Influence of dose and animal species on accelerated blood clearance of PEGylated liposomal doxorubicin.

We recently demonstrated that Doxil loses its long-circulating properties when injected repeatedly at doses below 2 mg/m(2) in dogs. In studies using other animal species, PEGylated liposomal doxorubicin has been reported not to induce the accelerated blood clearance (ABC) phenomenon. We investigated the issue of whether Doxil can elicit the ABC phenomenon in several species.

Ex-vivo/in-vitro anti-polyethylene glycol (PEG) immunoglobulin M production from murine splenic B cells stimulated by PEGylated liposome.

We have reported that PEGylated liposomes lose their long-circulating properties when injected twice into the same animal within a certain interval (the accelerated blood clearance (ABC) phenomenon). We assumed that this phenomenon was triggered via the abundant secretion of anti-polyethylene glycol (PEG) immunoglobulin M (IgM) in response to the first dose of PEGylated liposomes and that the spleen played an important role in the production of anti-PEG IgM. However, no direct evidence has yet confirmed this suspicion.

Anti-PEG IgM production via a PEGylated nano-carrier system for nucleic acid delivery.

For the systemic application of nucleic acids such as plasmid DNA and small interfering RNA, safe and efficient carriers that overcome the poor pharmacokinetic properties of nucleic acids are required. A cationic liposome that can formulate lipoplexes with nucleic acids has significant promise as an efficient delivery system in gene therapy. To achieve in vivo stability and long circulation, most lipoplexes are modified with PEG (PEGylation).

Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: a possible mechanism and the potential for clinical application.

We previously developed a PEG-coated cationic liposome that enabled dual targeting delivery of oxaliplatin (l-OHP) to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation consequently elicited potent antitumor efficacy in a murine solid tumor model after 3 sequential injections. However, the probable mechanism(s) for this enhanced antitumor activity has not been fully elucidated.

Intravenous administration of polyethylene glycol-coated (PEGylated) proteins and PEGylated adenovirus elicits an anti-PEG immunoglobulin M response.

A single intravenous administration of polyethylene glycol-coated (PEGylated) bovine serum albumin (BSA) and ovalbumin (OVA) elicited an anti-PEG immunoglobulin M (IgM) response, similar to that from PEGylated liposomes, although the administration did not elicit specific neutralizing antibodies to BSA and OVA. A cross-reactivity was observed between anti-PEG IgMs elicited by PEG-BSA and PEGylated liposomes. The anti-PEG IgM level induced by PEGylated proteins (BSA and OVA) reached the maximum at day 5 following intravenous injection.

Accelerated blood clearance of PEGylated liposomes containing doxorubicin upon repeated administration to dogs.

The accelerated blood clearance phenomenon involving anti-PEG IgM production has been recognized as an important issue for the design and development of PEGylated liposomes. Here, we show that empty PEGylated liposomes and Doxil, PEGylated liposomes containing doxorubicin, both caused anti-PEG IgM production and thereby a rapid clearance of the second and/or third dose of Doxil in Beagle dogs in a lipid-dose, inverse-dependent manner. It appears that the pharmacokinetic profile of the second and third administration of Doxil reflected the presence of anti-PEG IgM circulating in the blood.

Combination therapy with metronomic S-1 dosing and oxaliplatin-containing PEG-coated cationic liposomes in a murine colorectal tumor model: synergy or antagonism?

Combination therapy with 2 or more drugs with different mechanisms of action has been considered a promising strategy for the effective treatment of advanced and metastatic cancers. However, the rational design of combination therapy represents a potential prerequisite for its effectiveness. Recently, we showed that the combination of oral metronomic S-1 dosing with oxaliplatin (l-OHP)-containing PEG-coated "neutral" liposomes exerted excellent antitumor activity.

Combination therapy of metronomic S-1 dosing with oxaliplatin-containing polyethylene glycol-coated liposome improves antitumor activity in a murine colorectal tumor model.

Metronomic chemotherapy has been advocated recently as a novel chemotherapeutic regimen. Polyethylene glycol (PEG)-coated liposomes are well known to accumulate in solid tumors by virtue of the highly permeable angiogenic blood vessels characteristic for growing tumor tissue, the so-called "enhanced permeability and retention (EPR) effect". To expand the range of applications and investigate the clinical value of the combination strategy, the therapeutic benefit of metronomic S-1 dosing in combination with oxaliplatin (l-OHP)-containing PEG-coated liposomes was evaluated in a murine colon carcinoma-bearing mice model.

Anti-PEG IgM Response against PEGylated Liposomes in Mice and Rats.

We have reported that PEGylated liposomes lose their long-circulating properties when they are administered repeatedly at certain intervals to the same animal. This unexpected phenomenon is referred to as the accelerated blood clearance (ABC) phenomenon. We recently showed that the ABC phenomenon is triggered via the abundant secretion of anti-PEG IgM in response to the first dose of PEGylated liposomes.

Immunomodulatory effects of mono-, di-, and trimethylphenols in mice.

The relationship of air pollutants with the increasing prevalence of allergic diseases is a matter of concern in developed countries. In this study, the immunomodulatory effects of mono-, di-, and trimethylphenols in mice were examined as regards two aspects. First, whether or not these chemicals act as sensitizers was evaluated by local lymph node assay.

Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes.

It is well known that steric stabilization of the surface of liposomes by a polyethyleneglycol (PEG) conjugated lipid results in reduced recognition of the liposomes by the cells of the mononuclear phagocyte system and consequently extended circulation times of the liposomes (t1/2 approximately 20 h in rat). Recently, we reported on the "accelerated blood clearance (ABC) phenomenon", causing PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection. We also reported that abundant binding of IgM, secreted into the blood stream after the first dose and, to PEGylated liposomes, plays an essential role in the induction of the ABC phenomenon.

Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes.

Steric stabilization of the surface of liposomes by a PEG conjugated lipid results in reduced recognition of the liposomes by the cells of the mononuclear phagocyte system and consequently extended their circulation times (t(1/2) approximately 20h in rat). Recently, we reported on the "accelerated blood clearance phenomenon", causing "invisible" PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection. In addition, we reported that certain serum factor(s) secreted into the blood after the first dose of PEGylated liposomes play an essential role in the phenomenon.

Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes.

We recently reported that a second dose of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG2000-liposomes) is rapidly cleared from the blood and accumulates in the liver when injected twice in the same rat or mouse at several-day intervals (referred to as the "accelerated blood clearance (ABC) phenomenon").

Influence of the physicochemical properties of liposomes on the accelerated blood clearance phenomenon in rats.

We have recently reported that PEGylated liposomes (PL) are cleared rapidly from the blood circulation when they are administered twice in the same rat at certain intervals, even if the liposomes are sterically stabilized by a surface modification with PEG (referred to as the accelerated blood clearance (ABC) phenomenon, J. Control. Release, 88, 35-42 (2003)).

Effect of the physicochemical properties of initially injected liposomes on the clearance of subsequently injected PEGylated liposomes in mice.

Using mice as a model, we recently reported that the long-circulating properties of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG(2000)-liposomes) disappeared when they were intravenously injected at certain intervals [referred to as the "accelerated blood clearance (ABC) phenomenon"].

Accelerated clearance of a second injection of PEGylated liposomes in mice.

We recently reported that the firstly injected PEGylated liposomes dramatically affected the rate of blood clearance of secondly injected PEGylated liposomes in rats in a time interval of injection dependent manner [J. Control. Release (2003)].

Accelerated clearance of PEGylated liposomes in rats after repeated injections.

Polyethylene glycol-modified liposomes (PEGylated liposomes) represent promising carrier systems for therapeutic agents. Herein, we report on a study of the effect of repeated injection of PEGylated liposomes on their pharmacokinetics in rats. The first dose resulted in a reduction in the circulation time and an increase in hepatic accumulation of the second dose in a time-interval of injection-dependent manner.