title: The nanoparticulation by octaarginine-modified liposome improves α-galactosylceramide-mediated antitumor therapy via systemic administration.
abstract: Alpha-galactosylceramide (αGC), a lipid antigen present on CD1d molecules, is predicted to have clinical applications as a new class of adjuvant, because αGC strongly activates natural killer T (NKT) cells which produce large amounts of IFN-γ. Here, we incorporated αGC 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 αGC (αGC/R8-Lip) failed to improve the immune responses mediated by αGC compared with soluble αGC in vivo, although αGC/R8-Lip drastically enhanced αGC presentation on CD1d in antigen presenting cells in vitro. Thus, we optimized the αGC/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-γ. The optimization led to the accumulation of αGC/R8-Lip in the spleen and a positive therapeutic effect against highly malignant B16 melanoma cells. The optimized αGC/R8-Lip also enhanced αGC 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 αGC therapy.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Daiki
authors.initials: D
authors.lastname: Yamazaki
authors.forename: Jun
authors.initials: J
authors.lastname: Yamauchi
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D055610:Antigens, CD1d / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D007371:Interferon-gamma / Q000276:immunology; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D055611:Natural Killer T-Cells / Q000276:immunology; D009842:Oligopeptides / Q000737:chemistry; D013154:Spleen / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; D000970:Antineoplastic Agents; C584692:CD1d antigen, mouse; D005699:Galactosylceramides; D008081:Liposomes; D009842:Oligopeptides; C493154:alpha-galactosylceramide; C448619:octaarginine; D007371:Interferon-gamma
keywords: Alpha-galactosylceramide (PubChem CID: 2826713); Cancer immunotherapy; Cell penetrating peptide; Liposome; Natural killer T cell