WO2019128252A1 - Tin(ii) sulfide nanosheet-based drug delivery system and preparation method therefor - Google Patents

Tin(ii) sulfide nanosheet-based drug delivery system and preparation method therefor Download PDF

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WO2019128252A1
WO2019128252A1 PCT/CN2018/100239 CN2018100239W WO2019128252A1 WO 2019128252 A1 WO2019128252 A1 WO 2019128252A1 CN 2018100239 W CN2018100239 W CN 2018100239W WO 2019128252 A1 WO2019128252 A1 WO 2019128252A1
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stannous sulfide
nanosheet
delivery system
polyethylene glycol
folic acid
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PCT/CN2018/100239
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French (fr)
Chinese (zh)
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张晗
范涛健
谢中建
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深圳大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones

Definitions

  • the invention relates to the technical field of tumor treatment, in particular to a delivery system based on stannous sulfide nanosheets and a preparation method thereof.
  • Chemotherapy is a commonly used treatment in cancer treatment.
  • currently used therapeutic drugs such as doxorubicin (DOX) and paclitaxel often have the disadvantages of poor specificity and high toxicity. They also kill many normal ones while treating cancer. Cells with large side effects.
  • DOX doxorubicin
  • paclitaxel often have the disadvantages of poor specificity and high toxicity. They also kill many normal ones while treating cancer. Cells with large side effects.
  • nanomaterials as drug carriers to enhance their targeting.
  • traditional drug-loading systems often have problems such as low drug loading rate and poor drug-controlled release.
  • two-dimensional materials as carriers for anticancer drugs is a new type of anticancer technology developed in recent years.
  • This technology uses two-dimensional materials to carry drugs such as doxorubicin, combined with laser, magnetic field and other physical means, can achieve controlled release of drugs in the tumor site.
  • the two-dimensional material has a larger specific surface area and a higher drug loading rate, and has a good performance in the drug carrier.
  • the two-dimensional material of the inner layer wrinkles such as black phosphorus relies on its unique crystal structure to further increase the drug loading.
  • black phosphorus is expensive and is very susceptible to oxidation. Therefore, it is necessary to find a two-dimensional material drug carrier with a pleated structure, which is inexpensive and stable in nature.
  • the present invention provides a delivery system based on stannous sulfide nanosheets, which is loaded with an anticancer drug by using a stannous sulfide nanosheet as a carrier, the carrier is low in cost and easy to prepare, and has a good photothermal effect, thereby
  • the drug delivery system has the efficacy of photothermal treatment of stannous sulfide nano-slices to kill tumors and chemotherapy drugs for the treatment of tumors, and has extremely high clinical value for cancer treatment.
  • the present invention provides a delivery system based on a stannous sulfide nanosheet, comprising a stannous sulfide nanosheet, and a folic acid modified polyethylene glycol coated on the surface of the stannous sulfide nanosheet. And an anticancer drug loaded on the stannous sulfide nanosheet.
  • Stannous sulfide is a two-dimensional material that is bonded by van der Waals force between layers.
  • the raw materials required for preparing stannous sulfide nanosheets are non-toxic and abundant in the earth, and the loading rate of stannous sulfide nanosheets is high.
  • the light absorption is better, the toxicity is low, the price is cheap, the preparation is simple, the chemical stability is high, and it is an ideal anticancer drug carrier.
  • the stannous sulfide nanosheet has a length to width dimension of 50 nm to 200 nm and a thickness of 1 nm to 10 nm.
  • the stannous sulfide nanosheet has a length to width dimension of 50 nm to 100 nm and 80 nm to 150 nm.
  • the stannous sulfide nanosheet has a thickness of 2 nm to 8 nm and 3 nm to 5 nm.
  • Choosing the right size can ensure that the drug delivery system has a good passive enrichment effect on the tumor site, avoiding the problem that the delivery system cannot enter the tumor site due to the excessive size, and the size is too small, which makes the delivery system easy to leak from the tumor site.
  • Selecting a thinner thickness increases the specific surface area of the stannous sulfide nanosheet, thereby enhancing its photothermal effect and drug loading rate.
  • the mass ratio of the stannous sulfide nanosheet to the folic acid modified polyethylene glycol is 1:0.5-3. Further, the mass ratio of the two may be 1:1-2.
  • the folic acid-modified polyethylene glycol has a weight average molecular weight of from 2,000 to 30,000. Polyethylene glycol coating can improve the biocompatibility and stability of stannous sulfide nanosheets and improve their dispersibility in water.
  • the two ends of the polyethylene glycol molecular chain are folic acid and an amino group, respectively, and the folic acid is combined with polyethylene glycol through an amide bond, and the folic acid-modified polyethylene glycol Adsorbed on the surface of the stannous sulfide nanosheet by electrostatic attraction.
  • the mass ratio of the stannous sulfide nanosheet to the anticancer drug is 1:1-2.5, and the mass ratio is further 1:1-2.
  • the anticancer drug includes doxorubicin, and may also include other anticancer drugs.
  • the stannous sulfide nanosheet-based delivery system provided by the first aspect of the invention has low cost and easy preparation of the stannous sulfide nanosheet carrier, and has good photothermal effect, so that the delivery system has both stannous sulfide nanometers.
  • the photothermal heat of the film kills tumors and chemotherapy drugs for the treatment of tumors, and has a very high clinical value for cancer treatment.
  • the present invention provides a method for preparing a delivery system based on stannous sulfide nanosheets, comprising the steps of:
  • the organic solvent includes one or both of isopropanol and nitrogen methylpyrrolidone.
  • the mass concentration of the stannous sulfide after the grinding in the organic solvent is 0.5 to 5 mg/mL.
  • the dispersion in the preparation method of the present invention, in the step (1), in order to further improve the yield, the dispersion is ultrasonically probed for 4-8 hours before the water bath is ultrasonicated, and the probe ultrasonic power of the probe is 150. -600w, the temperature of the probe during the ultrasonic process is 5-20 °C. Since the ultrasonic effect of the probe on the stannous sulfide material is direct, in order to avoid degradation of the stannous sulfide material, the probe maintains a temperature of 5-20 ° C during the ultrasonic process, and further maintains the temperature at 10-15 ° C, when the temperature rises, Ice packs can be used to cool down.
  • the probe ultrasound with water bath ultrasound, the resulting stannous sulfide nanosheets are smaller and more uniform in size, and the yield of stannous sulfide nanosheets of the desired size is high.
  • the temperature of the water bath ultrasonication is maintained at 15-25 °C. If the temperature of the water bath is too high, the stannous sulfide nanosheet will be degraded.
  • the temperature range adopted by the invention is easy to realize under the premise of ensuring the stability of the material, and the operation difficulty is low. When the temperature of the water bath rises, water exchange or other cooling measures can be taken to ensure that the bath temperature is within a certain range.
  • the specific operation of collecting the precipitate by centrifugation is: firstly, centrifuging at a speed of 3000-6000 rpm for 0.5-1 h, taking the supernatant, and then the supernatant. The mixture was centrifuged at 15,000 to 20,000 rpm for 0.5-1 h, and the precipitate was collected.
  • the first step of low-speed centrifugation is to separate and remove the larger portion of the stannous sulfide nanosheets, and the second step of high-speed centrifugation to obtain the desired size of stannous sulfide nanosheets.
  • the drying operation may be performed under vacuum at normal temperature.
  • the stannous sulfide nanosheet has a length to width dimension of 50 nm to 200 nm and a thickness of 1 nm to 10 nm.
  • the stannous sulfide nanosheet has a length to width dimension of 50 nm to 100 nm and 80 nm to 150 nm.
  • the stannous sulfide nanosheet has a thickness of 2 nm to 8 nm and 3 nm to 5 nm.
  • the stirring speed is 600-1200 rpm, and further may be 800-1000 rpm.
  • the folic acid-modified polyethylene glycol may be directly purchased or may be prepared by adding a hydroxysuccinimide-activated folic acid to a dimethyl group of a diammonium-terminated polyethylene glycol.
  • a catalyst such as triethylamine
  • the mixed solution is stirred at a temperature of 300-600 rpm for 16-32 hours at room temperature and in the dark, after completion of the reaction. Filtration gave a folic acid modified polyethylene glycol.
  • the hydroxysuccinimide-activated folic acid can be prepared by dissolving folic acid in anhydrous dimethyl sulfoxide, adding hydroxysuccinimide and N,N'-dicyclohexylcarbimide to obtain a mixture. The mixture is stirred at room temperature, protected from light and triethylamine for 16-32 hours, and filtered after completion of the reaction to obtain the hydroxysuccinimide-activated folic acid.
  • the concentration of the aqueous dispersion of the stannous sulfide nanosheet is 0.2-2 mg/mL, and further may be 0.5-1.5 mg/mL, 0.8-1.0 mg/mL.
  • the mass ratio of the stannous sulfide nanosheet to the folic acid modified polyethylene glycol is 1:0.5-3. Further, the mass ratio of the two may be 1:1-2.
  • the folic acid-modified polyethylene glycol has a weight average molecular weight of from 2,000 to 30,000, and specifically may also be from 5,000 to 8,000.
  • the specific operation of collecting the precipitate by centrifugation is: after centrifugation at a rotational speed of 15000-20000 rpm for 0.5-1 h, the precipitate is collected.
  • the stirring speed is 600-1200 rpm, and further may be 800-1000 rpm.
  • the mass ratio of the stannous sulfide nanosheet to the anticancer drug is 1:1-2.5, and the mass ratio is further 1:1-2. Of course, it can also be added in excess, for example, the mass ratio of the stannous sulfide nanosheet to the anticancer drug is 1:3-4.
  • the anticancer drug comprises doxorubicin.
  • the preparation method of the stannous sulfide nanosheet-based delivery system provided by the second aspect of the invention has the advantages that the raw materials are easy to obtain, the preparation process is simple, and the scale production is easy to be realized.
  • Example 1 is an electron micrograph of a stannous sulfide nanosheet prepared in Example 1 of the present invention.
  • FIG. 2 is a graph showing a photothermal effect measurement temperature rise curve of a stannous sulfide nanosheet coated with folic acid-modified polyethylene glycol according to Example 1 of the present invention
  • FIG. 3 is a zeta potential of a stannous sulfide nanosheet-based drug delivery system according to Embodiment 1 of the present invention.
  • FIG. 4 is a graph showing the results of drug loading rate of a stannous sulfide nanosheet-based drug delivery system according to an embodiment of the present invention.
  • Figure 5 is a graph showing the results of in vivo experiments of a stannous sulfide nanosheet-based drug delivery system according to Example 1 of the present invention.
  • a method for preparing a delivery system based on stannous sulfide nanosheets comprising the steps of:
  • the stannous sulfide block After grinding the stannous sulfide block for 30 minutes, it is dispersed in isopropyl alcohol to obtain a dispersion having a concentration of 1 mg/mL; the above dispersion is ultrasonicated by a probe for 5 hours, and the probe ultrasonic power of the probe is 360w.
  • the probe maintains a temperature of 5-20 ° C during the ultrasonic process, and when the temperature rises, the ice pack is used for cooling; and the dispersion is ultrasonicated in a water bath for 10 hours to obtain the ultrasonic dispersion, and the ultrasonic bath is ultrasonically irradiated.
  • the temperature is maintained at 15-25 ° C, when the temperature of the water bath rises, the water bath temperature is maintained in the range of 15-25 ° C; after the ultrasonic dispersion is centrifuged, the centrifuge is centrifuged at 5000 rpm. h, taking the supernatant, and then centrifuging the supernatant at 17000 rpm for 0.5 h, collecting the precipitate, and drying to obtain a stannous sulfide nanosheet;
  • the drug system includes stannous sulfide nanosheets, folic acid modified polyethylene glycol coated on the surface of the stannous sulfide nanosheet, and an anticancer drug supported on the stannous sulfide nanosheet.
  • Example 1 is an electron micrograph of a stannous sulfide nanosheet prepared in Example 1 of the present invention. As can be seen from the figure, the obtained stannous sulfide nanosheet has a length to width dimension of 50 to 200 nm.
  • a method for preparing a delivery system based on stannous sulfide nanosheets comprising the steps of:
  • the stannous sulfide block After grinding the stannous sulfide block for 40 minutes, it is dispersed in nitromethylpyrrolidone to obtain a dispersion having a concentration of 1 mg/mL; the above dispersion is ultrasonicated with a probe for 6 hours, and the probe ultrasonic power of the probe is 360w, the probe maintains a temperature of 10-15 ° C during the ultrasonic process, and when the temperature rises, the ice pack is used for cooling; the dispersion is ultrasonicated in a water bath for 12 hours to obtain a superseded dispersion, and the water bath is ultrasonicated.
  • the temperature is maintained at 15-25 ° C, when the temperature of the water bath rises, by changing the water to ensure the temperature of the water bath is in the range of 15-25 ° C; after centrifuging the ultrasonicated dispersion, centrifuging at 4000 rpm 1h, the supernatant was taken, and then the supernatant was centrifuged at 16000 rpm for 1 h, and the precipitate was collected and dried to obtain a stannous sulfide nanosheet;
  • the stannous sulfide nanosheet coated with the folic acid-modified polyethylene glycol prepared in the first embodiment of the present invention is ultrasonically dispersed in water to obtain a dispersion of the stannous sulfide nanosheet concentration of 0.1 mg/mL, and the The dispersion was placed in a cuvette, and the cuvette was irradiated with a laser having a power density of 1 W/cm 2 and a wavelength of 808 nm, and the temperature of the dispersion was measured by an infrared thermometer. After 3 minutes, the laser power was turned off, and the temperature was lowered. In minutes, the cycle was repeated 3 times to obtain a temperature rise-down curve as shown in FIG. It can be seen from the temperature rise-down curve of FIG. 2 that the stannous sulfide nanosheets coated with the folic acid modified polyethylene glycol prepared in the examples of the present invention have a good photothermal effect.
  • the zeta potential of a stannous sulfide nanosheet coated with folic acid-modified polyethylene glycol alone and the zeta potential of doxorubicin (DOX) alone were compared to determine whether the drug was successfully loaded. Specifically, as shown in FIG. 3, it can be seen from the results of FIG. 3 that the doxorubicin load is successful.
  • the stannous sulfide nanosheet coated with the folic acid-modified polyethylene glycol prepared in the first embodiment of the present invention was ultrasonically dispersed in water to obtain a dispersion of the stannous sulfide nanosheet concentration of 0.1 mg/mL, respectively.
  • doxorubicin was added at a mass ratio of 0.5:1, 1:1, 2:1, 3:1, 4:1, and the mixture was stirred for 24 hours. The results are shown in Fig. 4.
  • the loading rate is about 180%.
  • the addition amount of doxorubicin is further increased, the load rate is increased less.
  • the loading rate of doxorubicin is 200%, so the ratio of doxorubicin to stannous sulfide nanosheet is controlled at 2-2.5:1. More suitable.
  • the first group PBS (phosphate buffered saline solution) was injected into the mouse by intratumoral injection to observe the tumor growth; the relative size of the tumor is shown in FIG.
  • the second group the tumor site was irradiated by laser with a power density of 1 W/cm 2 and a wavelength of 808 nm, and the tumor growth was observed.
  • the relative size of the tumor is shown in Fig. 5.
  • the third group 100 ⁇ g / mL of stannous sulfide nanosheets in PBS (phosphate buffered saline) dispersion was injected into mice by intratumoral injection, and a power density of 1 W / cm 2 and a wavelength of 808 nm were used.
  • the laser was used to irradiate the tumor site of the mouse to observe the tumor growth; the relative size of the tumor is shown in Fig. 5.
  • the fourth group the PBS dispersion of the stannous sulfide nanosheet-based delivery system prepared in Example 1 of the present invention (in which the concentration of the stannous sulfide nanosheet is 100 ⁇ g/mL) was injected into the mouse by intratumoral injection. In vivo, tumor growth was observed; the relative size of the tumor is shown in Figure 5.
  • the fifth group the PBS dispersion of the stannous sulfide nanosheet-based delivery system prepared in Example 1 of the present invention (in which the concentration of the stannous sulfide nanosheet is 100 ⁇ g/mL) was injected into the mouse by intratumoral injection.
  • a mouse with a power density of 1 W/cm 2 and a wavelength of 808 nm was irradiated to the tumor site of the mouse to observe the tumor growth; the relative size of the tumor is shown in FIG. 5 .
  • the tumor size is significantly controlled, which is due to the sulfurization of the embodiment of the present invention.
  • the tin-nano-sheet delivery system, the stannous sulfide nano-sheet carrier has a good photothermal effect, and the drug loading is high, so that the delivery system has the photothermal heat killing tumor and chemotherapy drugs of the stannous sulfide nano-sheet.

Abstract

A drug delivery system using a tin(II) sulfide nanosheet as a vector and a preparation method therefor. The drug delivery system comprises the tin(II) sulfide nanosheet, folic acid-modified polyethylene glycol that coats the surface of the tin(II) sulfide nanosheet, and an anticancer drug loaded on the tin(II) sulfide nanosheet. The drug delivery system has both the photothermal effect of the tin(II) sulfide nanosheet and the chemotherapeutic effect of a chemotherapeutic drug.

Description

一种基于硫化亚锡纳米片的递药系统及其制备方法Drug delivery system based on stannous sulfide nanosheet and preparation method thereof
本申请要求2017年12月26日提交中国专利局的，申请号为2017114348061，发明名称为“一种基于硫化亚锡纳米片的递药系统及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。The present application claims the priority of the Chinese patent application filed on Dec. 26, 2017, filed on Jan. 26, 2011, the entire disclosure of which is entitled The entire contents are incorporated herein by reference.
技术领域Technical field
本发明涉及肿瘤治疗技术领域，特别是涉及一种基于硫化亚锡纳米片的递药系统及其制备方法。The invention relates to the technical field of tumor treatment, in particular to a delivery system based on stannous sulfide nanosheets and a preparation method thereof.
背景技术Background technique
化疗是癌症治疗中常用的治疗手段，但是目前常用的治疗药物如阿霉素(DOX)、紫杉醇等往往存在特异性不好，毒性大的缺点，在治疗癌症的同时也会杀死许多正常的细胞，副作用较大。为了解决这一问题，人们尝试将纳米材料作为药物载体以增强其靶向性。但是，传统的载药系统往往存在药物负载率不高，药物控释效果不好等问题。Chemotherapy is a commonly used treatment in cancer treatment. However, currently used therapeutic drugs such as doxorubicin (DOX) and paclitaxel often have the disadvantages of poor specificity and high toxicity. They also kill many normal ones while treating cancer. Cells with large side effects. In order to solve this problem, attempts have been made to use nanomaterials as drug carriers to enhance their targeting. However, traditional drug-loading systems often have problems such as low drug loading rate and poor drug-controlled release.
将二维材料作为载体搭载抗癌药物是近些年发展起来的新型抗癌技术。这一技术利用二维材料搭载阿霉素等药物，配合激光，磁场等物理方式，能够实现药物在肿瘤部位可控释放。相比于传统的药物载体，二维材料的比表面积较大，药物负载率较高，在药物载体方面有着很好的表现。而相比于石墨烯等平面结构的二维材料，黑磷这类层内褶皱的二维材料依靠其独特的晶体结构，在载药量上又更进一步。但是黑磷价格昂贵，同时非常容易氧化。因此寻找一种具有褶皱结构，价格便宜，性质稳定的二维材料药物载体十分有必要。The use of two-dimensional materials as carriers for anticancer drugs is a new type of anticancer technology developed in recent years. This technology uses two-dimensional materials to carry drugs such as doxorubicin, combined with laser, magnetic field and other physical means, can achieve controlled release of drugs in the tumor site. Compared with the traditional drug carrier, the two-dimensional material has a larger specific surface area and a higher drug loading rate, and has a good performance in the drug carrier. Compared with two-dimensional materials such as graphene and other planar structures, the two-dimensional material of the inner layer wrinkles such as black phosphorus relies on its unique crystal structure to further increase the drug loading. However, black phosphorus is expensive and is very susceptible to oxidation. Therefore, it is necessary to find a two-dimensional material drug carrier with a pleated structure, which is inexpensive and stable in nature.
发明内容Summary of the invention
鉴于此，本发明提供了一种基于硫化亚锡纳米片的递药系统，以硫化亚锡纳米片为载体负载抗癌药物，载体成本低易制备，且具有良好的光热效果，从而使得该递药系统兼具硫化亚锡纳米片的光热杀死肿瘤和化疗药物的化疗治疗肿瘤的功效，对于癌症治疗具有极高的临床价值。In view of this, the present invention provides a delivery system based on stannous sulfide nanosheets, which is loaded with an anticancer drug by using a stannous sulfide nanosheet as a carrier, the carrier is low in cost and easy to prepare, and has a good photothermal effect, thereby The drug delivery system has the efficacy of photothermal treatment of stannous sulfide nano-slices to kill tumors and chemotherapy drugs for the treatment of tumors, and has extremely high clinical value for cancer treatment.
具体地，第一方面，本发明提供了一种基于硫化亚锡纳米片的递药系统，包括硫化亚锡纳米片，包覆在所述硫化亚锡纳米片表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡纳米片上的抗癌药物。Specifically, in a first aspect, the present invention provides a delivery system based on a stannous sulfide nanosheet, comprising a stannous sulfide nanosheet, and a folic acid modified polyethylene glycol coated on the surface of the stannous sulfide nanosheet. And an anticancer drug loaded on the stannous sulfide nanosheet.
硫化亚锡是一种层间通过范德华力结合的二维材料，制备硫化亚锡纳米片所需的原料无毒并且在地球上的含量十分丰富，且硫化亚锡纳米片药物负载率高，对光的吸收较好，毒性低，价格便宜，制备简单，化学稳定性高，是一种理想的抗癌药物载体。Stannous sulfide is a two-dimensional material that is bonded by van der Waals force between layers. The raw materials required for preparing stannous sulfide nanosheets are non-toxic and abundant in the earth, and the loading rate of stannous sulfide nanosheets is high. The light absorption is better, the toxicity is low, the price is cheap, the preparation is simple, the chemical stability is high, and it is an ideal anticancer drug carrier.
本发明中，所述硫化亚锡纳米片的长宽尺寸为50nm-200nm，厚度为1nm-10nm。可选地，所述硫化亚锡纳米片的长宽尺寸为50nm-100nm，80nm-150nm。可选地，所述硫化亚锡纳米片的厚度为2nm-8nm，3nm-5nm。选择适合的尺寸能够保证递药系统在肿瘤部位具有较好的被动富集效果，避免尺寸过大导致递药系统无法进入肿瘤部位，而尺寸过小导致递药系统易从肿瘤部位泄露的问题。选择较薄的厚度可以增大硫化亚锡纳米片的比表面积，从而增强其光热效果和药物负载率。In the present invention, the stannous sulfide nanosheet has a length to width dimension of 50 nm to 200 nm and a thickness of 1 nm to 10 nm. Optionally, the stannous sulfide nanosheet has a length to width dimension of 50 nm to 100 nm and 80 nm to 150 nm. Optionally, the stannous sulfide nanosheet has a thickness of 2 nm to 8 nm and 3 nm to 5 nm. Choosing the right size can ensure that the drug delivery system has a good passive enrichment effect on the tumor site, avoiding the problem that the delivery system cannot enter the tumor site due to the excessive size, and the size is too small, which makes the delivery system easy to leak from the tumor site. Selecting a thinner thickness increases the specific surface area of the stannous sulfide nanosheet, thereby enhancing its photothermal effect and drug loading rate.
本发明中，可选地，所述硫化亚锡纳米片与所述叶酸修饰的聚乙二醇的质量比为1:0.5-3。进一步地，两者的质量比可为1:1-2。所述叶酸修饰的聚乙二醇的重均分子量为2000-30000。聚乙二醇包覆可以提高硫化亚锡纳米片的生物相容性和稳定性，提高其在水中的分散性。所述叶酸修饰的聚乙二醇分子中，聚乙二醇分子链两端分别为叶酸和氨基，所述叶酸通过酰胺键与聚乙二醇结合在一 起，所述叶酸修饰的聚乙二醇通过静电引力吸附在所述硫化亚锡纳米片表面。In the present invention, optionally, the mass ratio of the stannous sulfide nanosheet to the folic acid modified polyethylene glycol is 1:0.5-3. Further, the mass ratio of the two may be 1:1-2. The folic acid-modified polyethylene glycol has a weight average molecular weight of from 2,000 to 30,000. Polyethylene glycol coating can improve the biocompatibility and stability of stannous sulfide nanosheets and improve their dispersibility in water. In the folic acid-modified polyethylene glycol molecule, the two ends of the polyethylene glycol molecular chain are folic acid and an amino group, respectively, and the folic acid is combined with polyethylene glycol through an amide bond, and the folic acid-modified polyethylene glycol Adsorbed on the surface of the stannous sulfide nanosheet by electrostatic attraction.
本发明中，可选地，所述硫化亚锡纳米片与所述抗癌药物的质量比为1:1-2.5，进一步地质量比为1:1-2。In the present invention, optionally, the mass ratio of the stannous sulfide nanosheet to the anticancer drug is 1:1-2.5, and the mass ratio is further 1:1-2.
本发明中，可选地，所述抗癌药物包括阿霉素，也可以包括其他抗癌药物。In the present invention, optionally, the anticancer drug includes doxorubicin, and may also include other anticancer drugs.
本发明第一方面提供的基于硫化亚锡纳米片的递药系统，其硫化亚锡纳米片载体成本低易制备，且具有良好的光热效果，从而使得该递药系统兼具硫化亚锡纳米片的光热杀死肿瘤和化疗药物的化疗治疗肿瘤的功效，对于癌症治疗具有极高的临床价值。The stannous sulfide nanosheet-based delivery system provided by the first aspect of the invention has low cost and easy preparation of the stannous sulfide nanosheet carrier, and has good photothermal effect, so that the delivery system has both stannous sulfide nanometers. The photothermal heat of the film kills tumors and chemotherapy drugs for the treatment of tumors, and has a very high clinical value for cancer treatment.
第二方面，本发明提供了一种基于硫化亚锡纳米片的递药系统的制备方法，包括以下步骤：In a second aspect, the present invention provides a method for preparing a delivery system based on stannous sulfide nanosheets, comprising the steps of:
(1)将硫化亚锡块体研磨20-60分钟后，分散于有机溶剂中，并于10-35℃水浴超声8-12小时，随后离心收集沉淀，烘干，得到硫化亚锡纳米片；(1) After grinding the stannous sulfide block for 20-60 minutes, dispersing in an organic solvent, and sonicating in a water bath at 10-35 ° C for 8-12 hours, then collecting the precipitate by centrifugation and drying to obtain a stannous sulfide nanosheet;
(2)将所述硫化亚锡纳米片分散于水中，得到硫化亚锡纳米片的水分散液，再向所述水分散液中加入叶酸修饰的聚乙二醇，搅拌10-16小时，离心收集沉淀，得到表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片；(2) dispersing the stannous sulfide nanosheet in water to obtain an aqueous dispersion of stannous sulfide nanosheet, adding folic acid modified polyethylene glycol to the aqueous dispersion, stirring for 10-16 hours, and centrifuging The precipitate is collected to obtain a stannous sulfide nanosheet having a surface coated with a folic acid modified polyethylene glycol;
(3)将所述表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片分散于水中，并加入抗癌药物，搅拌20-24小时后，离心收集沉淀，即得到基于硫化亚锡纳米片的递药系统，所述基于硫化亚锡纳米片的递药系统包括硫化亚锡纳米片，包覆在所述硫化亚锡纳米片表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡纳米片上的抗癌药物。(3) dispersing the stannous sulfide nanosheet coated with folic acid-modified polyethylene glycol in water, adding an anticancer drug, stirring for 20-24 hours, collecting the precipitate by centrifugation, thereby obtaining a stannous sulfide-based solution a nanosheet delivery system, the stannous sulfide nanosheet-based delivery system comprising a stannous sulfide nanosheet, a folic acid modified polyethylene glycol coated on the surface of the stannous sulfide nanosheet, and a load in the An anticancer drug on stannous sulfide nanosheets.
上述制备方法中，所述步骤(1)中，所述有机溶剂包括异丙醇、氮甲基吡咯烷酮中的一种或两种。研磨后的硫化亚锡在所述有机溶剂中的质量浓度为0.5-5mg/mL。In the above preparation method, in the step (1), the organic solvent includes one or both of isopropanol and nitrogen methylpyrrolidone. The mass concentration of the stannous sulfide after the grinding in the organic solvent is 0.5 to 5 mg/mL.
本发明制备方法中，所述步骤(1)中，为了进一步提高产率，在所述水浴超声之前，先将所述分散液采用探头超声4-8小时，所述探头超声的探头功率为150-600w，所述探头超声过程中的温度为5-20℃。由于探头超声对硫化亚锡材料的作用直接，为避免硫化亚锡材料降解，所述探头超声过程中保持温度为5-20℃，进一步地保持温度为10-15℃，当温度升高时，可使用冰袋进行降温。通过将探头超声与水浴超声结合使用，使得最终得到的硫化亚锡纳米片尺寸更小，更均一，获得所需尺寸的硫化亚锡纳米片的产率高。In the preparation method of the present invention, in the step (1), in order to further improve the yield, the dispersion is ultrasonically probed for 4-8 hours before the water bath is ultrasonicated, and the probe ultrasonic power of the probe is 150. -600w, the temperature of the probe during the ultrasonic process is 5-20 °C. Since the ultrasonic effect of the probe on the stannous sulfide material is direct, in order to avoid degradation of the stannous sulfide material, the probe maintains a temperature of 5-20 ° C during the ultrasonic process, and further maintains the temperature at 10-15 ° C, when the temperature rises, Ice packs can be used to cool down. By combining the probe ultrasound with water bath ultrasound, the resulting stannous sulfide nanosheets are smaller and more uniform in size, and the yield of stannous sulfide nanosheets of the desired size is high.
本发明制备方法中，可选地，水浴超声的温度保持在15-25℃。水浴温度过高会导致硫化亚锡纳米片降解，本发明采用的温度范围在保证材料稳定的前提下易于实现，操作难度低。当水浴温度升高，可通过换水或其他降温措施以保证水浴温度在一定范围内。In the preparation method of the present invention, optionally, the temperature of the water bath ultrasonication is maintained at 15-25 °C. If the temperature of the water bath is too high, the stannous sulfide nanosheet will be degraded. The temperature range adopted by the invention is easy to realize under the premise of ensuring the stability of the material, and the operation difficulty is low. When the temperature of the water bath rises, water exchange or other cooling measures can be taken to ensure that the bath temperature is within a certain range.
上述制备方法中，所述步骤(1)中，所述离心收集沉淀的具体操作为：先以3000-6000转/分钟的转速离心0.5-1h，取上清液，然后将所述上清液以15000-20000转/分钟的转速离心0.5-1h，收集沉淀。第一步的低转速离心是为了分离去除尺寸较大的那部分硫化亚锡纳米片，第二步的高速离心分离即获得所需尺寸的硫化亚锡纳米片。In the above preparation method, in the step (1), the specific operation of collecting the precipitate by centrifugation is: firstly, centrifuging at a speed of 3000-6000 rpm for 0.5-1 h, taking the supernatant, and then the supernatant. The mixture was centrifuged at 15,000 to 20,000 rpm for 0.5-1 h, and the precipitate was collected. The first step of low-speed centrifugation is to separate and remove the larger portion of the stannous sulfide nanosheets, and the second step of high-speed centrifugation to obtain the desired size of stannous sulfide nanosheets.
所述步骤(1)中，所述烘干操作可以是真空常温下进行。In the step (1), the drying operation may be performed under vacuum at normal temperature.
本发明中，所述硫化亚锡纳米片的长宽尺寸为50nm-200nm，厚度为1nm-10nm。可选地，所述硫化亚锡纳米片的长宽尺寸为50nm-100nm，80nm-150nm。可选地，所述硫化亚锡纳米片的厚度为2nm-8nm，3nm-5nm。In the present invention, the stannous sulfide nanosheet has a length to width dimension of 50 nm to 200 nm and a thickness of 1 nm to 10 nm. Optionally, the stannous sulfide nanosheet has a length to width dimension of 50 nm to 100 nm and 80 nm to 150 nm. Optionally, the stannous sulfide nanosheet has a thickness of 2 nm to 8 nm and 3 nm to 5 nm.
上述制备方法中，所述步骤(2)中，可选地，所述搅拌的速度为600-1200转/分钟，进一步地可为800-1000转/分钟。In the above preparation method, in the step (2), optionally, the stirring speed is 600-1200 rpm, and further may be 800-1000 rpm.
所述步骤(2)中，所述叶酸修饰的聚乙二醇可直接购买得到，也可采用如 下方式制备：将羟基琥珀酰亚胺活化叶酸加入到双氨端聚乙二醇的二甲基亚砜溶液中，并加入适量催化剂(如三乙胺)，得到混合溶液，所述混合溶液在室温、避光条件下以300-600转/分钟的转速搅拌反应16-32小时，反应完成后过滤，得到叶酸修饰的聚乙二醇。In the step (2), the folic acid-modified polyethylene glycol may be directly purchased or may be prepared by adding a hydroxysuccinimide-activated folic acid to a dimethyl group of a diammonium-terminated polyethylene glycol. In a sulfoxide solution, an appropriate amount of a catalyst (such as triethylamine) is added to obtain a mixed solution, and the mixed solution is stirred at a temperature of 300-600 rpm for 16-32 hours at room temperature and in the dark, after completion of the reaction. Filtration gave a folic acid modified polyethylene glycol.
所述羟基琥珀酰亚胺活化叶酸可采用如下方式制备：将叶酸溶解于无水二甲基亚砜中，再加入羟基琥珀酰亚胺和N,N'-二环己基碳酰亚胺得到混合液，所述混合液在室温、避光和三乙胺催化条件下进行搅拌反应16-32小时，反应完成后过滤，得到所述羟基琥珀酰亚胺活化叶酸。The hydroxysuccinimide-activated folic acid can be prepared by dissolving folic acid in anhydrous dimethyl sulfoxide, adding hydroxysuccinimide and N,N'-dicyclohexylcarbimide to obtain a mixture. The mixture is stirred at room temperature, protected from light and triethylamine for 16-32 hours, and filtered after completion of the reaction to obtain the hydroxysuccinimide-activated folic acid.
本发明制备方法步骤(2)中，所述硫化亚锡纳米片的水分散液的浓度为0.2-2mg/mL，进一步地可以是0.5-1.5mg/mL，0.8-1.0mg/mL。In the step (2) of the preparation method of the present invention, the concentration of the aqueous dispersion of the stannous sulfide nanosheet is 0.2-2 mg/mL, and further may be 0.5-1.5 mg/mL, 0.8-1.0 mg/mL.
本发明中，可选地，所述硫化亚锡纳米片与所述叶酸修饰的聚乙二醇的质量比为1:0.5-3。进一步地，两者的质量比可为1:1-2。所述叶酸修饰的聚乙二醇的重均分子量为2000-30000，具体还可以是5000-8000。In the present invention, optionally, the mass ratio of the stannous sulfide nanosheet to the folic acid modified polyethylene glycol is 1:0.5-3. Further, the mass ratio of the two may be 1:1-2. The folic acid-modified polyethylene glycol has a weight average molecular weight of from 2,000 to 30,000, and specifically may also be from 5,000 to 8,000.
本发明制备方法中，所述步骤(2)和步骤(3)中，所述离心收集沉淀的具体操作为：以15000-20000转/分钟的转速离心0.5-1h后，收集沉淀。In the preparation method of the present invention, in the step (2) and the step (3), the specific operation of collecting the precipitate by centrifugation is: after centrifugation at a rotational speed of 15000-20000 rpm for 0.5-1 h, the precipitate is collected.
所述步骤(3)中，可选地，所述搅拌的速度为600-1200转/分钟，进一步地可为800-1000转/分钟。In the step (3), optionally, the stirring speed is 600-1200 rpm, and further may be 800-1000 rpm.
本发明中，可选地，所述硫化亚锡纳米片与所述抗癌药物的质量比为1:1-2.5，进一步地质量比为1:1-2。当然也可以过量加入，如硫化亚锡纳米片与抗癌药物的质量比为1:3-4。本发明中，可选地，所述抗癌药物包括阿霉素。In the present invention, optionally, the mass ratio of the stannous sulfide nanosheet to the anticancer drug is 1:1-2.5, and the mass ratio is further 1:1-2. Of course, it can also be added in excess, for example, the mass ratio of the stannous sulfide nanosheet to the anticancer drug is 1:3-4. In the present invention, optionally, the anticancer drug comprises doxorubicin.
本发明第二方面提供的基于硫化亚锡纳米片的递药系统的制备方法，原料易得，制备过程简单，易于实现规模化生产。The preparation method of the stannous sulfide nanosheet-based delivery system provided by the second aspect of the invention has the advantages that the raw materials are easy to obtain, the preparation process is simple, and the scale production is easy to be realized.
本发明的优点将会在下面的说明书中部分阐明，一部分根据说明书是显而易 见的，或者可以通过本发明实施例的实施而获知。The advantages of the invention will be set forth in part in the description which follows.
附图说明DRAWINGS
图1为本发明实施例1制备得到的硫化亚锡纳米片的电镜图；1 is an electron micrograph of a stannous sulfide nanosheet prepared in Example 1 of the present invention;
图2为本发明实施例1的表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片的光热效果测量升温曲线图；2 is a graph showing a photothermal effect measurement temperature rise curve of a stannous sulfide nanosheet coated with folic acid-modified polyethylene glycol according to Example 1 of the present invention;
图3为本发明实施例1的基于硫化亚锡纳米片的递药系统的Zeta电位；3 is a zeta potential of a stannous sulfide nanosheet-based drug delivery system according to Embodiment 1 of the present invention;
图4为本发明实施例的基于硫化亚锡纳米片的递药系统的药物负载率结果图；4 is a graph showing the results of drug loading rate of a stannous sulfide nanosheet-based drug delivery system according to an embodiment of the present invention;
图5为本发明实施例1的基于硫化亚锡纳米片的递药系统的体内实验结果图。Figure 5 is a graph showing the results of in vivo experiments of a stannous sulfide nanosheet-based drug delivery system according to Example 1 of the present invention.
具体实施方式Detailed ways
以下所述是本发明实施例的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明实施例原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也视为本发明实施例的保护范围。The following are the preferred embodiments of the embodiments of the present invention, and it should be noted that those skilled in the art can make some improvements and refinements without departing from the principles of the embodiments of the present invention. And retouching is also considered to be the scope of protection of the embodiments of the present invention.
实施例1Example 1
一种基于硫化亚锡纳米片的递药系统的制备方法，包括以下步骤：A method for preparing a delivery system based on stannous sulfide nanosheets, comprising the steps of:
(1)将硫化亚锡块体研磨30分钟后，分散于异丙醇中，得到浓度为1mg/mL的分散液；将上述分散液采用探头超声5小时，所述探头超声的探头功率为360w，所述探头超声过程中保持温度为5-20℃，期间当温度升高时，使用冰袋进行降温；再将所述分散液于水浴超声10小时，得到经超声后的分散液，水浴超声的温度保持在15-25℃，当水浴温度升高，通过换水以保证水浴温度在 15-25℃范围内；将所述经超声后的分散液离心后，以5000转/分钟的转速离心0.5h，取上清液，然后将所述上清液以17000转/分钟的转速离心0.5h，收集沉淀，烘干，得到硫化亚锡纳米片；(1) After grinding the stannous sulfide block for 30 minutes, it is dispersed in isopropyl alcohol to obtain a dispersion having a concentration of 1 mg/mL; the above dispersion is ultrasonicated by a probe for 5 hours, and the probe ultrasonic power of the probe is 360w. The probe maintains a temperature of 5-20 ° C during the ultrasonic process, and when the temperature rises, the ice pack is used for cooling; and the dispersion is ultrasonicated in a water bath for 10 hours to obtain the ultrasonic dispersion, and the ultrasonic bath is ultrasonically irradiated. The temperature is maintained at 15-25 ° C, when the temperature of the water bath rises, the water bath temperature is maintained in the range of 15-25 ° C; after the ultrasonic dispersion is centrifuged, the centrifuge is centrifuged at 5000 rpm. h, taking the supernatant, and then centrifuging the supernatant at 17000 rpm for 0.5 h, collecting the precipitate, and drying to obtain a stannous sulfide nanosheet;
(2)将所述硫化亚锡纳米片分散于水中，得到浓度为0.5mg/mL的硫化亚锡纳米片的水分散液，再按照硫化亚锡纳米片与叶酸修饰的聚乙二醇(FA-PEG-NH 2)的质量比为1:2，向所述水分散液中加入叶酸修饰的聚乙二醇，以800转/分钟搅拌12小时后，再以17000转/分钟的转速离心0.5h，收集沉淀，得到表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片； (2) Dispersing the stannous sulfide nanosheet in water to obtain an aqueous dispersion of stannous sulfide nanosheets at a concentration of 0.5 mg/mL, and then using stannous sulfide nanosheets and folic acid modified polyethylene glycol (FA) The mass ratio of -PEG-NH 2 ) was 1:2, and folic acid-modified polyethylene glycol was added to the aqueous dispersion, and the mixture was stirred at 800 rpm for 12 hours, and then centrifuged at 17,000 rpm for 0.5 hour. h, collecting precipitates, obtaining stannous sulfide nanosheets coated with folic acid modified polyethylene glycol;
(3)将所得表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片分散于水中，并按照硫化亚锡纳米片与抗癌药物的质量比为1:2加入抗癌药物阿霉素，以800转/分钟搅拌24小时后，然后以17000转/分钟的转速离心0.5h，收集沉淀，即得到基于硫化亚锡纳米片的递药系统，所述基于硫化亚锡纳米片的递药系统包括硫化亚锡纳米片，包覆在所述硫化亚锡纳米片表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡纳米片上的抗癌药物。(3) dispersing the obtained stannous sulfide nanosheet coated with folic acid-modified polyethylene glycol in water, and adding the anticancer drug Azomycin according to the mass ratio of the stannous sulfide nanosheet to the anticancer drug 1:2 After stirring for 24 hours at 800 rpm, and then centrifuging at 17,000 rpm for 0.5 h, the precipitate was collected to obtain a delivery system based on stannous sulfide nanosheets, which was based on stannous sulfide nanosheets. The drug system includes stannous sulfide nanosheets, folic acid modified polyethylene glycol coated on the surface of the stannous sulfide nanosheet, and an anticancer drug supported on the stannous sulfide nanosheet.
图1为本发明实施例1制备得到的硫化亚锡纳米片的电镜图，从图中可以看出，所得硫化亚锡纳米片的长宽尺寸为50-200nm。1 is an electron micrograph of a stannous sulfide nanosheet prepared in Example 1 of the present invention. As can be seen from the figure, the obtained stannous sulfide nanosheet has a length to width dimension of 50 to 200 nm.
实施例2Example 2
一种基于硫化亚锡纳米片的递药系统的制备方法，包括以下步骤：A method for preparing a delivery system based on stannous sulfide nanosheets, comprising the steps of:
(1)将硫化亚锡块体研磨40分钟后，分散于氮甲基吡咯烷酮中，得到浓度为1mg/mL的分散液；将上述分散液采用探头超声6小时，所述探头超声的探头功率为360w，所述探头超声过程中保持温度为10-15℃，期间当温度升高时，使用冰袋进行降温；再将所述分散液于水浴超声12小时，得到经超声后的 分散液，水浴超声的温度保持在15-25℃，当水浴温度升高，通过换水以保证水浴温度在15-25℃范围内；将所述经超声后的分散液离心后，以4000转/分钟的转速离心1h，取上清液，然后将所述上清液以16000转/分钟的转速离心1h，收集沉淀，烘干，得到硫化亚锡纳米片；(1) After grinding the stannous sulfide block for 40 minutes, it is dispersed in nitromethylpyrrolidone to obtain a dispersion having a concentration of 1 mg/mL; the above dispersion is ultrasonicated with a probe for 6 hours, and the probe ultrasonic power of the probe is 360w, the probe maintains a temperature of 10-15 ° C during the ultrasonic process, and when the temperature rises, the ice pack is used for cooling; the dispersion is ultrasonicated in a water bath for 12 hours to obtain a superseded dispersion, and the water bath is ultrasonicated. The temperature is maintained at 15-25 ° C, when the temperature of the water bath rises, by changing the water to ensure the temperature of the water bath is in the range of 15-25 ° C; after centrifuging the ultrasonicated dispersion, centrifuging at 4000 rpm 1h, the supernatant was taken, and then the supernatant was centrifuged at 16000 rpm for 1 h, and the precipitate was collected and dried to obtain a stannous sulfide nanosheet;
(2)将所述硫化亚锡纳米片分散于水中，得到浓度为1.0mg/mL的硫化亚锡纳米片的水分散液，再按照硫化亚锡纳米片与叶酸修饰的聚乙二醇(FA-PEG-NH 2)的质量比为1:2.5，向所述水分散液中加入叶酸修饰的聚乙二醇，以800转/分钟搅拌16小时后，再以16000转/分钟的转速离心1h，收集沉淀，得到表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片； (2) Dispersing the stannous sulfide nanosheet in water to obtain an aqueous dispersion of stannous sulfide nanosheets at a concentration of 1.0 mg/mL, and then using stannous sulfide nanosheets and folic acid modified polyethylene glycol (FA) The mass ratio of -PEG-NH 2 ) was 1:2.5, and folic acid-modified polyethylene glycol was added to the aqueous dispersion, stirred at 800 rpm for 16 hours, and then centrifuged at 16,000 rpm for 1 hour. Collecting a precipitate to obtain a stannous sulfide nanosheet having a surface coated with a folic acid-modified polyethylene glycol;
(3)将所得表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片分散于水中，并按照硫化亚锡纳米片与抗癌药物的质量比为1:2.5加入抗癌药物阿霉素，以800转/分钟搅拌24小时后，然后以16000转/分钟的转速离心1h，收集沉淀，即得到基于硫化亚锡纳米片的递药系统，所述基于硫化亚锡纳米片的递药系统包括硫化亚锡纳米片，包覆在所述硫化亚锡纳米片表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡纳米片上的抗癌药物。(3) dispersing the obtained stannous sulfide nanosheet coated with folic acid-modified polyethylene glycol in water, and adding the anticancer drug Azomycin according to the mass ratio of the stannous sulfide nanosheet to the anticancer drug of 1:2.5 After stirring for 24 hours at 800 rpm, and then centrifuging at 16,000 rpm for 1 h, the precipitate was collected to obtain a delivery system based on stannous sulfide nanosheets, which was delivered based on stannous sulfide nanosheets. The system includes stannous sulfide nanosheets, folic acid modified polyethylene glycol coated on the surface of the stannous sulfide nanosheet, and an anticancer drug supported on the stannous sulfide nanosheet.
效果实施例Effect embodiment
为对本发明实施例技术方案带来的有益效果进行有力支持，特提供以下测试：In order to strongly support the beneficial effects brought by the technical solutions of the embodiments of the present invention, the following tests are provided:
(1)光热效应测量(1) Photothermal effect measurement
将本发明实施例1制备得到的表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片超声分散于水中，得到硫化亚锡纳米片浓度为0.1mg/mL的分散液，将所述分散液装入比色皿中，采用功率密度为1W/cm 2，波长为808nm的激光垂直照 射比色皿，并采用红外测温仪测量分散液温度，照射3分钟后关闭激光电源，降温4分钟，循环3次，得到如图2所示的升温-降温曲线。从图2的升温-降温曲线可以获知，本发明实施例制备得到的表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片具有良好的光热效应。 The stannous sulfide nanosheet coated with the folic acid-modified polyethylene glycol prepared in the first embodiment of the present invention is ultrasonically dispersed in water to obtain a dispersion of the stannous sulfide nanosheet concentration of 0.1 mg/mL, and the The dispersion was placed in a cuvette, and the cuvette was irradiated with a laser having a power density of 1 W/cm 2 and a wavelength of 808 nm, and the temperature of the dispersion was measured by an infrared thermometer. After 3 minutes, the laser power was turned off, and the temperature was lowered. In minutes, the cycle was repeated 3 times to obtain a temperature rise-down curve as shown in FIG. It can be seen from the temperature rise-down curve of FIG. 2 that the stannous sulfide nanosheets coated with the folic acid modified polyethylene glycol prepared in the examples of the present invention have a good photothermal effect.
(2)载药验证(2) Drug verification
将本发明实施例1制备得到的基于硫化亚锡纳米片的递药系统分散于水中，得到硫化亚锡纳米片浓度为0.1mg/mL的分散液，并测量获得该分散液的Zeta电位；并与单独的表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片的Zeta电位和单独的阿霉素(DOX)的Zeta电位进行对比，以确定是否载药成功。具体如图3所示，从图3结果可以获知阿霉素负载成功。Dissolving the stannous sulfide nanosheet-based delivery system prepared in Example 1 of the present invention in water to obtain a dispersion of the stannous sulfide nanosheet concentration of 0.1 mg/mL, and measuring the zeta potential of the dispersion; The zeta potential of a stannous sulfide nanosheet coated with folic acid-modified polyethylene glycol alone and the zeta potential of doxorubicin (DOX) alone were compared to determine whether the drug was successfully loaded. Specifically, as shown in FIG. 3, it can be seen from the results of FIG. 3 that the doxorubicin load is successful.
将本发明实施例1制备得到的表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片超声分散于水中，得到硫化亚锡纳米片浓度为0.1mg/mL的分散液，分别按阿霉素与硫化亚锡纳米片的质量比为0.5:1、1:1、2:1、3:1、4:1向所述分散液中加入阿霉素，搅拌24h，阿霉素负载率结果如图4所示，当阿霉素与硫化亚锡纳米片的质量比为2:1时，负载率约为180％，当进一步提高阿霉素的加入量时，负载率提升较小，当阿霉素与硫化亚锡纳米片的质量比为4:1时，阿霉素的负载率为200％，因此将阿霉素与硫化亚锡纳米片的投料比控制在2-2.5:1较合适。The stannous sulfide nanosheet coated with the folic acid-modified polyethylene glycol prepared in the first embodiment of the present invention was ultrasonically dispersed in water to obtain a dispersion of the stannous sulfide nanosheet concentration of 0.1 mg/mL, respectively. To the dispersion, doxorubicin was added at a mass ratio of 0.5:1, 1:1, 2:1, 3:1, 4:1, and the mixture was stirred for 24 hours. The results are shown in Fig. 4. When the mass ratio of doxorubicin to stannous sulfide nanosheet is 2:1, the loading rate is about 180%. When the addition amount of doxorubicin is further increased, the load rate is increased less. When the mass ratio of doxorubicin to stannous sulfide nanosheet is 4:1, the loading rate of doxorubicin is 200%, so the ratio of doxorubicin to stannous sulfide nanosheet is controlled at 2-2.5:1. More suitable.
(3)体内实验(3) In vivo experiment
具体地，按如下方式进行五组实验：Specifically, five sets of experiments were performed as follows:
第一组：将PBS(磷酸缓冲盐溶液)通过瘤内注射的方式打入小鼠体内，观察肿瘤生长情况；其肿瘤相对尺寸如图5所示。The first group: PBS (phosphate buffered saline solution) was injected into the mouse by intratumoral injection to observe the tumor growth; the relative size of the tumor is shown in FIG.
第二组：单纯采用功率密度为1W/cm 2，波长为808nm的激光对小鼠肿瘤部位进行照射，观察肿瘤生长情况；其肿瘤相对尺寸如图5所示。 The second group: the tumor site was irradiated by laser with a power density of 1 W/cm 2 and a wavelength of 808 nm, and the tumor growth was observed. The relative size of the tumor is shown in Fig. 5.
第三组：将100μg/mL的硫化亚锡纳米片的PBS(磷酸缓冲盐溶液)分散液通过瘤内注射的方式打入小鼠体内，并采用功率密度为1W/cm 2，波长为808nm的激光对小鼠肿瘤部位进行照射，观察肿瘤生长情况；其肿瘤相对尺寸如图5所示。 The third group: 100 μg / mL of stannous sulfide nanosheets in PBS (phosphate buffered saline) dispersion was injected into mice by intratumoral injection, and a power density of 1 W / cm 2 and a wavelength of 808 nm were used. The laser was used to irradiate the tumor site of the mouse to observe the tumor growth; the relative size of the tumor is shown in Fig. 5.
第四组：将本发明实施例1制备的基于硫化亚锡纳米片的递药系统的PBS分散液(其中硫化亚锡纳米片的浓度为100μg/mL)通过瘤内注射的方式打入小鼠体内，观察肿瘤生长情况；其肿瘤相对尺寸如图5所示。The fourth group: the PBS dispersion of the stannous sulfide nanosheet-based delivery system prepared in Example 1 of the present invention (in which the concentration of the stannous sulfide nanosheet is 100 μg/mL) was injected into the mouse by intratumoral injection. In vivo, tumor growth was observed; the relative size of the tumor is shown in Figure 5.
第五组：将本发明实施例1制备的基于硫化亚锡纳米片的递药系统的PBS分散液(其中硫化亚锡纳米片的浓度为100μg/mL)通过瘤内注射的方式打入小鼠体内，并采用功率密度为1W/cm 2，波长为808nm的激光对小鼠肿瘤部位进行照射，观察肿瘤生长情况；其肿瘤相对尺寸如图5所示。 The fifth group: the PBS dispersion of the stannous sulfide nanosheet-based delivery system prepared in Example 1 of the present invention (in which the concentration of the stannous sulfide nanosheet is 100 μg/mL) was injected into the mouse by intratumoral injection. In vivo, a mouse with a power density of 1 W/cm 2 and a wavelength of 808 nm was irradiated to the tumor site of the mouse to observe the tumor growth; the relative size of the tumor is shown in FIG. 5 .
从图5的结果可以获知，小鼠经过本发明实施例的基于硫化亚锡纳米片的递药系统的治疗之后，肿瘤大小得到了很明显的控制，这是由于本发明实施例的基于硫化亚锡纳米片的递药系统，其硫化亚锡纳米片载体具有良好的光热效果，载药量高，从而使得该递药系统兼具硫化亚锡纳米片的光热杀死肿瘤和化疗药物的化疗治疗肿瘤的功效。It can be seen from the results of Fig. 5 that after the treatment of the sodium stannous nanosheet-based delivery system of the present invention, the tumor size is significantly controlled, which is due to the sulfurization of the embodiment of the present invention. The tin-nano-sheet delivery system, the stannous sulfide nano-sheet carrier has a good photothermal effect, and the drug loading is high, so that the delivery system has the photothermal heat killing tumor and chemotherapy drugs of the stannous sulfide nano-sheet. The efficacy of chemotherapy in the treatment of tumors.
需要说明的是，根据上述说明书的揭示和阐述，本发明所属领域的技术人员还可以对上述实施方式进行变更和修改。因此，本发明并不局限于上面揭示和描述的具体实施方式，对本发明的一些等同修改和变更也应当在本发明的权利要求的保护范围之内。此外，尽管本说明书中使用了一些特定的术语，但这些术语只是为了方便说明，并不对本发明构成任何限制。It should be noted that those skilled in the art to which the invention pertains may also make changes and modifications to the above-described embodiments. Therefore, the invention is not limited to the specific embodiments disclosed and described herein, and the equivalents of the invention are intended to be included within the scope of the appended claims. In addition, although specific terms are used in the specification, these terms are merely for convenience of description and do not limit the invention.

Claims (15)

  1. 一种基于硫化亚锡纳米片的递药系统，其特征在于，包括硫化亚锡纳米片，包覆在所述硫化亚锡纳米片表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡纳米片上的抗癌药物。A delivery system based on stannous sulfide nanosheets, comprising: stannous sulfide nanosheets, folic acid modified polyethylene glycol coated on the surface of the stannous sulfide nanosheets, and supported on the sulfide Anticancer drugs on stannite nanosheets.
  2. 如权利要求1所述的递药系统，其特征在于，所述硫化亚锡纳米片的长宽尺寸为50-200nm。The delivery system of claim 1 wherein said stannous sulfide nanoplatelets have a length to width dimension of from 50 to 200 nm.
  3. 如权利要求1所述的递药系统，其特征在于，所述硫化亚锡纳米片的厚度为1-10nm。The delivery system of claim 1 wherein said stannous sulfide nanoplatelets have a thickness of from 1 to 10 nm.
  4. 如权利要求1所述的递药系统，其特征在于，所述硫化亚锡纳米片与所述叶酸修饰的聚乙二醇的质量比为1:0.5-3。The delivery system of claim 1 wherein the mass ratio of said stannous sulfide nanoplatelets to said folic acid modified polyethylene glycol is 1: 0.5-3.
  5. 如权利要求1所述的递药系统，其特征在于，所述硫化亚锡纳米片与所述抗癌药物的质量比为1:1-2.5。The drug delivery system according to claim 1, wherein the mass ratio of said stannous sulfide nanosheet to said anticancer drug is from 1:1 to 2.5.
  6. 如权利要求1所述的递药系统，其特征在于，所述叶酸修饰的聚乙二醇分子中，聚乙二醇分子链两端分别为叶酸和氨基，所述叶酸通过酰胺键与聚乙二醇结合在一起，所述叶酸修饰的聚乙二醇通过静电引力吸附在所述硫化亚锡纳米片表面。The drug delivery system according to claim 1, wherein in the folic acid-modified polyethylene glycol molecule, the two ends of the polyethylene glycol molecular chain are folic acid and an amino group, respectively, and the folic acid passes through the amide bond and the polyethylene glycol. The diols are bonded together and the folic acid-modified polyethylene glycol is adsorbed on the surface of the stannous sulfide nanosheet by electrostatic attraction.
  7. 如权利要求1所述的递药系统，其特征在于，所述抗癌药物包括阿霉素。The delivery system of claim 1 wherein said anticancer drug comprises doxorubicin.
  8. 一种基于硫化亚锡纳米片的递药系统的制备方法，其特征在于，包括以下步骤：A method for preparing a drug delivery system based on stannous sulfide nanosheets, comprising the steps of:
    (1)将硫化亚锡块体研磨20-60分钟后，分散于有机溶剂中，并于10-35℃水浴超声8-12小时，随后离心收集沉淀，烘干，得到硫化亚锡纳米片；(1) After grinding the stannous sulfide block for 20-60 minutes, dispersing in an organic solvent, and sonicating in a water bath at 10-35 ° C for 8-12 hours, then collecting the precipitate by centrifugation and drying to obtain a stannous sulfide nanosheet;
    (2)将所述硫化亚锡纳米片分散于水中，得到硫化亚锡纳米片的水分散液， 再向所述水分散液中加入叶酸修饰的聚乙二醇，搅拌10-16小时，离心收集沉淀，得到表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片；(2) dispersing the stannous sulfide nanosheet in water to obtain an aqueous dispersion of stannous sulfide nanosheet, adding folic acid modified polyethylene glycol to the aqueous dispersion, stirring for 10-16 hours, and centrifuging The precipitate is collected to obtain a stannous sulfide nanosheet having a surface coated with a folic acid modified polyethylene glycol;
    (3)将所述表面包覆有叶酸修饰的聚乙二醇的硫化亚锡纳米片分散于水中，并加入抗癌药物，搅拌20-24小时后，离心收集沉淀，即得到基于硫化亚锡纳米片的递药系统，所述基于硫化亚锡纳米片的递药系统包括硫化亚锡纳米片，包覆在所述硫化亚锡纳米片表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡纳米片上的抗癌药物。(3) dispersing the stannous sulfide nanosheet coated with folic acid-modified polyethylene glycol in water, adding an anticancer drug, stirring for 20-24 hours, collecting the precipitate by centrifugation, thereby obtaining a stannous sulfide-based solution a nanosheet delivery system, the stannous sulfide nanosheet-based delivery system comprising a stannous sulfide nanosheet, a folic acid modified polyethylene glycol coated on the surface of the stannous sulfide nanosheet, and a load in the An anticancer drug on stannous sulfide nanosheets.
  9. 如权利要求8所述的制备方法，其特征在于，所述步骤(1)中，所述有机溶剂包括异丙醇、氮甲基吡咯烷酮中的一种或两种。The preparation method according to claim 8, wherein in the step (1), the organic solvent comprises one or both of isopropanol and nitrogen methylpyrrolidone.
  10. 如权利要求8所述的制备方法，其特征在于，所述步骤(1)中，在所述水浴超声之前，先将所述分散液采用探头超声4-8小时，所述探头超声的探头功率为150-600w。The preparation method according to claim 8, wherein in the step (1), before the ultrasonic bathing, the dispersion is ultrasonically probed for 4-8 hours, and the probe ultrasonic power of the probe is used. It is 150-600w.
  11. 如权利要求10所述的制备方法，其特征在于，所述探头超声过程中的温度为5-20℃。The preparation method according to claim 10, wherein the temperature during the ultrasonication of the probe is 5-20 °C.
  12. 如权利要求8所述的制备方法，其特征在于，所述步骤(1)中，所述离心收集沉淀的具体操作为：先以3000-6000转/分钟的转速离心0.5-1h，取上清液，然后将所述上清液以15000-20000转/分钟的转速离心0.5-1h，收集沉淀。The preparation method according to claim 8, wherein in the step (1), the specific operation of collecting the precipitate by centrifugation is: firstly centrifuging at a speed of 3000-6000 rpm for 0.5-1 h, and taking the supernatant. The solution was then centrifuged at 15,000-20000 rpm for 0.5-1 h and the precipitate was collected.
  13. 如权利要求8所述的制备方法，其特征在于，所述步骤(2)中，所述硫化亚锡纳米片的水分散液的浓度为0.2-2mg/mL。The preparation method according to claim 8, wherein in the step (2), the concentration of the aqueous dispersion of the stannous sulfide nanosheet is 0.2-2 mg/mL.
  14. 如权利要求8所述的制备方法，其特征在于，所述步骤(2)中，所述硫化亚锡纳米片与所述叶酸修饰的聚乙二醇的质量比为1:0.5-3。The preparation method according to claim 8, wherein in the step (2), the mass ratio of the stannous sulfide nanosheet to the folic acid-modified polyethylene glycol is 1:0.5-3.
  15. 如权利要求8所述的制备方法，其特征在于，所述步骤(2)和步骤(3)中，所述离心收集沉淀的具体操作为：以15000-20000转/分钟的转速离心0.5-1h 后，收集沉淀。The preparation method according to claim 8, wherein in the step (2) and the step (3), the specific operation of collecting the precipitate by centrifugation is: centrifuging at a speed of 15000-20000 rpm for 0.5-1 h. After that, the precipitate was collected.
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