of liposomal bilayer membranes decreased compared with those without PEG. From these results, we concluded that the solute permeability of PEG-liposomes is affected by not only the properties of the liposomal bilayer membranes such as phase separation and membrane fluidity, but also the PEG chain length of the liposomal surface.In this study, we investigated the effects of PEG-lipid concentration on CF leakage from PEG-liposomes to elucidate the permeation mechanism of PEG-liposomes in more detail. ExperimentalMaterials L-a -Dipalmitoylphosphatidylcholine (DPPC, 99.6% pure) was obtained from NOF Co., Ltd., and Distearoyl-N-monomethoxy poly-(ethylene glycol)-succinyl-phosphatidylethanolamines (DSPE-PEG) were acquired from NOF Co., Ltd. (Tokyo, Japan). The weight-average molecular weights of poly(ethylene glycol) were 1000, 2000, 3000 and 5000. 5-(6)-Carboxyfluorescein (CF, 99% pure) was purchased from Molecular Probes, Inc. (OR, U.S.A.) and was used without further purification. 1,6-Diphenyl-1,3,5-hexatriene (DPH, 98% pure) and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH, 95% pure) were purchased from Sigma Chemical Co. (MO, U.S.A.) and were also used without further purification. Dulbecco's Phosphate-buffered saline (PBS) powder composed of NaCl, KCl, Na 2 HPO 4 and KH 2 PO 4 was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). PBS powder was dissolved in water for injection (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan), and an isotonic solution of pH 7.4 was used. All other chemicals were commercial products of reagent grade.Preparation of PEG-Liposomes PEG-liposomes were prepared using DPPC and DSPE-PEG, which were first dissolved in chloroform in a test tube. The solvent was then removed by blowing nitrogen gas into the test tube, and the residual solvent was further dried overnight at room temperature in a desiccator under a vacuum. PBS was added to the ...

Hybrid, Nanoscale Phospholipid/Block Copolymer Vesicles

“…The effect of PB-PEO on vesicle permeability is reminiscent of the effect that PEG-ylation exerts on the self-assembly and permeability of liposomes [30][31][32][33]. It was observed that addition of increasing concentrations of DSPE-PEG (DSPE: distearoylphosphatidylethanolamine; M W(PEG) > 2000) decreases the CF permeability of the PEG-ylated liposomes [32].…”

“…It was observed that addition of increasing concentrations of DSPE-PEG (DSPE: distearoylphosphatidylethanolamine; M W(PEG) > 2000) decreases the CF permeability of the PEG-ylated liposomes [32]. The PEG-block of the PB-PEO polymer, when introduced into the lipid membrane, could have a similar effect.…”

Carboxyfluorescein Leakage from Poly(ethylene glycol)-Grafted Liposomes Induced by the Interaction with Serum

“…The increased circulation halflife of PEG-liposomes has been attributed to the steric repulsive barrier due to the covalently attached PEG around the liposomes. 10,11) We have reported, [12][13][14] the effect of PEG-lipid on the physicochemical properties of liposomes. The addition of PEG-lipid to liposomes caused lateral phase separation, and the fluidity in the interfacial region of the liposomal bilayer membranes was markedly increased.…”

Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

“…12 Polyethylene glycol (PEG)-lipids can be incorporated into the lipid bilayer to enhance biocompatibility and increase circulation times. 13 This modification is especially effective in passively targeting malignant tissue, with increased liposomal uptake through leaky tumor microvasculature and prolonged retention time due to reduced lymphatic drainage occurring via the enhanced permeability and retention (EPR) effect. 14,15 We have previously demonstrated that peripheral administration of PEGylated nanoparticles containing anticancer Survivin siRNA leads to a significant reduction in tumor growth in a murine xenograft model of breast cancer.…”