Abstract
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. However, the details of the underlying mechanism for the induction of anti-PEG IgM production are yet to be elucidated. The present study demonstrated that the spleen is a major organ involved in the secretion of anti-PEG IgM in mice and rats. Anti-PEG IgM production was detected in nude, T-cell deficient mice, but not in SCID mice with B- and T-cell deficiencies. These observations indicate that splenic B-cells secret anti-PEG IgM without help from T-cells. Sequential injections of PEGylated liposomes into the same mice did not promote isotype switching from IgM to IgG. Accordingly, PEGylated liposomes may function as a type-2, T-cell-independent antigen (TI-2 antigen) during anti-PEG IgM production. Although the underlying mechanism that causes an anti-PEG IgM response against PEGylated liposomes is not yet clear, our findings give implications in revealing the anti-PEG IgM response against PEGylated liposome.
Highlights
It is well known that surface modification of liposomes with polyethylene glycol (PEG) improves the pharmacokinetics of liposomes after intravenous injection
PEGylated liposomes with a mean size of around 100 nm are attractive for tumor targeting because of a unique feature known as the enhanced permeability and retention (EPR) effect [3], for which the liposomes accumulate in tissue with leaky blood vessels after intravenous injection
Anti-PEG IgM production was detected in mice following a single intravenous injection of PEGylated liposomes at a dose of 1 μmol PL/kg (Figure 1)
Summary
It is well known that surface modification of liposomes with polyethylene glycol (PEG) improves the pharmacokinetics of liposomes after intravenous injection. PEGylated liposomes remain in circulation for a prolonged duration. PEGylated liposomes with a mean size of around 100 nm are attractive for tumor targeting because of a unique feature known as the enhanced permeability and retention (EPR) effect [3], for which the liposomes accumulate in tissue with leaky blood vessels (i.e., tumors and inflamed tissue) after intravenous injection. The enlarged capillary gaps (>400 nm) in tumor vasculature allow penetration by PEGylated liposomes, which have prolonged circulating properties, from the blood into the interstitial spaces of tumor tissues. The most successful example of PEGylated liposomes in clinical use are the doxorubicin-containing PEGylated liposomes, known under the commercial name Doxil/Caelyx—that exploits polymer coating technology and the concept of the EPR effect
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