Liposome-mediated delivery of gallium to macrophage-like cells in vitro: demonstration of a transferrin-independent route for intracellular delivery of metal ions.
Gallium (Ga) prevents the activation of macrophages and might be useful as an immunosuppressive agent. It is taken up by the malignant cells through the transferrin (Tf) receptor pathway, but this pathway may be insufficient in the case of non-malignant cells. We studied the Tf-independent, liposome-mediated delivery of Ga to macrophage-like cells in vitro by a growth inhibition assay. The growth inhibitory properties of Ga for other types of cells was also evaluated. Ga complexed with nitrilotriacetate (GaNTA) and encapsulated in DSPG-liposomes was 16 and 48 times more potent for RAW 264 cells than free GaNTA and Ga-nitrate, respectively. CV1-P cells were also somewhat sensitive to liposomal Ga, but other cell lines with lower endocytotic capacity were insensitive. The inhibition of RAW 264 cell growth induced by liposomal or free GaNTA was partially reversed with iron-loading of the cells, indicating that this form of Ga causes an intracellular iron deficiency similar to that produced by Tf-bound Ga. Our results indicate that encapsulation of Ga in negatively charged liposomes provides a transferrin independent route for intracellular delivery of the compound to macrophages, which is of special interest in the treatment of autoimmune diseases, such as rheumatoid arthritis.
Mönkkönen
J
J
School of Pharmacy, University of Wisconsin, Madison 53706.
Brown
C S
CS
Thompson
T T
TT
Heath
T D
TD
D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004339:Drug Compounding; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000502:physiology; D005708:Gallium / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006427:Hemin / Q000378:metabolism; D007502:Iron Chelating Agents / Q000493:pharmacokinetics; D007538:Isoniazid / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008081:Liposomes; D008264:Macrophages / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism; D008670:Metals / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051379:Mice; D009571:Nitrilotriacetic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D011730:Pyridoxal / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D014168:Transferrin / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000378:metabolism
D007502:Iron Chelating Agents; D008081:Liposomes; D008670:Metals; D014168:Transferrin; D000643:Ammonium Chloride; D011730:Pyridoxal; C021079:pyridoxal isonicotinoyl hydrazone; D006427:Hemin; D005708:Gallium; D009571:Nitrilotriacetic Acid; D007538:Isoniazid