Development and Characterization of Liposomal Tumor Necrosis Factor (Tnf)

Abstract

Free and liposomal formulations of caprylated TNF-SAM2, a TNF mutant, were evaluated in both a canine model for TNF-induced hypotension and in the murine Meth A sarcoma model for efficacy. The liposomal formulations consisted of caprylated TNF-SAM2 either bound to the outer leaflet of small unilamellar vesicles (SUVs) or encapsulated in multilamellar vesicles (MLVs). Whereas systemic administration of parental TNF-a to anesthesized mongrel dogs resulted in acute shock with a precipitous fall in systemic arterial pressure (SAP), the SUV-TNF-SAM2 resulted in no net hypotension. Both the free and liposomal-TNF-SAM2 elicited a hyperdynamic response with tachycardia and elevated cardiac output and SAP, which was not observed with parental TNF-a. Two tail-vein injections of these formulations were administered 4–5 days apart to BALB/c mice in which Meth A sarcoma cells were previously implanted subcutaneously or intradermally. Free TNF-SAM2 at 4 × 10 U/mouse caused highly significani tumor control compared to PBS on days 5 and 12; however, substantial toxicity (-24% lethality; was observed at this level. The liposomal formulations of caprylated TNF-SAM2 demonstratec significant tumor control at all dose levels (up to 8 × 10 U/mouse) on day 12 (p<0.025) wit! either no or reduced lethality (0–15%); the tumor responses were comparable to those with fret TNF-SAM2. We conclude that the liposomal caprylated-TNF-SAM2 formulations exhibit; therapeutic index superior to that of free parental TNF-a or free TNF-SAM2.