Delivery of cytokines by liposomes. I. Preparation and characterization of interleukin-2 encapsulated in long-circulating sterically stabilized liposomes.
In an attempt to enhance the therapeutic efficacy of interleukin-2 (IL-2), recombinant human IL-2 was encapsulated either in large conventional liposomes or in small (mean diameter 65 nm), unilamellar, long-circulating, extravasating liposomes [referred to as sterically stabilized liposomes (SSLs)]. The SSL-IL-2 activity was assessed in vitro and in mice in comparison with soluble IL-2, IL-2 in conventional liposomes (non-SSL-IL-2), and pegilated IL-2 (PEG-IL-2). The main observations were as follows: (a) SSLs were far better carriers than conventional liposomes with regard to encapsulation efficiency and pharmacokinetics; (b) > 85% of IL-2 biological activity was consistently encapsulated in SSLs; (c) SSL-IL-2 was much more stable than soluble IL-2 at 4 and 37 degrees C; (d) SSL-IL-2, but not "empty" liposomes, bound in vitro to IL-2 receptor-bearing T-cells, indicating that the domain of the cytokine molecule involved in binding to the receptor is exposed on the outer liposome membrane; (e) release of IL-2 from the liposomes was not required for its in vitro biological activity; (f) plasma half-lives (t1/2 alpha, t1/2 beta) and area under the curve (AUC) of SSL-IL-2 were 10-30 times greater than those of soluble IL-2 and similar to those of PEG-IL-2; and (g) IL-2 is released from the SSLs in vivo with a t1/2 of approximately 40 min, although the SSL-IL-2s retained their steric stabilization in the plasma for > 4 h, with little liposome accumulation in the reticuloendothelial system. These data, together with the improved immunomodulatory and antitumor activity of SSL-IL-2 in mice, suggest that SSL-IL-2 might be a therapeutic agent superior to soluble IL-2.
Kedar
E
E
Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Rutkowski
Y
Y
Braun
E
E
Emanuel
N
N
Barenholz
Y
Y
D000818:Animals; D002460:Cell Line; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004355:Drug Stability; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
D004337:Drug Carriers; D007376:Interleukin-2; D008081:Liposomes