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摘要:目的
研究仿生姜黄素介导的声动力治疗在抗恶性黑色素瘤治疗中的作用，旨在为恶性黑色素瘤的治疗提供新的策略。
方法运用超声声振法包覆黑色素瘤细胞膜在姜黄素表面，形成仿生姜黄素；运用TEM观察仿生姜黄素的形貌；流式细胞术分析体外靶向性、细胞凋亡及胞内产活性氧（reactive oxygen species, ROS）的效果。体外实验分为对照组、US组、姜黄素组、仿生姜黄素组和仿生姜黄素+US组，每组3只小鼠；运用病理HE染色评估仿生姜黄素的体内安全性；运用HE染色、CD31染色、Ki67染色、TUNEL染色评估超声联合仿生姜黄素体内抗黑色素瘤治疗的效果。
结果仿生姜黄素形貌较均一，具有壳核结构；FlowJo流式细胞分析结果显示仿生姜黄素可以更好地被黑色素瘤细胞摄取；细胞凋亡率显示对照组（10.30±0.61）%，单独超声（US）组（10.41±3.13）%，姜黄素组（24.97±1.38）%，仿生姜黄素组（31.39±3.84）%，仿生姜黄素+US组（40.89±0.79）%，仿生姜黄素+US组细胞凋亡率高于其余各组（P<0.05）；ROS流式细胞分析结果显示，与对照组相比，US组荧光强度值几乎无增加，其余组荧光强度均有不同程度的增加；仿生姜黄素组荧光强度〔（1.10±0.38）%〕与姜黄素组〔（0.73±0.26）%〕比较无明显差异（P>0.05），仿生姜黄素+US组荧光强度值〔（3.35±0.04）%〕高于其余各组（P<0.05）。HE染色显示各治疗组心、肝、脾、肺、肾组织形态未见明显异常，肿瘤HE染色显示仿生姜黄素+US组细胞形态变化最大，其次是仿生姜黄素组、姜黄素组，US组肿瘤细胞形态未见明显异常；CD31染色、Ki67染色、TUNEL染色分别显示仿生姜黄素+US组棕色区域面积最大、红色荧光数目最多、绿色荧光数目最多，其次是仿生姜黄素组、姜黄素组。
结论仿生姜黄素形貌均一，具有壳核结构，具有良好的靶向性；联合超声后，具有良好的体内外抗肿瘤治疗效果。
Abstract:ObjectiveTo study the role of curcumin-mediated sonodynamic therapy in the treatment of malignant melanoma, and to provide a new strategy for the treatment of malignant melanoma.
MethodsThe ultrasonic sound and vibration method was applied to coat curcumin with mouse melanoma cell membrane, thereby forming biomimetic curcumin. The morphology of biomimetic curcumin was observed by transmission electron microscope. Flow cytometry was used to analyze the effect of biomimetic curcumin in terms of in vitro targeting, apoptosis, and intracellular reactive oxygen species (ROS) production. The in vivo experiment was divided into control group, US group, turmeric group, imitation turmeric group, and imitation turmeric+US group, with 3 mice in each group. The in vivo safety of biomimetic curcumin was evaluated by HE staining. In addition, HE, CD31, Ki67, and TUNEL stainings were performed to evaluate the in vivo anti-melanoma therapeutic effect of ultrasound combined with biomimetic curcumin.
ResultsThe biomimetic curcumin had a generally uniform morphology and possessed a core-shell structure. Flow cytometry analysis performed with FlowJo showed that the biomimetic curcumin could be effectively taken up by melanoma cells. The apoptosis rate was (10.30±0.61)% in the control group, (10.41±3.13)% in the ultrasound group, (24.97±1.38)% in the curcumin group, (31.39±3.84)% in the biomimetic curcumin group, and (40.89±0.79)% in the biomimetic curcumin and ultrasound combination group. The apoptosis rate in the biomimetic curcumin and ultrasound combination group was higher than those in the other groups (P<0.05). The results of ROS flow cytometry showed that, compared with the control group, the ultrasound group demonstrated almost no increase in the fluorescence intensity, while the other groups showed an increase in the fluorescence intensity to varying degrees. There was no significant difference in the fluorescence intensity between the biomimetic curcumin group ([1.10±0.38]%) and the curcumin group ([0.73±0.26]%) (P>0.05). The fluorescence intensity of the biomimetic curcumin and ultrasound combination group ([3.35±0.04]%) was higher than those of the other groups (P<0.05). HE staining showed no obvious abnormalities in the morphology of heart, liver, spleen, lung, and kidney tissues in any of the treatment groups. HE staining showed the most significant changes in cell morphology in the biomimetic curcumin and ultrasound combination group, followed by the biomimetic curcumin group and the curcumin group. No obvious abnormalities in tumor cell morphology were observed in the ultrasound group. According to the respective results of CD31 staining, Ki67 staining, and TUNEL staining, the biomimetic curcumin and ultrasound combination group had the largest brown area, the highest number of red fluorescence, and the highest number of green fluorescence, followed by the biomimetic curcumin group and the curcumin group.
ConclusionThe biomimetic curcumin displays uniform morphology, a core-shell structure, and good targeting properties. When it is used in combination with ultrasound, biomimetic curcumin demonstrates a good anti-tumor therapeutic effect both in vivo and in vitro.
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Keywords:
- Biomimetic materials /
- Sonosensitizer /
- Malignant melanoma /
- Sonodynamic therapy
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图 1 姜黄素（A）与仿生姜黄素（B）的TEM图
Figure 1. TEM image of curcumin (A) and biomimetic curcumin (B)
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图 2 仿生姜黄素体外细胞实验结果
Figure 2. Results of biomimetic curcumin in vitro cell experiment
Cur: curcumin; US: ultrasound. A, Flow cytometry diagram of the cell phagocytosis of biomimetic curcumin; B, statistical analysis of cell apoptosis rate of cells treated with biomimetic curcumin combined with ultrasound (n=3); C, statistical analysis of intracellular ROS production in cells treated with biomimetic curcumin combined with ultrasound (n=3); D, experimental results of cell apoptosis after treatment with biomimetic curcumin combined with ultrasound; E, experimental results of intracellular ROS production after treatment with biomimetic curcumin combined with ultrasound. ** P<0.01, *** P<0.001.
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图 3 各治疗组脏器的 HE 染色图
Figure 3. The HE staining of organ tissues given different treatments
The abbreviations are explained in the note to Fig 2.
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