Construction of a synergistic photothermic/chemotherapeutic nanosystem for anti-tumor and study of its drug controlled release behavior
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摘要: 传统治疗肿瘤的方式包括手术、放疗和化疗。手术治疗创伤大、易复发，放疗周期过长，尽管化疗被认为是消灭肿瘤细胞的首选但其存在着明显的毒副作用，长期化疗会严重影响患者的生存质量。因而，设计一种响应性功能载体实现抗肿瘤药物的高效运输及协同抑瘤在临床上具有广阔的前景。本研究以CuS为光热剂，采用溶剂热及去模板法在CuS表面包被上介孔二氧化硅(mSiO2)，借助mSiO2的大比表面积制备出高负载盐酸阿霉素(DOX)的纳米药物体系(CuS@mSiO2-DOX)。XRD、UV-Vis、SEM、TEM及DLS结果证实成功的合成了颗粒尺寸约为300-400 nm的CuS@mSiO2-DOX纳米体系，且DOX的负载效率可高达99.76%。CuS@mSiO2-DOX在pH=5.5、t=45℃的条件下24 h时药物释放率达到63.44%，相比正常生理环境(pH=7.4、t=35℃)释放率提高了近20倍，呈现出明显的pH及温度响应释放特性。对纳米载药体系CuS@mSiO2的光热性能及体外细胞毒性进行了测试，结果显示CuS@mSiO2 表现出良好的光热稳定性、光热转换效率达到31.67%，且对正常的人肝细胞(HL-7702)呈低毒性。CuS@mSiO2纳米体系具有较好的生物相容性、良好的光热转换及载药性能，吸附DOX后体系表现出优异的pH及激光响应型药物控释性能，在联合光热-化疗协同抗肿瘤领域有望得到广泛应用。Abstract: Traditional methods of cancer treatment include surgery, radiotherapy, and chemotherapy. The surgical treatment is highly traumatic and easy to recur, while the period of radiotherapy is too long. Although chemotherapy is considered as the first choice to destroy tumor cells, it has obvious toxic and side effects, and the long-term chemotherapy can seriously affect the quality of the patients’ life. In this study, CuS was selected as a photothermal agent, and mesoporous silica (mSiO2) was coated on the surface of CuS using the solvothermal and template removal methods. With the aid of the large specific surface area of mSiO2, a highly doxorubicin hydrochloride (DOX) loaded nanodrug system was prepared (CuS@mSiO2-DOX). XRD, UV-Vis, SEM, TEM, and DLS results jointly confirm that the CuS@mSiO2-DOX nanosystem with a particle size of approximately 300-400 nm is successfully synthesized, and the loading efficiency of DOX in this system can reach up to 99.76%. The 24 h-drug release rate of CuS@mSiO2-DOX reaches 63.44% under the conditions of pH=5.5 and t=45℃, which is nearly 20 times higher than that under the normal physiological environment (pH=7.4 and t=35℃), indicating that the CuS@mSiO2-DOX nanosystem possesses obvious pH and temperature responsive release characteristics. In addition, the photothermal performance and in-vitro cytotoxicity of the CuS@mSiO2 nanodrug delivery system was tested, and the results show that CuS@mSiO2 exhibits a good photothermal stability with a photothermal conversion efficiency of 31.67%, and which also reveals low toxicity to normal human liver cells (HL-7702). CuS@mSiO2 nanosystem has good biocompatibility, outstanding photothermal conversion and drug loading properties, and after DOX adsorption, the system exhibits excellent pH and laser responsive drug controlled release performance, which is expected to be widely used in the field of combining the photothermal-chemotherapy to synergistically resist tumor.
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Key words:
- biomedical materials /
- tumor /
- nanosystems /
- photo-thermal /
- chemotherapy /
- drug controlled release /
- mesoporous silica /
- CuS
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图 1 CuS@mSiO2-盐酸阿霉素(DOX)的制备过程示意图
Figure 1. A schematic representation of the preparation process of CuS@mSiO2- doxorubicin hydrochloride (DOX)
图 2 CuS、CuS@mSiO2、CuS@mSiO2-DOX的XRD光谱
Figure 2. XRD spectra of CuS, CuS@mSiO2, and CuS@mSiO2-DOX
图 3 CuS、CuS@mSiO2和CuS@mSiO2-DOX的UV-vis-NIR吸收光谱
Figure 3. UV-vis-NIR absorption spectra of CuS, CuS@mSiO2 and CuS@mSiO2-DOX
图 4 (a)CuS纳米颗粒形貌；(b)CuS@mSiO2纳米颗粒形貌；(c)CuS@mSiO2-DOX纳米颗粒形貌；(d)CuS纳米颗粒TEM明场像，右上方嵌入图为CuS颗粒内部的高分辨像；(e)CuS@mSiO2纳米颗粒的TEM明场像；(f)CuS@mSiO2-DOX 纳米颗粒的TEM明场像
Figure 4. Surface morphological images of (a) CuS NPs, (b) CuS@mSiO2 NPs and (c) CuS@mSiO2-DOX NPs; (d) TEM bright field image of CuS NPs, the inset in the upper right corner is the high resolution image inside a typical CuS NP, and TEM bright-field images of (e) CuS@mSiO2 NPs and (f) CuS@mSiO2-DOX NPs
图 5 (a)CuS，(b)CuS@mSiO2和(c)CuS@mSiO2-DOX纳米体系的粒径分布
Figure 5. Size distribution of (a) CuS, (b) CuS@mSiO2, and (c) CuS@mSiO2-DOX nanosystems
图 6 CuS@mSiO2纳米体系对HL-7702细胞的MTT毒性测试
Figure 6. Effect of CuS@mSiO2 nanosystem on HL-7702 cells viability by MTT assay
图 8 不同pH和温度条件下的CuS@mSiO2-DOX的药物释放率曲线
Figure 8. Drug release rate curves for CuS@mSiO2-DOX under different pH and temperature conditions
图 9 (a)0.5 mg·ml−1 CuS@mSiO2激光(808 nm, 1.5 W·cm−2)照射5 min、冷却15 min循环5次的温度变化曲线；(b)不同浓度的CuS@mSiO2纳米体系溶液在激光(808 nm, 1.5 W·cm−2)照射下的温度变化曲线；(c)从图a得到的时间常数τs；(d)不同浓度的CuS@mSiO2-DOX纳米体系溶液在激光(808 nm, 1.5 W·cm−2)照射下的温度变化曲线及激光照射前后CuS@mSiO2-DOX纳米体系溶液颜色变化插图；(e)0.5 mg·ml−1 CuS@mSiO2-DOX激光(808 nm, 1.5 W·cm−2)照射5 min，冷却15 min温度变化曲线；(f)从图e得到的时间常数τs
Figure 9. (a) Temperature change curve of 0.5 mg·ml−1 CuS@mSiO2 under laser (808 nm,1.5 W·cm−2) irradiation for 5 min and cooled for 15 min for 5 cycles; (b) Temperature change curves of different concentrations of CuS@mSiO2 solutions under laser (808 nm,1.5 W·cm−2) irradiation; (c) The time constant τs obtained from (a); (d) Temperature change curves of different concentrations of CuS@mSiO2-DOX solutions under laser (808 nm,1.5 W·cm−2) irradiation and the inset shows color change of CuS@mSiO2-DOX solutions before and after laser irradiation; (e) Temperature change curve of 0.5 mg·ml−1 CuS@mSiO2-DOX under laser (808 nm,1.5 W·cm−2) irradiation for 5 min and cooled for 15 min; (f) The time constant τs obtained from (e)
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