Liposome-encapsulated dichloromethylene diphosphonate induces macrophage apoptosis in vivo and in vitro.
Dichloromethylene diphosphonate (MDPCl2) encapsulated in multilamellar liposomes was selectively incorporated by macrophages, immediately transferred to lysosomes, then released from liposomes into lysosomes by enzymatic digestion of the liposomal lipid layers. From 4 h after ingesting liposome-encapsulated MDPCL2 murine macrophages in vivo and in vitro acquired the ultrastructural features of apoptosis, such as condensed nuclear chromatic, nuclear fragmentation, cell shrinkage, and blebbing of the plasma membrane. Murine peritoneal macrophages and isolated rat Kupffer cells incubated in the medium containing liposome-encapsulated MDPCl2 increased DNA fragmentation in a dose-dependent manner. Electrophoretic analysis of extracted DNA from the isolated Kupffer cells showed DNA fragmentation. Another diphosphonate, Alendronate (4-amino-1-hydroxy-butylidene-1,1-diphosphonate) had less potent macrophage cytotoxicity. However, MDPCl2, Alendronate, and gadolinium chloride in solution were not cytotoxic to macrophages. These results implied that the intralysosomal accumulation of MDPCl2 generates signals to induce macrophage apoptosis.
Naito
M
M
Second Department of Pathology, Niigata University School of Medicine, Japan.
Nagai
H
H
Kawano
S
S
Umezu
H
H
Zhu
H
H
Moriyama
H
H
Yamamoto
T
T
Takatsuka
H
H
Takei
Y
Y
D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001710:Biotin; D004002:Clodronic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004253:DNA Nucleotidylexotransferase; D004337:Drug Carriers; D005260:Female; D005682:Gadolinium / Q000494:pharmacology; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism / Q000493:pharmacokinetics; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D012313:RNA / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014544:Uridine Triphosphate
D004337:Drug Carriers; D008081:Liposomes; D004002:Clodronic Acid; D012313:RNA; D001710:Biotin; D004247:DNA; D005682:Gadolinium; D004253:DNA Nucleotidylexotransferase; C038958:gadolinium chloride; D014544:Uridine Triphosphate; D019386:Alendronate