Polyethylene Glycol Prevents in Vitro Aggregation of Slightly Negatively-Charged Liposomes Induced by Heparin in the Presence of Bivalent Ions
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概要
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Liposomes are of great interest as drug delivery vehicles, and studies have focused on understanding how the physical and chemical characteristics of liposomes can be modified to improve their in vivo behavior. In a previous study, we found that the slightly negatively-charged liposomes aggregate only in the culture medium of human umbilical vein endothelial cells, whereas the liposomes modified with polyethylene glycol (PEG) (PEGylated) did not aggregate. In the present study, we investigated the underlying mechanism of this phenomenon. Firstly, it was found that heparin in the culture medium is one of the factors that cause aggregation of the non-PEGylated liposomes. Since the addition of ethylenediaminetetraacetic acid (EDTA) prevented the aggregation, metal ions, such as Ca2+ and Mg2+, in the culture medium could also be important in driving the aggregation. In the presence of heparin, higher concentrations of Ca2+ or Mg2+ increased the particle size of the non-PEGylated liposomes, although no change in the particle size of PEGylated liposomes was observed. Under conditions in which aggregation occurred, we measured the binding and uptake of liposomes by macrophages in vitro. The binding and uptake of non-PEGylated liposomes were significantly increased with increasing Ca2+ concentrations, whereas those of PEGylated liposomes were unchanged. While the formation of aggregations of cationic or anionic liposomes has been reported previously, there are few reports addressing the aggregation of slightly negatively-charged or neutral liposomes. Thus, our data provide useful insights on the effect of PEGylation on liposomal aggregation and in vivo behavior.
著者
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Okuda Haruhiro
National Institute of Health Sciences
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Kawanishi Toru
National Institute Of Health Sciences
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YOMOTA Chikako
National Institute of Health Sciences
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Shibata Hiroko
National Institute of Health Sciences
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