Pegylated liposomal doxorubicin (Doxil) and 99mTc-HYNIC PEG liposomes (HPL) were reported earlier to cause hypersensitivity reactions (HSRs) in a substantial percentage of patients treated i.v. with these formulations. Here we report that (1) Doxil, HPL, pegylated phosphatidylethanolamine (PEG-PE)-containing empty liposomes matched with Doxil and HPL in size and lipid composition, and phosphatidylglycerol (PG)-containing negatively charged vesicles were potent C activators in human serum in vitro, whereas small neutral liposomes caused no C activation. (2) Doxil and other size-matched PEG-PE and/or PG-containing liposomes also caused massive cardiopulmonary distress with anaphylactoid shock in pigs via C activation, whereas equivalent neutral liposomes caused no hemodynamic changes. (3) A clinical study showed more frequent and greater C activation in patients displaying HSR than in non-reactive patients. These data suggest that liposome-induced HSRs in susceptible individuals may be due to C activation, which, in turn, is due to the presence of negatively charged PEG-PE in these vesicles.
The arnphipathic anthracycline base doxorubicin (DXR) was accumulated in the aqueous phase of the liposomes where it reached a level as high as 100-fold its concentration in the remote loading medium. Most of the intraliposomal D X R was present in an aggregated state. Eflicient (>90%) and stable loading into the liposomes' and ligandoliposomes' aqueous phase was obtained by using gradients of ammonium sulfate in which the ammonium sulfate concentration in the liposomes was higher than its concentration in the extraliposomal medium [(NH,),SO,)lip. > > [(NH,),SO,)med.]. The "remote" loading is a result of the D X R exchange with ammonia from (NH,),SO,. Both the ammonium and sulfate contribute to high level and stability of the loading. The ammonium sulfate gradient method differs from most other chemical approaches used for remote loading of liposomes since it neither requircs to prepare the liposomes in ijcidic pH, nor to alkalinize the extraliposomal aqucous phase. Although most of the intraliposomal D X R is present in an aggregated gel-like state, the drug is bioavailable. This approach permits the preparation of DXRloaded liposomes of a broad spectrum of types, sizes, and composition, including sterically-stabilized liposomes, irnmunoliposomes, and sterically-stabilized immunoliposomes. Due to the long shelf stability (>6 mo), no "bedside" remote 455
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