The nanoparticulation by octaarginine-modified liposome improves α-galactosylceramide-mediated antitumor therapy via systemic administration
The nanoparticulation by octaarginine-modified liposome improves α-galactosylceramide-mediated antitumor therapy via systemic administration
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DOI：
10.1016/j.jconrel.2013.07.004
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发表时间：
2013-10-28
影响因子：
10.8
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
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作者：
Nakamura, Takashi;Yamazaki, Daiki;Harashima, Hideyoshi
α-半乳糖神经酰胺（α-GC），一种存在于CD 1d分子上的脂质抗原，预计将作为一类新的佐剂具有临床应用，因为α-GC强烈激活产生大量IFN-γ的自然杀伤T（NKT）细胞。在这里，我们将α GC纳入硬脂酰化辛炔改性脂质体（R8-Lip），我们最初开发的疫苗输送系统，并研究了纳米颗粒化的效果。出乎意料的是，与体内可溶性α GC相比，全身施用的掺入α GC的R8-Lip（α GC/R8-Lip）未能改善由α GC介导的免疫应答，尽管α GC/R8-Lip在体外显著增强了抗原呈递细胞中α GC在CD 1d上的呈递。因此，我们在体内优化了α GC/R8-Lip以克服这种逆相关性。在体内优化中，我们发现脂质体的尺寸控制和R8修饰对于提高IFN-γ的产生是关键的。优化导致α GC/R8-Lip在脾脏中的积累和对高度恶性B16黑素瘤细胞的积极治疗效果。优化的α GC/R8-Lip还增强了抗原呈递细胞中CD 1d上的α GC呈递，并导致NKT细胞群体的扩增。在本文中，我们表明，R8-Lip是一种有效的递送系统，并且脂质体构建中的尺寸控制和R8修饰是实现全身性α GC治疗的有前途的技术。(C)2013作者由Elsevier B出版。V.保留所有权利。
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.