Development of tumor-specific caffeine-potentiated chemotherapy using a novel drug delivery system with Span 80 nano-vesicles.
Development of tumor-specific caffeine-potentiated chemotherapy using a novel drug delivery system with Span 80 nano-vesicles.
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DOI：
10.3892/or.2015.3761
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发表时间：
2015-04
期刊：
影响因子：
4.2
通讯作者：
Miura H
中科院分区：
文献类型：
--
作者：
Nakata H;Miyazaki T;Iwasaki T;Nakamura A;Kidani T;Sakayama K;Masumoto J;Miura H
近年来，咖啡因的化疗对骨肉瘤表现出很高的疗效，尽管也观察到了副作用。最近，我们开发了一种新的药物传递系统（DDS）与非离子囊泡制备的司盘80具有有前途的物理化学性质作为一个有吸引力的可能替代常用的脂质体。在此，我们证明了通过具有Span 80纳米囊泡的新型DDS施用的肿瘤特异性咖啡因增强的小鼠骨肉瘤化疗显示出显著的抗肿瘤作用以及有限的不良反应。将骨肉瘤细胞系LM 8移植到C3 H/HeJ小鼠中，然后给予治疗剂。使用异环磷酰胺（IFO）以及咖啡因作为增强剂。新鲜制备含有IFO和/或咖啡因的Span 80囊泡。在第0、2和4天，向小鼠施用不同的药剂组合：单独的IFO（直接i. v.），IFO囊泡（IV）、IV +咖啡因、IV +咖啡因囊泡（CV）、单独的PBS囊泡（PV）和作为阴性对照的单独的PBS（PBS i. v.）。然后，在第7天处死小鼠。体外抗肿瘤作用也进行了分析。此外，还进行了生育力检查。在体外，IV+CV的组合在早期阶段显示出显著的细胞凋亡诱导。与其他组相比，IV+CV组的肿瘤体积显著减小。组织学分析显示，IV和IV+CV组的存活肿瘤面积显著较低。IFO直接i. v.组显示一定程度的肾损伤以及精子发生的显著抑制，而IV或IV+CV组显示无显著变化。生育力试验显示，IV+CV给药的雄性小鼠生育力正常，在其后代中未检测到畸形。该DDS模型对转移性骨肉瘤的治疗具有潜在的临床应用价值。
In recent years, chemotherapy with caffeine has manifested potently high efficacy against osteosarcoma, although adverse effects have been observed. Recently, we developed a novel drug delivery system (DDS) with nonionic vesicles prepared from Span 80 which have promising physicochemical properties as an attractive possible alternative to commonly used liposomes. Herein, we demonstrated that tumor-specific caffeine-potentiated chemotherapy for murine osteosarcoma administered by a novel DDS with Span 80 nano-vesicles showed significant antitumor effects as well as limited adverse effects. The osteosarcoma cell line, LM8, was transplanted into C3H/HeJ mice which then were administered therapeutic agents. Ifosfamide (IFO) was employed as well as caffeine as an enhancer. Span 80 vesicles containing IFO and/or caffeine were freshly prepared. On days 0, 2 and 4, different combinations of the agents were administered to mice: IFO alone (direct i.v.), IFO vesicles (IV), IV + caffeine, IV + caffeine vesicles (CV), PBS alone vesicles (PV), and PBS alone as negative control (PBS i.v.). Then, the mice were sacrificed on day 7. Antitumor effects of the reagents were also analyzed in vitro. Moreover, fertility examination was performed. In vitro, a combination of IV+CV showed significant induction of apoptosis in the early phase. Tumor volumes in the IV+CV group were significantly reduced compared with the other groups. Histological analyses showed that the IV and IV+CV groups had significantly lower viable tumor areas. The IFO direct i.v. group showed a certain grade of renal injury as well as marked suppression of spermatogenesis, while the IV or IV+CV group showed no marked changes. The fertility test revealed that the male mice with IV+CV administration had normal fertility, and no malformations were detected in their progeny. This DDS model is of potential importance for clinical application in the therapy of metastatic osteosarcoma.
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