期刊
JOURNAL OF CONTROLLED RELEASE
卷 171, 期 2, 页码 216-224出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2013.07.004
关键词
Liposome; Cancer immunotherapy; Cell penetrating peptide; Natural killer T cell
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Grants-in-Aid for Scientific Research [24790037] Funding Source: KAKEN
Alpha-galactosylceramide (alpha GC), a lipid antigen present on CD1d molecules, is predicted to have clinical applications as a new class of adjuvant, because alpha GC strongly activates natural killer T (NKT) cells which produce large amounts of IFN-gamma. Here, we incorporated alpha GC into stearylated octaarginine-modified liposomes (R8-Lip), our original delivery system developed for vaccines, and investigated the effect of nanoparticulation. Unexpectedly, the systemic administered R8-Lip incorporating alpha GC (alpha GC/R8-Lip) failed to improve the immune responses mediated by alpha GC compared with soluble alpha GC in vivo, although alpha GC/R8-Lip drastically enhanced alpha GC presentation on CD1d in antigen presenting cells in vitro. Thus, we optimized the alpha GC/R8-Lip in vivo to overcome this inverse correlation. In optimization in vivo, we found that size control of liposome and R8-modification were critical for enhancing the production of IFN-gamma. The optimization led to the accumulation of alpha GC/R8-Lip in the spleen and a positive therapeutic effect against highly malignant B16 melanoma cells. The optimized alpha GC/R8-Lip also enhanced alpha GC presentation on CD1d in antigen presenting cells and resulted in an expansion in the population of NKT cells. Herein, we show that R8-Lip is a potent delivery system, and size control and R8-modification in liposomal construction are promising techniques for achieving systemic alpha GC therapy. (C) 2013 The Authors. Published by Elsevier B. V. All rights reserved.
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