WO2020172917A1 - 铜离子掺杂碳点、制备及其作为光动力治疗光敏剂的应用 - Google Patents
铜离子掺杂碳点、制备及其作为光动力治疗光敏剂的应用 Download PDFInfo
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- WO2020172917A1 WO2020172917A1 PCT/CN2019/078209 CN2019078209W WO2020172917A1 WO 2020172917 A1 WO2020172917 A1 WO 2020172917A1 CN 2019078209 W CN2019078209 W CN 2019078209W WO 2020172917 A1 WO2020172917 A1 WO 2020172917A1
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- carbon dots
- copper ion
- doped carbon
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B32/00—Carbon; Compounds thereof
- C01B32/90—Carbides
- C01B32/914—Carbides of single elements
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/34—Copper; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B32/00—Carbon; Compounds thereof
- C01B32/15—Nano-sized carbon materials
Definitions
- the invention relates to a copper ion-doped carbon dot, its preparation and its application as a photodynamic therapy photosensitizer, and belongs to the technical field of biomedical materials.
- Carbon dots are a new type of carbon nanomaterial with a size below 10nm. It has excellent properties such as high fluorescence quantum yield, good photostability, resistance to photobleaching, extremely low toxicity and easy functionalization, which can be used in biological and medical research.
- the field has broad application prospects, which can be applied to the fields of biological analysis and detection, biological imaging, cancer treatment, and nanomedicine.
- Photodynamic therapy is a new method of using laser to activate photosensitive drugs to treat tumors and other diseases. For example, irradiating the tumor site with a specific wavelength can activate the photosensitive drugs that selectively accumulate in the tumor tissue, trigger a photochemical reaction to produce singlet oxygen, and kill cancer cells.
- Photodynamic therapy has been used to treat a variety of diseases such as tumors, skin diseases, eye diseases, and acne. Compared with traditional tumor therapy, the advantage of photodynamic therapy is that it can be treated accurately and effectively, and the side effects of this therapy are small.
- the laser used in photodynamic therapy does not penetrate deep into the tissue.
- Intracavitary and deep tumors need to be irradiated by introducing optical fibers into the lesion site, which is difficult to operate.
- the tumor When the tumor is large in size, it needs to be irradiated at multiple points, which is more cumbersome.
- people who are allergic to photosensitizers and deep tumors that cannot be reached by optical fibers cannot be treated with this method.
- the present invention provides a copper ion-doped carbon dot, which has high efficiency in generating singlet oxygen, stable structure, and better application in photodynamic therapy.
- the present invention also provides the preparation method of the copper ion-doped carbon dots and its application as a photosensitizer for photodynamic therapy.
- the present invention adopts a method for preparing copper ion-doped carbon dots, using copper nitrate as a dopant, and forming a complex of polyacrylic acid and copper ions through in-situ polymerization as a precursor, and then heat Decarbonization generates carbonized products, which are then extracted and purified to obtain the carbon dots.
- the method for preparing copper ion-doped carbon dots specifically includes the following steps:
- step 2) Spread the powder A of step 2) in a crucible, put it into a muffle furnace, pyrolyze in an air atmosphere, take out the carbonized powder in the crucible, grind it in a mortar and ultrasonically disperse it in a certain amount of ultrapure multiple times Let stand in the water. Filter with suction, pour out the supernatant, put it into a dialysis bag with a certain molecular weight cut-off, dialyze in ultrapure water, and freeze-dry to obtain yellow-brown carbon dots.
- the temperature range of vacuum drying in the step 2) is 30-45°C.
- the heating rate is 2-10°C/min
- the pyrolysis temperature is 300-500°C
- the pyrolysis time is 1.5-2h.
- an organic aqueous microporous filter membrane with a pore size of 0.22 ⁇ m is used during suction filtration.
- the molecular weight cut-off of the dialysis bag is 500-1000
- the dialysis time is 48-72h
- the freeze-drying time is 56-72h
- a yellow-brown carbon dot is obtained.
- the present invention also provides a copper ion doped carbon dot obtained by the preparation method.
- the present invention also provides an application of copper ion-doped carbon dots prepared by the above preparation method as a photosensitizer for photodynamic therapy.
- the copper ion-doped carbon dots prepared by the present invention are not only easily dispersed in organic solvents such as absolute ethanol, N,N-dimethylformamide, dichloromethane, etc., but also can be better dispersed in water and phosphate buffer solutions (PBS), biological culture medium and other aqueous systems.
- organic solvents such as absolute ethanol, N,N-dimethylformamide, dichloromethane, etc.
- PBS phosphate buffer solutions
- the copper ion-doped carbon dots prepared by the present invention have a small average particle size, have abundant oxygen and nitrogen functional groups on the surface, and can be well dispersed in organic solvents such as ethanol, and are easy to passivate or modify the surface.
- Figure 1 is a high-resolution transmission electron microscope image of the copper ion doped carbon dots of the present invention
- Fig. 2 is the ultraviolet-visible absorption spectrum and fluorescence emission spectrum diagram of the copper ion-doped carbon dots in ultrapure water (excitation wavelength is 330nm);
- Figure 3 shows the EPR spectra of the TEMP trapping agent of the copper ion-doped carbon dots of the present invention under LED laser irradiation and without LED laser irradiation.
- Fig. 4 shows the results of testing the cytotoxicity using the MTT method after co-cultivating the copper-ion-doped carbon dots with different concentrations of the HeLa cells in the present invention for 24 hours;
- Figure 5 shows the results of the cytotoxicity test of the MTT method after co-cultivating the HeLa cells with different concentrations of copper ion-doped carbon dots of the present invention for 24 hours and then irradiating for 10 minutes.
- a method for preparing copper ion-doped carbon dots that can be used for photodynamic therapy specifically includes the following steps:
- step 3 Spread the powder A of step 2) in a crucible, put it into a muffle furnace, and pyrolyze in an air atmosphere at a heating rate of 10°Cmin -1 , a pyrolysis temperature of 400°C, and a pyrolysis time of 2h.
- the carbonized powder in the crucible was ground in a mortar and then dispersed in 20mL of ultrapure water by ultrasound several times, then left to stand, and filtered with an aqueous microporous membrane with a pore size of 0.22 ⁇ m. The supernatant was poured out and repeated 5 times.
- Put into a dialysis bag with a molecular weight cut-off of 500-1000 dialyzed in ultrapure water for 72 hours, and then freeze-dried for 72 hours to finally obtain yellow-brown carbon dots.
- the high-resolution transmission electron micrograph of the prepared copper ion-doped carbon dots is shown in Figure 1. It can be seen that the carbon dots have a similar spherical structure with a size of about 5 nm. There are obvious lattice diffraction fringes inside, indicating that the carbon dots Good crystallinity.
- Figure 2 shows the ultraviolet-visible absorption spectrum and fluorescence emission spectrum of copper ion-doped carbon dots in ultrapure water prepared by the present invention (excitation wavelength is 330nm), and the analysis shows that it shows bright green fluorescence under a 365nm ultraviolet lamp. Under the excitation of 330nm light, the copper ion-doped carbon dot aqueous solution has a fluorescence emission peak at 420nm.
- EPR electron paramagnetic resonance spectrometer
- a method for preparing copper ion-doped carbon dots that can be used for photodynamic therapy specifically includes the following steps:
- Vacuum filter the solution obtained above with an organic microporous filter membrane with a pore size of 0.22 ⁇ m collect the filter residue, disperse it in 20mL of ultrapure water, and then filter with an organic microporous filter membrane with a pore size of 0.22 ⁇ m. Collect the filter residue, repeat 5 times, dry the filter residue in vacuum at 30°C, and collect powder A;
- step 3 Spread the powder A of step 2) in a crucible, put it in a muffle furnace, and pyrolyze in an air atmosphere at a heating rate of 5°Cmin -1 , a pyrolysis temperature of 300°C, and a pyrolysis time of 1.5h.
- a method for preparing copper ion-doped carbon dots that can be used for photodynamic therapy specifically includes the following steps:
- Vacuum filter the solution obtained above with an organic microporous filter membrane with a pore size of 0.22 ⁇ m collect the filter residue, disperse it in 20mL of ultrapure water, and then filter with an organic microporous filter membrane with a pore size of 0.22 ⁇ m. Collect the filter residue, repeat 5 times, dry the filter residue in vacuum at 45°C, and collect powder A;
- step 3 Spread the powder A of step 2) in a crucible, put it into a muffle furnace, and pyrolyze in an air atmosphere at a heating rate of 2°Cmin -1 , a pyrolysis temperature of 500°C, and a pyrolysis time of 1.5h.
- the copper ion-doped carbon dots prepared by the invention are used as photosensitizers in photodynamic therapy to increase the amount of singlet oxygen generated under light, thereby improving the effect of photodynamic therapy, and can be applied to skin cancer, lung cancer, and pancreatic cancer , Esophageal cancer and brain glioma, as well as some skin diseases and ophthalmological diseases.
- Hela cell culture conditions In a 60nm cell culture dish, add 3 mL of DMEM culture solution containing 10% fetal bovine serum, and place it in a 37°C, 5% CO 2 constant temperature incubator. Hela is an adherent cell. When the cells grow to 80%, digest with 1 mL of 0.25% trypsin solution for 2 minutes. Use 1 mL of culture solution containing 10% fetal bovine serum to stop the trypsinization. Repeatedly pipetting the bottom cells of the dish to make it full dispersion. Centrifuge at 100 rpm for 5 min, discard the supernatant, add fresh medium to the cell pellet, pipette evenly and transfer to a new culture dish at a ratio of 1:4 to continue culturing for later use.
- the MTT method was used to detect the cytotoxicity of the prepared copper ion-doped carbon dots.
- the MTT method is a common method for detecting cell survival and growth.
- the detection principle is: the succinate dehydrogenase in the mitochondria of living cells can reduce the exogenous MTT (thiazole blue) into water-insoluble blue-purple crystal formazan It is deposited in the cells, but the dead cells have no such function. Then use DMSO (dimethyl sulfoxide) to dissolve the formazan in the cells, and then use an enzyme-linked immunoassay to measure the absorbance at 540nm or 720nm. This indirectly reflects the cell survival rate.
- MTT thiazole blue
- DMSO dimethyl sulfoxide
- the results of MTT cytotoxicity test showed that Hela cells were co-cultured with copper ion-doped carbon dots of different concentrations for 24 hours, and then illuminated for 10 minutes. The results are shown in Figure 5. It can be seen from Figure 5 that the cytotoxicity of copper ion-doped carbon dots with different concentrations is significantly greater than that of non-illuminated under dark conditions. When the concentration of copper ion-doped carbon dots is 0.25 mg mL -1 , the cytotoxicity of the The cytotoxicity under dark conditions is 1.5 times. It shows that the copper ion doped carbon dot has the value of photodynamic therapy.
- the preparation method of the present invention has the advantages of simple reaction steps, low cost, environmental protection and the like.
- the prepared copper ion-doped carbon dots have uniform particle size, stable structure, and fluorescence performance.
- the copper ion-doped carbon dots prepared by the invention can generate singlet oxygen under visible light and near-infrared wavelength light irradiation. They are ideal photosensitizers for photodynamic therapy and are suitable for skin cancer, lung cancer, pancreatic cancer, and esophageal cancer. And glioma, as well as some skin diseases and ophthalmological diseases, have broad application prospects.
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Biochemistry (AREA)
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- Ophthalmology & Optometry (AREA)
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- Medicinal Preparation (AREA)
Abstract
本发明公开一种铜离子掺杂碳点及其制备方法，属于生物医用材料领域，利用硝酸铜为掺杂剂，通过原位聚合生成聚丙烯酸与铜离子的络合物作为前驱体，然后经过热解碳化生成碳化产物，再经过提取、纯化得到所述碳点。本发明制得的铜离子掺杂碳点用于光动力治疗时，不需要光动力治疗和光热治疗协同作用，操作过程简单，适用于皮肤癌、肺癌、胰腺癌、食道癌和脑胶质瘤，以及一些皮肤病和眼科疾病等治疗过程。
Description
本发明涉及一种铜离子掺杂碳点、制备及其作为光动力治疗光敏剂的应用，属于生物医用材料技术领域。
碳点是一种新型的碳纳米材料，尺寸在10nm以下，具有荧光量子产率高、光稳定性好、抗光漂白、毒性极低和易于功能化等优异性能，从而在生物学和医学研究领域有广阔的应用前景，可应用于生物分析与检测、生物成像、癌症治疗和纳米药物等领域。
光动力疗法是用激光活化光敏药物来治疗肿瘤等疾病的一种新方法。例如，用特定波长照射肿瘤部位，能使选择性聚集在肿瘤组织的光敏药物活化，引发光化学反应产生单线态氧，杀死癌细胞。光动力疗法已被用于治疗多种肿瘤、皮肤病、眼科疾病、和痤疮等疾病。与传统肿瘤疗法相比，光动力疗法的优势在于能够进行精确有效地治疗，且这种疗法的副作用很小。
目前，在光动力治疗中使用的激光在组织中的穿透力不深，腔内及深部肿瘤需要通过光导纤维导入病灶部位来照射，操作难度较大。当肿瘤体积较大时，需列阵多点照射，较为烦琐，而且，在治疗后需较长时间避免强光照射，还可能数天内出现局部的反应性水肿。另外，光敏剂过敏者以及光导纤维不能到达的深部肿瘤均不能使用该法治疗。
现有报道的铜氮共掺杂碳点(Guo,Xiao-Lu,et al."A novel strategy of transition-metal doping to engineer absorption of carbon dots for near-infrared photothermal/photodynamic therapies."Carbon 134(2018):519-530)，是采用乙二胺四乙酸二钠和氯化铜反应合成的。其得到的碳点中不仅掺杂了铜离子和氮原子，还含有金属钠离子，而且该碳点需要光动力和光热协同治疗才能产生作用，因此操作过程复杂繁琐，不利于实际应用。此外，在此过程中碳点的单线态氧产率不高，单一的光动力治疗效果欠佳。
发明内容
针对上述现有技术存在的问题，本发明提供一种铜离子掺杂碳点，产生单线态氧效率高，结构稳定，应用于光动力治疗效果更佳。
本发明还同时提供了上述铜离子掺杂碳点的制备方法和其作为光动力治疗光敏剂的应用。
为了实现上述目的，本发明采用的一种铜离子掺杂碳点的制备方法，利用硝酸铜为掺杂剂，通过原位聚合生成聚丙烯酸与铜离子的络合物作为前驱体，然后经过热解碳化生成碳化产物，再经过提取、纯化得到所述碳点。
作为改进，所述铜离子掺杂碳点的制备方法，具体包括以下步骤：
1)称取0.3mol L
-1丙烯酸、0.2mol L
-1硝酸铜溶液、过硫酸铵和水合肼，加至烧杯中，待反应一段时间后，溶液静置过夜；
2)将上述得到的溶液抽滤，收集滤渣，分散于一定量的超纯水中，抽滤，收集滤渣，在一定温度下真空干燥，收集粉末A；
3)将步骤2)的粉末A铺在坩埚中，放入马弗炉，在空气氛围下热解，取出坩埚中的碳化粉末，于研钵中研磨后超声多次分散于一定量的超纯水中，静置。抽滤，倒出上清液，装入一定截留分子量的透析袋，在超纯水中透析，冻干得到黄褐色的碳点。
作为改进，所述步骤1)中加入10-20mL丙烯酸、2-10mL硝酸铜溶液、10-30mL过硫酸铵和5-10mL水合肼，反应时间为25-40min。
作为改进，所述步骤2)中真空干燥的温度范围为30-45℃。
作为改进，所述步骤3)中升温速率为2-10℃/min，热解温度为300-500℃，热解时间为1.5-2h。
作为改进，所述步骤2)、步骤3)中抽滤时，采用孔径为0.22μm的有机水性微孔滤膜。
作为改进，所述步骤3)中透析袋截留分子量为500-1000，透析时间为48-72h，冻干时间为56-72h，最后得到黄褐色的碳点。
另外，本发明还提供了一种所述制备方法得到的铜离子掺杂碳点。
最后，本发明还提供了一种采用上述制备方法制得铜离子掺杂碳点作为光动力治疗光敏剂的应用。
与现有技术相比，本发明的有益效果是：
1)本发明制得铜离子掺杂碳点不仅易分散于无水乙醇、N,N-二甲基甲酰胺、二氯甲烷等有机溶剂，而且能较好地分散于水、磷酸盐缓冲溶液(PBS)、生物培养基等水溶液体系中。
2)本发明制得铜离子掺杂碳点的平均粒径小，表面具有丰富的含氧和含氮官能团，又可以在乙醇等有机溶剂中很好地分散，易于进行表面钝化或修饰。
3)采用可见光及近红外波长的光照射本发明制备的铜离子掺杂碳点时，可产生单线态氧，且单线态氧产率高达0.86，与目前用于光动力治疗的理想光敏剂玫瑰红(罗丹明6G CAS号989-38-8)相比，玫瑰红的单线态氧产率为0.75，基于此，本发明的铜离子掺杂碳点，能有效用于光动力治疗制剂尤其是光敏剂的制备。
4)本发明制得的铜离子掺杂碳点用于光动力治疗时，不需要光动力治疗和光热治疗协同作用，操作过程简单，有利于实际应用。
图1为本发明的铜离子掺杂碳点的高分辨透射电镜图；
图2为本发明的铜离子掺杂碳点在超纯水中的紫外-可见吸收光谱和荧光发射光谱图(激发波长为330nm)；
图3为本发明的铜离子掺杂碳点，分别在有LED激光照射和无LED激光照射的情况下，TEMP捕获剂的EPR光谱。
图4为本发明的不同浓度铜离子掺杂碳点与Hela细胞共培养24h后，采用MTT法测试细胞毒性的结果；
图5为本发明的不同浓度铜离子掺杂碳点与Hela细胞共培养24h后，再经光照10min的MTT法细胞毒性测试结果。
下述实施例是对于本发明内容的进一步说明以作为对本发明技术内容的阐释，但本发明的实质内容并不仅限于下述实施例所述，本领域的普通技术人员可以且应当知晓任何基于本发明实质精神的简单变化或替换均应属于本发明所要求的保护范围。
实施例1
一种可用于光动力治疗的铜离子掺杂碳点的制备方法，具体包括以下步骤：
1)称取15mL的0.3mol L
-1丙烯酸、5mL的0.2mol L
-1硝酸铜溶液、20mL过硫酸铵和10mL水合肼，加至烧杯中，待反应30min后将溶液静置过夜；
2)将上述得到的溶液用孔径为0.22μm的有机微孔滤膜真空抽滤，收集滤渣，分散于20mL的超纯水中，再用孔径为0.22μm的有机微孔滤膜真空抽滤，收集滤渣，重复5次，将滤渣在35℃下真空干燥，收集粉末A；
3)将步骤2)的粉末A铺在坩埚中，放入马弗炉，在空气氛围下热解，升温速率为10℃min
-1，热解温度为400℃，热解时间为2h，取出坩埚中的碳化粉末，于研钵中研磨后超声多次分散于20mL的超纯水中，静置，用孔径0.22μm的水性微孔滤膜真空抽滤，倒出上清液，重复5次，装入截留分子量为500-1000的透析袋，在超纯水中透析72h，之后冻干处理72h，最终得到黄褐色的碳点。
制得的铜离子掺杂碳点，其高分辨透射电镜图如图1所示，可见碳点形貌为类似球形结构，尺寸大约为5nm，内部呈现明显的晶格衍射条纹，说明该碳点结晶性较好。
另外，图2为本发明制得铜离子掺杂碳点在超纯水中的紫外可见吸收光谱和荧光发射光谱图(激发波长为330nm)，分析可知在365nm的紫外灯下呈明亮的绿色荧光，在330nm光激发下，铜离子掺杂碳点水溶液在420nm有一个荧光发射峰。
最后，检测所制备的铜离子掺杂碳点在水溶液中产生的单线态氧，步骤如下：
(a)称取制备好的铜离子掺杂碳点0.0200g溶解在1mL的超纯水中，用超纯水稀释100倍，得到0.2mg mL
-1的铜离子掺杂碳点溶液；
(b)向2mL离心管A中加入上述所制取的0.2mg mL
-1的铜离子掺杂碳点溶液1mL，再向离心管A中加入2,2,6,6-四甲基哌啶(TEMP)10μL，离心管A用LED灯(激发波长300-500nm)光照10min；
(c)用直径0.55mm的毛细管抽取30-50μL待测样品，将毛细管放入测试管底部，将样品调节到测试管中央再放入电子顺磁共振波谱仪(EPR)中，EPR管放置在谐振腔中心位置；EPR测定参数如下：中心磁场3430.00Gauss，扫场宽度60.00Gauss，扫描次数10，时间常数10.49ms；
(d)另外，向2mL离心管B中加入上述所制取的0.2mg mL
-1的铜离子掺杂碳 点溶液1mL，再向离心管B中加入TEMP 10μL，离心管B置于黑暗条件下，重复操作步骤(c)，所得出的结果如图3所示。分析图3可知，铜离子掺杂碳点在LED激光(激发波长300-500nm)照射下能产生单线态氧，而在黑暗条件只有少量甚至没有单线态氧的产生。
实施例2
一种可用于光动力治疗的铜离子掺杂碳点的制备方法，具体包括以下步骤：
1)称取10mL的0.3mol L
-1丙烯酸、2mL的0.2mol L
-1硝酸铜溶液、10mL过硫酸铵和5mL水合肼，加至烧杯中，待反应25min后将溶液静置过夜；
2)将上述得到的溶液用孔径为0.22μm的有机微孔滤膜真空抽滤，收集滤渣，分散于20mL的超纯水中，再用孔径为0.22μm的有机微孔滤膜真空抽滤，收集滤渣，重复5次，将滤渣在30℃下真空干燥，收集粉末A；
3)将步骤2)的粉末A铺在坩埚中，放入马弗炉，在空气氛围下热解，升温速率为5℃min
-1，热解温度为300℃，热解时间为1.5h，取出坩埚中的碳化粉末，于研钵中研磨后超声多次分散于20mL的超纯水中，静置，用孔径0.22μm的水性微孔滤膜真空抽滤，倒出上清液，重复5次，装入截留分子量为500-1000的透析袋，在超纯水中透析48h，之后冻干处理56h，最终得到黄褐色的碳点。
实施例3
一种可用于光动力治疗的铜离子掺杂碳点的制备方法，具体包括以下步骤：
1)称取20mL的0.3mol L
-1丙烯酸、10mL的0.2mol L
-1硝酸铜溶液、30mL过硫酸铵和10mL水合肼，加至烧杯中，待反应40min后将溶液静置过夜；
2)将上述得到的溶液用孔径为0.22μm的有机微孔滤膜真空抽滤，收集滤渣，分散于20mL的超纯水中，再用孔径为0.22μm的有机微孔滤膜真空抽滤，收集滤渣，重复5次，将滤渣在45℃下真空干燥，收集粉末A；
3)将步骤2)的粉末A铺在坩埚中，放入马弗炉，在空气氛围下热解，升温速率为2℃min
-1，热解温度为500℃，热解时间为1.5h，取出坩埚中的碳化粉末，于研钵中研磨后超声多次分散于20mL的超纯水中，静置，用孔径0.22μm的水性微孔滤膜真空抽滤，倒出上清液，重复5次，装入截留分子量为500-1000的透析袋，在超纯水中透析60h，之后冻干处理64h，最终得到黄褐色的碳点。
实施例4
本发明制得铜离子掺杂碳点是作为光敏剂应用在光动力治疗中，来增加光照下产生单线态氧的量，从而提高光动力治疗的效果，可适用于皮肤癌，肺癌，胰腺癌，食道癌和脑胶质瘤以及一些皮肤病和眼科疾病等的治疗过程。
Hela细胞培养条件：在60nm细胞培养皿中，加入3mL含10％胎牛血清的DMEM培养液，置于37℃、5％CO
2恒温培养箱中培养。Hela为贴壁细胞，待细胞长到80％时，用1mL的0.25％的胰蛋白酶液消化2min，用1mL含10％胎牛血清的培养液终止胰酶作用，反复吹打皿底细胞使其充分分散。在100rpm转速下，离心5min，弃去上清液，在细胞沉淀中加入新鲜培养基，吹打均匀后以1：4的比例转到新培养皿中继续培养待用。
采用MTT法检测制得的铜离子掺杂碳点的细胞毒性。MTT法是一种常见的检测细胞存活和生长的方法，检测原理是：活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT(噻唑蓝)还原成不溶于水的蓝紫色结晶甲瓒以沉积在细胞中，死细胞却无此功能，然后用DMSO(二甲基亚砜)溶解出细胞中的甲瓒，再用酶联免疫检测仪在540nm或720nm波长条件下测定其吸光度，以此间接反映细胞存活率。
MTT细胞毒性测试结果显示Hela细胞(人类子宫颈癌细胞)与不同浓度的铜离子掺杂碳点共培养24h后，不光照，结果如图4所示。由图4可知，Hela细胞的存活率仍维持在80％以上，表明制得的铜离子掺杂碳点具有良好的生物相容性。
MTT细胞毒性测试结果显示Hela细胞与不同浓度的铜离子掺杂碳点共培养24h后，再光照10min，结果如图5所示。由图5可知，不同浓度的铜离子掺杂碳点经光照后，其细胞毒性明显大于在黑暗条件下未经光照的，当铜离子掺杂碳点的浓度为0.25mg mL
-1时，光照下的细胞毒性是黑暗条件下的1.5倍。说明铜离子掺杂碳点具有光动力治疗应用价值。
本发明的制备方法具有反应步骤简单、成本低、绿色环保等优点，所制备的铜离子掺杂碳点粒径均匀，结构稳定，具有荧光性能。
本发明制得铜离子掺杂碳点在可见光及近红外波长的光照射下，可产生单线态氧，是用于光动力治疗的理想光敏剂，适用于皮肤癌，肺癌，胰腺癌，食道癌和脑胶质瘤，以及一些皮肤病和眼科疾病等的治疗过程，有着广泛的应用前景。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换或改进等，均应包含在本发明的保护范围之内。
Claims (9)
- 铜离子掺杂碳点的制备方法，其特征在于，利用硝酸铜为掺杂剂，通过原位聚合生成聚丙烯酸与铜离子的络合物作为前驱体，然后经过热解碳化生成碳化产物，再经过提取、纯化得到所述碳点。
- 根据权利要求1所述的铜离子掺杂碳点的制备方法，其特征在于，具体包括以下步骤：1)称取0.3mol L -1丙烯酸、0.2mol L -1硝酸铜溶液、过硫酸铵和水合肼，加至烧杯中，待反应一段时间后，溶液静置过夜；2)将上述得到的溶液抽滤，收集滤渣，分散于一定量的超纯水中，抽滤，收集滤渣，在一定温度下真空干燥，收集粉末A；3)将步骤2)的粉末A铺在坩埚中，放入马弗炉，在空气氛围下热解，取出坩埚中的碳化粉末，于研钵中研磨后超声多次分散于一定量的超纯水中，静置，抽滤，倒出上清液，装入一定截留分子量的透析袋，在超纯水中透析，冻干得到黄褐色的碳点。
- 根据权利要求2所述的铜离子掺杂碳点的制备方法，其特征在于，所述步骤1)中加入10-20mL丙烯酸、2-10mL硝酸铜溶液、10-30mL过硫酸铵和5-10mL水合肼，反应时间为25-40min。
- 根据权利要求2所述的铜离子掺杂碳点的制备方法，其特征在于，所述步骤2)中真空干燥的温度范围为30-45℃。
- 根据权利要求2所述的铜离子掺杂碳点的制备方法，其特征在于，所述步骤3)中升温速率为2-10℃/min，热解温度为300-500℃，热解时间为1.5-2h。
- 根据权利要求2所述的铜离子掺杂碳点的制备方法，其特征在于，所述步骤2)、步骤3)中抽滤时，采用孔径为0.22μm的有机水性微孔滤膜。
- 根据权利要求2所述的铜离子掺杂碳点的制备方法，其特征在于，所述步骤3)中透析袋截留分子量为500-1000，透析时间为48-72h，冻干时间为56-72h，最后得到黄褐色的碳点。
- 一种由权利要求1-7任一项所述制备方法得到的铜离子掺杂碳点。
- 一种采用权利要求1-7任一项所述制备方法制得铜离子掺杂碳点作为光动力治疗光敏剂的应用。
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| CN113318070A (zh) * | 2021-05-25 | 2021-08-31 | 上海交通大学 | 一种可注射水凝胶及其制备和应用 |
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| CN111909691B (zh) * | 2020-06-23 | 2022-11-29 | 南京师范大学 | 一种可光热抗菌近红外碳量子点的制备方法及其产品和应用 |
| CN113648414B (zh) * | 2021-08-12 | 2023-02-28 | 上海市第六人民医院 | 一种金属离子配位的碳点/二氧化钛异质结及其制备方法和应用 |
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