Biodistribution and tumor localization of stealth liposomal tumor necrosis factor-alpha in soft tissue sarcoma bearing rats.
The blood residence half-life and organ distribution of recombinant human tumor necrosis factor-alpha (TNF-alpha) encapsulated in sterically stabilized liposomes, were investigated in rats bearing a soft tissue sarcoma in the hind leg. We studied the decay in blood concentration of "empty" liposomes using the aqueous marker 67gallium-desferal, as well as the blood concentration of soluble TNF-alpha and liposome encapsulated TNF-alpha using l25I. Encapsulation efficacy of TNF-alpha was 24%. The pharmacokinetics of TNF-alpha were markedly altered after encapsulation in liposomes, with a 33-fold increase in mean residence time of TNF-alpha in the blood, and a concomitant 14-fold increase in the area under the plasma concentration vs. time curve for liposomal TNF-alpha. Although the liposomes exhibit Stealth characteristics, uptake by mononuclear phagocyte-rich organs (e.g., liver and spleen) was noticeable, especially at later time points. Encapsulation of TNF-alpha in sterically stabilized liposomes resulted in a marked increase in localization of the cytokine in tumor measured as total uptake over time. However, peak TNF-alpha concentration levels in tumor were not significantly enhanced compared with free TNF-alpha. Besides the augmented localization of TNF-alpha after encapsulation in sterically stabilized liposomes, a diminished toxicity was observed.
Department of Surgical Oncology, University Hospital Rotterdam and Dijkzigt/Daniel den Hoed Cancer Center, The Netherlands.
A H
AH
van der Veen
A M
AM
Eggermont
A L
AL
Seynhaeve
van Tiel
T L
TL
ten Hagen
D000818:Animals; D004337:Drug Carriers; D006207:Half-Life; D008081:Liposomes; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D012513:Sarcoma, Experimental / Q000378:metabolism*; D012983:Soft Tissue Neoplasms / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D004337:Drug Carriers; D008081:Liposomes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha