Document Detail


Delivery of cytokines by liposomes. III. Liposome-encapsulated GM-CSF and TNF-alpha show improved pharmacokinetics and biological activity and reduced toxicity in mice.
MedLine Citation:
PMID:  9181456     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In an attempt to potentiate the therapeutic index of cytokines, recombinant mouse granulocyte/macrophage colony-stimulating factor (GM-CSF) and recombinant human tumor necrosis factor alpha (TNF-alpha) were encapsulated in large (0.3-2.2 microns) multilamellar vesicles composed of various lipids, using several encapsulation methods. Liposomal cytokine activity was tested in vitro and in vivo and was compared with that of the soluble cytokines. The main observations were as follows: (a) The mean encapsulation efficiency, as determined by bioassays, was 49-79%, depending on the formulation, for GM-CSF, and 48% for TNF-alpha; (b) some of the entrapped cytokine preparations displayed high stability at 4 degrees C, with < 30% loss of biologic activity during a 4-month period; (c) release of TNF-alpha, but not of GM-CSF, from the liposomes was required for their biological activity in vitro; (d) plasma half-lives (t1/2 alpha, t1/2 beta) and the area under the curve (AUC) of the entrapped cytokines were 10-20 times greater than those of the soluble cytokines; (e) the toxicity of liposomal TNF-alpha was one-third and one-seventh that of soluble TNF-alpha in normal and tumor-bearing mice, respectively; (f) administration of liposomal GM-CSF (5 x 10(4)-2 x 10(5) U, one to five times) to normal and 5-fluorouracil-treated mice led to a two- to fourfold increase in the absolute number of peritoneal and spleen leukocytes and of GM colony-forming cells in the spleen, as compared with the levels obtained using soluble GM-CSF; and (g) under the experimental conditions used, neither free nor liposomal GM-CSF significantly increased the absolute number of blood leukocytes, although liposomal GM-CSF markedly (threefold) enhanced the level of blood granulocytes. Collectively, these findings suggest that liposome-entrapped GM-CSF and TNF-alpha may be more efficacious immunomodulators than the soluble cytokines.
Authors:
E Kedar; O Palgi; G Golod; I Babai; Y Barenholz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of immunotherapy (Hagerstown, Md. : 1997)     Volume:  20     ISSN:  1524-9557     ISO Abbreviation:  J. Immunother.     Publication Date:  1997 May 
Date Detail:
Created Date:  1997-07-30     Completed Date:  1997-07-30     Revised Date:  2008-03-18    
Medline Journal Info:
Nlm Unique ID:  9706083     Medline TA:  J Immunother     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  180-93     Citation Subset:  IM    
Affiliation:
Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cytokines / pharmacokinetics*,  therapeutic use,  toxicity*
Drug Carriers
Female
Fibrosarcoma / secondary,  therapy
Granulocyte-Macrophage Colony-Stimulating Factor / pharmacokinetics*,  therapeutic use,  toxicity*
Hematopoiesis / drug effects,  immunology
Humans
Immunosuppressive Agents / pharmacology
Liposomes / chemistry,  pharmacokinetics,  therapeutic use*
Lung Neoplasms / secondary,  therapy
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Recombinant Proteins / pharmacokinetics,  therapeutic use,  toxicity
Sarcoma, Experimental / therapy
Solubility
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha / pharmacokinetics*,  therapeutic use,  toxicity*
Chemical
Reg. No./Substance:
0/Cytokines; 0/Drug Carriers; 0/Immunosuppressive Agents; 0/Liposomes; 0/Recombinant Proteins; 0/Tumor Necrosis Factor-alpha; 83869-56-1/Granulocyte-Macrophage Colony-Stimulating Factor

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