PEG minocycline-liposomes ameliorate CNS autoimmune disease.
BACKGROUND
Minocycline is an oral tetracycline derivative with good bioavailability in the central nervous system (CNS). Minocycline, a potent inhibitor of matrix metalloproteinase (MMP)-9, attenuates disease activity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning. Here, we investigated whether less frequent treatment with long-circulating polyethylene glycol (PEG) minocycline liposomes are effective in treating EAE.


RESULTS
Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells (PBMCs), we determined that PEG minocycline-liposome preparations stabilized with CaCl(2) are effective in diminishing MMP-9 activity. Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline. Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes, and the overall expression of MMP-9 in the CNS. There was also a significant suppression of MMP-9 expression and proteolytic activity in splenocytes of treated animals, but not in CNS-infiltrating leukocytes. Thus, leukocytes gaining access to the brain and spinal cord require the same absolute amount of MMP-9 in all treatment groups, but minocycline decreases the absolute cell number.


CONCLUSIONS
Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases. Also, inhibition of MMP-9 remains a promising treatment target in EAE and patients with MS.
Hu
Wei
W
Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
Metselaar
Josbert
J
Ben
Li-Hong
LH
Cravens
Petra D
PD
Singh
Mahendra P
MP
Frohman
Elliot M
EM
Eagar
Todd N
TN
Racke
Michael K
MK
Kieseier
Bernd C
BC
Stüve
Olaf
O
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D008081:Liposomes; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000008:administration & dosage* / Q000627:therapeutic use; D020721:Nervous System Autoimmune Disease, Experimental / Q000188:drug therapy / Q000276:immunology; D011092:Polyethylene Glycols / Q000378:metabolism* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D008081:Liposomes; D061965:Matrix Metalloproteinase Inhibitors; D011092:Polyethylene Glycols; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D008911:Minocycline