Shimizu Takeshi, Kishida Tsunao, Hasegawa Urara, Ueda Yuji, Imanishi Jiro, Yamagishi Hisakazu, Akiyoshi Kazunari, Otsuji Eigo, Mazda Osam
Department of Surgery, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602-8566, Japan.
Biochem Biophys Res Commun. 2008 Mar 7;367(2):330-5. doi: 10.1016/j.bbrc.2007.12.112. Epub 2007 Dec 26.
For a valid cytokine immunotherapy of malignancies, a suitable delivery system that ensures slow-release of cytokines is required, because short half-life in vivo of the molecules ruins therapeutic efficacy while causing severe systemic toxic effects. We previously showed that the cholesterol-bearing pullulan (CHP)-based hydrogel nanoparticles, or nanogel, encapsulates, stabilizes and releases various molecules. Here we applied this nanogel to administration in vivo of interleukin-12 (IL-12). Recombinant murine IL-12 (rmIL-12) was successfully incorporated into CHP nanogel simply by incubated with CHP at room temperature. After subcutaneously injected into mice, the CHP/rmIL-12 complex led to a prolonged elevation in IL-12 concentration in the sera. Repetitive administrations of the CHP/rmIL-12, but not rmIL-12 alone, induced drastic growth retardation of preestablished subcutaneous fibrosarcoma without causing any serious toxic event. The present study proposes a novel therapeutic intervention technology, taking advantage of slow and sustained release of bioactive cytokines from the self-assembling biocompatible nanoparticles.
对于有效的恶性肿瘤细胞因子免疫疗法，需要一种合适的递送系统来确保细胞因子的缓慢释放，因为这些分子在体内的半衰期短会破坏治疗效果，同时导致严重的全身毒性作用。我们之前表明，基于含胆固醇支链淀粉（CHP）的水凝胶纳米颗粒，即纳米凝胶，能够包封、稳定并释放各种分子。在此，我们将这种纳米凝胶应用于白细胞介素-12（IL-12）的体内给药。重组小鼠IL-12（rmIL-12）只需在室温下与CHP孵育，就能成功地被包入CHP纳米凝胶中。皮下注射到小鼠体内后，CHP/rmIL-12复合物使血清中IL-12浓度长时间升高。重复给予CHP/rmIL-12，而非单独给予rmIL-12，可诱导预先建立的皮下纤维肉瘤显著生长迟缓，且未引发任何严重的毒性事件。本研究利用自组装生物相容性纳米颗粒缓慢持续释放生物活性细胞因子，提出了一种新型治疗干预技术。
