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‐enca...

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Bibliographic Details
Published in:Journal of leukocyte biology 1996-09, Vol.60 (3), p.337-344
Main Authors: Naito, Makoto, Nagai, Hirotaka, Kawano, Sunao, Umezu, Hajime, Zhu, Hong, Moriyama, Hiroshi, Yamamoto, Takashi, Takatsuka, Hisakazu, Takei, Yoshiyuki
Format: Article
Language:English
Subjects:
Alendronate - pharmacology
Animals
Apoptosis - drug effects
Biotin
Clodronic Acid - administration & dosage
Clodronic Acid - pharmacokinetics
Clodronic Acid - pharmacology
DNA - metabolism
DNA fragmentation
DNA Nucleotidylexotransferase
Drug Carriers
electron microscopy
Female
Gadolinium - pharmacology
immunohistochemistry
Kupffer Cells - cytology
Kupffer Cells - drug effects
Kupffer Cells - metabolism
Liposomes - metabolism
Liposomes - pharmacokinetics
lysosomes
Macrophages, Peritoneal - cytology
Macrophages, Peritoneal - drug effects
Macrophages, Peritoneal - metabolism
Mice
Mice, Inbred BALB C
Microscopy, Electron
Rats
Rats, Wistar
RNA - metabolism
Uridine Triphosphate
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Summary: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 chromatin, 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‐hydroxybutylidene‐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. J. Leukoc. Biol. 60: 337–344; 1996.
ISSN:0741-5400
1938-3673
DOI:10.1002/jlb.60.3.337