Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times

Lasic, D. D.; Martin, Frank; Gabizón, Alberto; Huang, Shi Kun; Papahadjopoulos, Demetrios

doi:10.1016/0005-2736(91)90162-2

Cited by 514 publications

(215 citation statements)

References 25 publications

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“…Some surface modifications have been suggested in order to reduce the interaction of liposomes with the immune system. Studies have demonstrated that the addition of a polymeric hydrophilic coat to the liposome surface significantly increases its half-life in the bloodstream by reducing the recognition and interaction with plasma proteins and RES macrophages (28,29). These longcirculation liposomes are known as PEGylated liposomes, due to the use of polyethylene glycol as a coating agent.…”

Section: Intravenous Deliverymentioning

confidence: 99%

Liposomal photosensitizers: potential platforms for anticancer photodynamic therapy

Muehlmann

Joanitti

Silva

et al. 2011

Braz J Med Biol Res

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Section: Intravenous Deliverymentioning

confidence: 99%

Liposomal photosensitizers: potential platforms for anticancer photodynamic therapy

Muehlmann

Joanitti

Silva

et al. 2011

Braz J Med Biol Res

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“…To explain this result, the coating of the liposomes must be considered. Poly(ethylene)glycol-modified dipalmitoyl phosphatidyl-ethanolamine (PEG(2000)-DPPE), the liposome coating used in pH-MTO, is able to significantly inhibit the uptake of the liposomes by the Kupffer cells in the liver (Lasic et al, 1991). In contrast, the PA-MTO liposomes were uncoated and probably carrying negative surface charges and therefore more likely to be rapidly taken up by the mononuclear phagocytic system (MPS).…”

Section: Efficacymentioning

confidence: 99%

“…In addition to the different loading techniques of the liposomes with MTO, the pH-MTO liposomes contained poly (ethylene) glycol (PEG)-modified dipalmitoyl phosphatidylethanolamine (PEG(2000)-DPPE) to provide them with long circulating properties (Allen, 1989;Lasic et al, 1991;Gabizon et al, 1993). In order to compare the pharmacokinetic parameters of these two liposomal formulations with the aqueous solution that is currently on the market, the concentrations of MTO were measured using high-performance liquid chromatography (HPLC) in blood, liver, heart, spleen and kidneys of mice after intravenous administration of the three formulations.…”

mentioning

confidence: 99%

Comparative pharmacokinetic and cytotoxic analysis of three different formulations of mitoxantrone in mice

Rentsch

Horber²,

Schwendener³

et al. 1997

Br J Cancer

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MTO, 6.1 imol kg-' for PA-MTO and 4.5 Imol kg-' for pH-MTO. The concentrations of MTO were determined using high-performance liquid chromatography (HPLC) in blood, liver, heart, spleen and kidneys of the mice. Additionally, the toxicity and anti-tumour activity of MTO was evaluated in a xenograft model using a human LXFL 529/6 large-cell lung carcinoma. The dose administered was 90% of the maximum tolerated dose (MTD) of the corresponding formulation (8.1 Amol kg-' for free MTO, 12.1 iimol kg-' for PA-MTO and pH-MTO). The pharmacokinetic behaviour of PA-MTO in blood was faster than that of free MTO, but the cytotoxic effect was improved. In contrast, pH-MTO showed a tenfold increased area under the curve (AUC) in blood compared with free MTO, without improvement of the cytotoxic effect. This discrepancy between the pharmacokinetic and cytotoxic results could be explained by the fact that MTO in pH-MTO liposomes remains mainly in the vascular space, whereas MTO in PA-MTO liposomes is rapidly distributed into deep compartments, even more so than free MTO.

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“…Furthermore, drawing from the concept of lipid rafts [15,18,19] -domains that are believed to exist in cellular membranes -we have designed heterogeneous domain-containing PEGylated liposomes that are considerably more active than their homogeneous counterparts (Scheme 1). These raft-mimetic PEGylated polyvalent liposomes are attractive not only for designing inhibitors for toxins and pathogens, but also for the design of efficient targeted drug delivery systems.While liposomes have been investigated extensively for applications in drug delivery, as described above, conventional liposomes are limited in effectiveness because of their low colloidal stability and their rapid uptake by macrophage cells of the immune system, predominantly in the liver and spleen [20]. The ability to enhance the physical stability and extend the circulation lifetime through modification with PEG, achieved by using lipids with PEG attached to their hydrophilic head groups, has proven to be useful in the context of drug delivery [17,[20][21][22].…”

mentioning

confidence: 99%

Stable and Potent Polyvalent Anthrax Toxin Inhibitors: Raft‐Inspired Domain Formation in Liposomes that Contain PEGylated Lipids

Rai¹,

Vance²,

Poon³

et al. 2008

Chemistry A European J

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The design of polyvalent molecules [1][2][3][4][5], consisting of multiple copies of a ligand attached to a suitable scaffold, represents a promising approach for designing potent inhibitors of pathogens and microbial toxins [1,[6][7][8][9][10][11]. Liposomes are particularly attractive scaffolds for designing polyvalent inhibitors [9,10,[12][13][14][15]; however, the poor colloidal stability of conventional liposomes and their short circulation times in vivo [16,17] are major obstacles limiting their therapeutic use. We describe the design of highly stable and active polyvalent anthrax toxin inhibitors based on liposomes incorporating polyethylene glycol (PEG)-functionalized lipids (PEGylated liposomes). Furthermore, drawing from the concept of lipid rafts [15,18,19] -domains that are believed to exist in cellular membranes -we have designed heterogeneous domain-containing PEGylated liposomes that are considerably more active than their homogeneous counterparts (Scheme 1). These raft-mimetic PEGylated polyvalent liposomes are attractive not only for designing inhibitors for toxins and pathogens, but also for the design of efficient targeted drug delivery systems.While liposomes have been investigated extensively for applications in drug delivery, as described above, conventional liposomes are limited in effectiveness because of their low colloidal stability and their rapid uptake by macrophage cells of the immune system, predominantly in the liver and spleen [20]. The ability to enhance the physical stability and extend the circulation lifetime through modification with PEG, achieved by using lipids with PEG attached to their hydrophilic head groups, has proven to be useful in the context of drug delivery [17,[20][21][22]. We first tested whether the use of PEGylated liposomes (Scheme 1b) would enable the design of stable and active polyvalent anthrax lethal toxin (LeTx) inhibitors.To that end, we made liposomes (100 nm diameter) composed of a 19:1 mixture of 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC) and a pyridyl dithiopropionate derivative of L-α-Distearoyl Phosphatidylethanolamine-N-[Amino(Polyethylene Glycol)2000] (DSPE-PEG2000-PDP). We functionalized these liposomes with an inhibitory peptide HTSTYWWLDGAPC [9,23] (4.7%) that binds to the heptameric cell-binding component of anthrax toxin, [PA 63 ] 7 , thereby blocking the binding of the toxic enzyme lethal factor (LF). Inhibition of the binding of LF to [PA 63 ] 7 prevents the cytosolic delivery of LF, thereby inhibiting cell death. Peptide-functionalized PEGylated liposomes protected RAW264.7 cells from LeTx with a half maximal inhibitory concentration (IC 50 ) of about 35 nM on a per-peptide basis; control PEGylated liposomes functionalized with thioglycerol showed no inhibitory activity (Fig. 1a). Furthermore, as seen in Fig. 1a, the activity of the polyvalent PEGylated liposomes (Scheme 1b) was comparable to that of conventional (non-PEGylated) DSPC-based liposomes (Scheme 1a) with the same peptide density (20 nM), indicating that the use of ...

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Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times

Cited by 514 publications

References 25 publications

Liposomal photosensitizers: potential platforms for anticancer photodynamic therapy

Liposomal photosensitizers: potential platforms for anticancer photodynamic therapy

Comparative pharmacokinetic and cytotoxic analysis of three different formulations of mitoxantrone in mice

Stable and Potent Polyvalent Anthrax Toxin Inhibitors: Raft‐Inspired Domain Formation in Liposomes that Contain PEGylated Lipids

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