TY - JOUR
T1 - Delivery of Cytokines by Liposomes. I. Preparation and Characterization of Interleukin-2 Encapsulated in Long-Circulating Sterically Stabilized Liposomes
AU - Kedar, Eli
AU - Rutkowski, Yaron
AU - Braun, Efrat
AU - Emanuel, Noam
AU - Barenholz, Yechezkel
PY - 1994/7
Y1 - 1994/7
N2 - 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°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 (t ½ α, t 1½ β) 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 1 ½ of ~ 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.
AB - 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°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 (t ½ α, t 1½ β) 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 1 ½ of ~ 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.
KW - Cytokines
KW - Interleukin-2
KW - Liposomes
KW - Pegilated interleukin-2
KW - ¯
UR - http://www.scopus.com/inward/record.url?scp=0028242318&partnerID=8YFLogxK
U2 - 10.1097/00002371-199407000-00005
DO - 10.1097/00002371-199407000-00005
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 8081559
AN - SCOPUS:0028242318
SN - 1524-9557
VL - 16
SP - 47
EP - 59
JO - Journal of Immunotherapy
JF - Journal of Immunotherapy
IS - 1
ER -