WO2019153688A1 - Drug delivery system based on stannous sulphide quantum dots and preparation method therefor - Google Patents

Drug delivery system based on stannous sulphide quantum dots and preparation method therefor Download PDF

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WO2019153688A1
WO2019153688A1 PCT/CN2018/100237 CN2018100237W WO2019153688A1 WO 2019153688 A1 WO2019153688 A1 WO 2019153688A1 CN 2018100237 W CN2018100237 W CN 2018100237W WO 2019153688 A1 WO2019153688 A1 WO 2019153688A1
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stannous sulfide
quantum dots
sulfide quantum
delivery system
polyethylene glycol
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PCT/CN2018/100237
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French (fr)
Chinese (zh)
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张晗
谢中建
范涛健
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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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention claims the application No. 201810134790.0 filed on Feb. 09, 2018, the priority of the prior application entitled “A Stabilization System Based on Stannous Sulfide Quantum Dots and Its Preparation Method", the above prior application The content is incorporated into this text by way of introduction.
  • the invention relates to the technical field of tumor treatment, in particular to a delivery system based on stannous sulfide quantum dots 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 drug carrier having a pleated structure, which is inexpensive and stable in nature.
  • the present invention provides a stannous sulfide quantum dot-based delivery system, which uses a stannous sulfide quantum dot as a carrier to carry an anticancer drug, which has low carrier cost and is easy to prepare, and has a good photothermal effect, thereby
  • the drug delivery system combines the photothermal heat of stannous sulfide quantum dots to kill tumors and chemotherapy drugs to treat tumors, and has high clinical value for cancer treatment.
  • the present invention provides a stannous sulfide quantum dot based drug delivery system comprising a stannous sulfide quantum dot, a folic acid modified polyethylene glycol coated on the surface of the stannous sulfide quantum dot And an anticancer drug loaded on the stannous sulfide quantum dots.
  • 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 quantum dots are non-toxic and rich in content on the earth, and the stannous sulfide quantum dot drug loading rate 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 size of the stannous sulfide quantum dots is less than or equal to 10 nm. Choosing the right size can ensure that the drug delivery system has a better passive enrichment effect at the tumor site, and avoids the problem that the delivery system cannot enter the tumor site due to excessive size. Selecting a smaller size increases the specific surface area of the stannous quantum dots, thereby enhancing their photothermal effect and drug loading rate.
  • the stannous sulfide quantum dots have a size of 1-10 nm. Further, the stannous sulfide quantum dots have a size of 1-5 nm or 5-10 nm.
  • the mass ratio of the stannous sulfide quantum dots to the folic acid-modified polyethylene glycol is 1:0.5-20. Further, the mass ratio of the stannous sulfide quantum dots to the folic acid modified polyethylene glycol may be 1:1-10 or 1:10-20.
  • 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 quantum dots 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 bonded to the polyethylene glycol through an amide bond, and the folic acid is modified.
  • Polyethylene glycol is adsorbed on the surface of the stannous sulfide quantum dots by electrostatic attraction.
  • the mass ratio of the stannous sulfide quantum dots to the anticancer drug is 1:1 to 2.5, and further the mass ratio is 1:1-2.
  • the anticancer drug includes doxorubicin, and may also include other anticancer drugs.
  • the stannous sulfide quantum dot-based delivery system provided by the first aspect of the present invention has a low cost and easy preparation of a stannous sulfide quantum dot carrier, and has a good photothermal effect, so that the delivery system has both stannous sulfide.
  • the photothermal heat of quantum dots kills the efficacy of chemotherapy and chemotherapy for tumors and chemotherapy drugs, and has extremely high clinical value for cancer treatment.
  • the present invention provides a method for preparing a delivery system based on a stannous sulfide quantum dot, comprising the steps of:
  • the organic solvent includes one or both of isopropanol and nitromethylpyrrolidone.
  • 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 5-10 °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 5-10 ° C during the ultrasonic process, and when the temperature rises, the ice pack can be used for cooling.
  • the resulting stannous sulfide quantum dots are smaller and more uniform in size, resulting in a higher yield of stannous sulfide quantum dots of the desired size.
  • the specific operation of collecting the precipitate by centrifugation is: firstly, centrifuging at a rotational speed of 1,300-16,000 rpm for 0.5-1 h, taking the supernatant, and then the supernatant. The mixture was centrifuged at 17,000-25,000 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 quantum dots, and the second step of high-speed centrifugation to obtain the desired size of stannous sulfide quantum dots.
  • the concentration of the aqueous dispersion of the stannous sulfide quantum dots is 0.2-2 mg/mL.
  • the stirring speed is 600-1200 rpm.
  • the stirring speed is 600-1200 rpm.
  • 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 preparation method of the stannous sulfide quantum dot-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 large-scale production is easy to be realized.
  • Example 1 is an electron micrograph of a stannous sulfide quantum dot prepared in Example 1 of the present invention
  • Example 2 is a graph showing the photothermal effect measurement temperature rise of the stannous sulfide quantum dots coated with folic acid-modified polyethylene glycol on the surface of Example 1 of the present invention
  • FIG. 3 is a zeta potential of a stannous sulfide quantum dot-based delivery system according to Embodiment 1 of the present invention.
  • FIG. 4 is a graph showing the results of drug loading of a stannous sulfide quantum dot-based delivery system according to an embodiment of the present invention.
  • the present invention provides a stannous sulfide quantum dot based drug delivery system comprising a stannous sulfide quantum dot, a folic acid modified polyethylene glycol coated on the surface of the stannous sulfide quantum dot And an anticancer drug loaded on the stannous sulfide quantum dots.
  • 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 quantum dots are non-toxic and rich in content on the earth, and the stannous sulfide quantum dot drug loading rate 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 size of the stannous sulfide quantum dots is less than or equal to 10 nm.
  • the stannous sulfide quantum dots have a size of 1-10 nm.
  • the stannous sulfide quantum dots have a size of 1-5 nm.
  • the stannous sulfide quantum dots have a size of 5-10 nm.
  • the size of the stannous sulfide quantum dots is 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm or 10 nm.
  • the number of layers of the stannous sulfide quantum dots is not particularly limited.
  • Choosing the right size can ensure that the drug delivery system has a better passive enrichment effect at the tumor site, and avoids the problem that the delivery system cannot enter the tumor site due to excessive size. Selecting a smaller size increases the specific surface area of the stannous quantum dots, thereby enhancing their photothermal effect and drug loading rate.
  • the mass ratio of the stannous sulfide quantum dots to the folic acid modified polyethylene glycol is 1:0.5-20. Further, the mass ratio of the two may be 1:1-10. Further, the mass ratio of the two may be 1:10-20.
  • 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 quantum dots 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 quantum dots by electrostatic attraction.
  • the mass ratio of the stannous sulfide quantum dots to the anticancer drug is 1:1 to 2.5, and the mass ratio is 1:1-2. .
  • the mass ratio here is actually the mass (loading amount) of the anticancer drug loaded on the stannous sulfide quantum dot.
  • the final load can be controlled by adjusting the feed ratio according to the actual situation, for example, the load can be 50%-220%.
  • the anticancer drug includes doxorubicin, and may also include other anticancer drugs.
  • the anticancer drug is supported on the stannous sulfide quantum dot, and the folic acid modified polyethylene glycol is coated on the surface of the stannous sulfide quantum dot loaded with the anticancer drug, or
  • the folic acid-modified polyethylene glycol does not completely encapsulate the stannous sulfide quantum dots, and the anticancer drug is supported on the stannous sulfide quantum dots by a space between the folic acid-modified polyethylene glycols .
  • the stannous sulfide quantum dot-based delivery system provided by the first aspect of the invention has low cost and easy preparation of the stannous sulfide quantum dot carrier, and has good photothermal effect, so that the delivery system has both stannous sulfide quantum.
  • the efficacy of the photothermal heat killing tumor and chemotherapy drugs for the treatment of tumors has a very high clinical value for cancer treatment.
  • the present invention provides a method for preparing a delivery system based on a stannous sulfide quantum dot, comprising the steps of:
  • the organic solvent includes one or both of isopropanol and nitromethylpyrrolidone.
  • the mass concentration of the stannous sulfide after grinding in the organic solvent is from 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 5-10 °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 5-10 ° C during the ultrasonic process, and when the temperature rises, the ice pack can be used for cooling.
  • the resulting stannous sulfide quantum dots are smaller and more uniform in size, resulting in a higher yield of stannous sulfide quantum dots of the desired size.
  • the temperature of the water bath ultrasonication is maintained at 5-10 °C. If the temperature of the water bath is too high, the stannous sulfide quantum dots will be degraded.
  • the temperature range adopted by the present 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. Alternatively, the dispersion was sonicated in a 10 ° C water bath for 8-12 hours.
  • the specific operation of collecting the precipitate by centrifugation is: firstly, centrifuging at a rotational speed of 1,300-16,000 rpm for 0.5-1 h, taking the supernatant, and then the supernatant. The mixture was centrifuged at 17,000-25,000 rpm for 0.5-1 h, and the precipitate was collected.
  • the ultrasonicated dispersion is centrifuged at 15,000 rpm for 0.5-1 h, the supernatant is taken, and then the supernatant is centrifuged at 20000 rpm for 0.5-1 h, and collected. precipitation.
  • the first step of low-speed centrifugation is to separate and remove the larger portion of the stannous sulfide quantum dots, and the second step of high-speed centrifugation to obtain the desired size of stannous sulfide quantum dots.
  • the drying operation may be performed under vacuum at normal temperature.
  • 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 quantum dots 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 quantum dots to the folic acid-modified polyethylene glycol is 1:0.5-20.
  • the mass ratio of the two may be 1:1-10.
  • the mass ratio of the two may be 1:10-20.
  • 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. Alternatively, after centrifugation at a speed of 18,000-20000 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 ratio of the stannous sulfide quantum dots to the anticancer drug is 1:0.5-3. Further, optionally, the ratio of the stannous sulfide quantum dots to the anticancer drug is 1:1 to 3, and may be excessively added, for example, the mass ratio of the stannous sulfide quantum dots to the anticancer drug is 1:3. -4.
  • the anticancer drug comprises doxorubicin.
  • the preparation method of the stannous sulfide quantum dot-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 large-scale production is easy to be realized.
  • a method for preparing a delivery system based on stannous sulfide quantum dots 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 with a probe for 5 hours, and the probe ultrasonic power of the probe is 360 W, the probe During the ultrasonic process, the temperature is maintained at 5-10 ° C. During the temperature increase, the ice pack is used to cool down; then the dispersion is ultrasonicated in a water bath for 8 hours to obtain the ultrasonic dispersion, and the temperature of the ultrasonic bath is maintained at 5-10.
  • Example 1 is an electron micrograph of a stannous sulfide quantum dot prepared in Example 1 of the present invention. As can be seen from the figure, the obtained stannous sulfide quantum dot has a length to width dimension of less than 10 nm.
  • a method for preparing a delivery system based on stannous sulfide quantum dots comprising the steps of:
  • the stannous sulfide block was dispersed in nitromethylpyrrolidone to obtain a dispersion having a concentration of 1 mg/mL; the above dispersion was ultrasonicated with a probe for 8 hours, and the probe ultrasonic power of the probe was 150 W.
  • the temperature is kept at 10 °C.
  • the ice pack is used to cool down.
  • the dispersion is ultrasonicated in a water bath for 12 hours to obtain the ultrasonic dispersion.
  • the temperature of the ultrasonic bath is kept at 5-10 °C.
  • the water bath temperature is adjusted to be in the range of 5-10 ° C; after the ultrasonic dispersion is centrifuged, centrifuge at 13,000 rpm for 1 h, the supernatant is taken, and then the upper liquid is taken. The supernatant was centrifuged at 18,000 rpm for 1 h, and the precipitate was collected and dried to obtain a stannous sulfide quantum dot;
  • a method for preparing a delivery system based on stannous sulfide quantum dots comprising the steps of:
  • the ice pack is used to cool down; then the dispersion is sonicated in a water bath for 10 hours to obtain the ultrasonic dispersion, and the temperature of the ultrasonic bath is kept at 5- 10 ° C, when the temperature of the water bath rises, by changing the water to ensure that the temperature of the water bath is in the range of 5-10 ° C; after centrifugation of the ultrasonicated dispersion, centrifugation at 16000 rpm for 0.5 h, the supernatant is taken. Then, the supernatant was centrifuged at 25,000 rpm for 0.5 h, and the precipitate was collected and dried to obtain a stannous sulfide quantum dot;
  • the stannous sulfide quantum dot 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 stannous sulfide quantum dot concentration of 0.1 mg/mL, and the dispersion was obtained.
  • a laser with a power density of 1 W/cm 2 and a wavelength of 808 nm was used to vertically illuminate the cuvette, and the temperature of the dispersion was measured by an infrared thermometer. After 10 minutes of irradiation, the laser power was turned off and the temperature was lowered for 10 minutes. After 6 cycles, a temperature rise-down curve as shown in Fig. 2 was obtained. It can be seen from the temperature rise-down curve of FIG. 2 that the stannous sulfide quantum dots 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 the stannous sulfide quantum dots 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 quantum dots coated with the folic acid-modified polyethylene glycol prepared in the first embodiment of the present invention were ultrasonically dispersed in water to obtain a dispersion of stannous sulfide quantum dots having a concentration of 0.1 mg/mL, respectively.
  • the ratio of the mass ratio of the doxorubicin to the stannous sulfide quantum dots was 0.5:1, 1:1, 2:1, 3:1, and the doxorubicin was added to the dispersion, and the mixture was stirred for 24 hours.
  • the doxorubicin loading rate was as shown in Fig. 4.
  • the loading amount (that is, the mass ratio of doxorubicin to stannous sulfide quantum dots in the formed delivery system) is about 220%.
  • the addition amount of doxorubicin is further increased, the loading rate is no longer significantly increased, so it is suitable to control the dosing ratio of doxorubicin to stannous sulfide quantum dots at 1:1-3.
  • the first group PBS (phosphate buffered saline solution) was injected into the mice by intratumoral injection to observe the tumor growth.
  • PBS phosphate buffered saline solution
  • the second group the tumor site of the mouse was irradiated with a laser with a power density of 1 W/cm 2 and a wavelength of 808 nm, and the tumor growth was observed.
  • the third group 100 ⁇ g / mL of stannous sulfide quantum dot in PBS (phosphate buffered saline solution) dispersion was injected into the mouse by intratumoral injection, and the power density was 1 W/cm 2 and the wavelength was 808 nm. The laser was used to irradiate the tumor site of the mouse to observe the tumor growth.
  • PBS phosphate buffered saline solution
  • the fourth group the PBS dispersion of the stannous sulfide quantum dot-based delivery system prepared in Example 1 of the present invention (in which the concentration of stannous sulfide quantum dots is 100 ⁇ g/mL) is injected into the mouse by intratumoral injection. In vivo, observe tumor growth.
  • the fifth group the PBS dispersion of the stannous sulfide quantum dot-based delivery system prepared in Example 1 of the present invention (in which the concentration of stannous sulfide quantum dots 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.
  • Tumor size was clearly controlled after treatment of the mice based on the stannous sulfide quantum dot-based delivery system of the present invention. After 14 days, the tumor size of the first group was about 5 times that of the third group, and the tumor size of the first group was about 10 times that of the fifth group. This is because the stannous sulfide quantum dot-based delivery system of the embodiment of the present invention has a good photothermal effect and a high drug loading amount, so that the delivery system has the stannous sulfide quantum. The point of photothermal kills the efficacy of chemotherapy and chemotherapy for tumors and chemotherapy drugs.

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Abstract

A drug delivery system based on stannous sulphide quantum dots and a preparation method therefor, comprising stannous sulphide quantum dots, folic acid-modified polyethylene glycol coated on the surface of the stannous sulphide quantum dots, and anti-cancer drugs loaded on the stannous sulphide quantum dots.

Description

一种基于硫化亚锡量子点的递药***及其制备方法Drug delivery system based on stannous sulfide quantum dots and preparation method thereof
本发明要求于2018年02月09日递交的申请号为201810134790.0，发明名称为“一种基于硫化亚锡量子点的递药***及其制备方法”的在先申请的优先权，上述在先申请的内容以引入的方式并入本文本中。The present invention claims the application No. 201810134790.0 filed on Feb. 09, 2018, the priority of the prior application entitled "A Stabilization System Based on Stannous Sulfide Quantum Dots and Its Preparation Method", the above prior application The content is incorporated into this text by way of introduction.
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量子点的递药***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 quantum dots 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***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 drug carrier having 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量子点的递药***，以硫化亚锡量子点为载体负载抗癌药物，载体成本低且易制备，且具有良好的光热效果，从而使得该递药***兼具硫化亚锡量子点的光热杀死肿瘤和化疗药物的化疗***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 stannous sulfide quantum dot-based delivery system, which uses a stannous sulfide quantum dot as a carrier to carry an anticancer drug, which has low carrier cost and is easy to prepare, and has a good photothermal effect, thereby The drug delivery system combines the photothermal heat of stannous sulfide quantum dots to kill tumors and chemotherapy drugs to treat tumors, and has 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量子点的递药***，包括硫化亚锡量子点，包覆在所述硫化亚锡量子点表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡量子点上的抗癌药物。Specifically, in a first aspect, the present invention provides a stannous sulfide quantum dot based drug delivery system comprising a stannous sulfide quantum dot, a folic acid modified polyethylene glycol coated on the surface of the stannous sulfide quantum dot And an anticancer drug loaded on the stannous sulfide quantum dots.
硫化亚锡是一种层间通过范德华力结合的二维材料，制备硫化亚锡量子点所需的原料无毒并且在地球上的含量十分丰富，且硫化亚锡量子点药物负载率高，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 quantum dots are non-toxic and rich in content on the earth, and the stannous sulfide quantum dot drug loading rate 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，所述硫化亚锡量子点的尺寸小于或等于10nm。选择适合的尺寸能够保证递药***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***无法进入肿瘤部位的问题。选择较小尺寸可以增大硫化亚锡量子点的比表面积，从而增强其光热效果和药物负载率。In the present invention, the size of the stannous sulfide quantum dots is less than or equal to 10 nm. Choosing the right size can ensure that the drug delivery system has a better passive enrichment effect at the tumor site, and avoids the problem that the delivery system cannot enter the tumor site due to excessive size. Selecting a smaller size increases the specific surface area of the stannous quantum dots, thereby enhancing their photothermal effect and drug loading rate.
本发明中，所述硫化亚锡量子点的尺寸为1-10nm。进一步地，所述硫化亚锡量子点的尺寸为1-5nm或为5-10nm。In the present invention, the stannous sulfide quantum dots have a size of 1-10 nm. Further, the stannous sulfide quantum dots have a size of 1-5 nm or 5-10 nm.
本发明中，所述硫化亚锡量子点与所述叶酸修饰的聚乙二醇的质量比为1∶0.5-20。进一步地，所述硫化亚锡量子点与所述叶酸修饰的聚乙二醇的质量 比可为1∶1-10或为1∶10-20。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量子点的生物相容性和稳定性，提高其在水中的分散性。In the present invention, the mass ratio of the stannous sulfide quantum dots to the folic acid-modified polyethylene glycol is 1:0.5-20. Further, the mass ratio of the stannous sulfide quantum dots to the folic acid modified polyethylene glycol may be 1:1-10 or 1:10-20. 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 quantum dots and improve their dispersibility in water.
本发明中，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量子点表面。In the present invention, 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 bonded to the polyethylene glycol through an amide bond, and the folic acid is modified. Polyethylene glycol is adsorbed on the surface of the stannous sulfide quantum dots by electrostatic attraction.
本发明中，可选地，所述递药***中，所述硫化亚锡量子点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, in the delivery system, the mass ratio of the stannous sulfide quantum dots to the anticancer drug is 1:1 to 2.5, and further the mass ratio is 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量子点的递药***，其硫化亚锡量子点载体成本低且易制备，且具有良好的光热效果，从而使得该递药***兼具硫化亚锡量子点的光热杀死肿瘤和化疗药物的化疗***的功效，对于癌症治疗具有极高的临床价值。The stannous sulfide quantum dot-based delivery system provided by the first aspect of the present invention has a low cost and easy preparation of a stannous sulfide quantum dot carrier, and has a good photothermal effect, so that the delivery system has both stannous sulfide. The photothermal heat of quantum dots kills the efficacy of chemotherapy and chemotherapy for tumors and chemotherapy drugs, and has extremely high clinical value for cancer treatment.
第二方面，本发明提供了一种基于硫化亚锡量子点的递药***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 a stannous sulfide quantum dot, 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5℃-10℃水浴超声8-12小时，随后离心收集沉淀，烘干，得到硫化亚锡量子点；(1) After grinding the stannous sulfide block for 20-60 minutes, disperse in an organic solvent, and sonicate in a water bath at 5 ° C - 10 ° C for 8-12 hours, then collect the precipitate by centrifugation and dry to obtain a stannous sulfide quantum dot. ;
(2)将所述硫化亚锡量子点分散于水中，得到硫化亚锡量子点的水分散液，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量子点；(2) Dispersing the stannous sulfide quantum dots in water to obtain an aqueous dispersion of stannous sulfide quantum dots, 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 quantum dot 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量子点分散于水中，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 锡量子点的递药***，所述基于硫化亚锡量子点的递药***包括硫化亚锡量子点，包覆在所述硫化亚锡量子点表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡量子点上的抗癌药物。(3) Dispersing the stannous sulfide quantum dots coated with the 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 quantum dot delivery system, the stannous sulfide quantum dot-based delivery system comprising stannous sulfide quantum dots, folic acid-modified polyethylene glycol coated on the surface of the stannous sulfide quantum dots, and a load in the chamber An anticancer drug on a stannous quantum dot.
上述制备方法中，所述步骤(1)中，所述有机溶剂包括异丙醇和氮甲基吡咯烷酮中的一种或两种。In the above preparation method, in the step (1), the organic solvent includes one or both of isopropanol and nitromethylpyrrolidone.
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。可选地，所述探头超声过程中的温度为5-10℃。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5-10℃，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量子点尺寸更小，更均一，获得所需尺寸的硫化亚锡量子点的产率高。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. Optionally, the temperature of the probe during the ultrasonic process is 5-10 °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 5-10 ° C during the ultrasonic process, and when the temperature rises, the ice pack can be used for cooling. By combining the probe ultrasound with water bath ultrasound, the resulting stannous sulfide quantum dots are smaller and more uniform in size, resulting in a higher yield of stannous sulfide quantum dots of the desired size.
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13000-16000转/分钟的转速离心0.5-1h，取上清液，然后将所述上清液以17000-25000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量子点，第二步的高速离心分离即获得所需尺寸的硫化亚锡量子点。In the above preparation method, in the step (1), the specific operation of collecting the precipitate by centrifugation is: firstly, centrifuging at a rotational speed of 1,300-16,000 rpm for 0.5-1 h, taking the supernatant, and then the supernatant. The mixture was centrifuged at 17,000-25,000 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 quantum dots, and the second step of high-speed centrifugation to obtain the desired size of stannous sulfide quantum dots.
本发明制备方法中，所述步骤(2)中，所述硫化亚锡量子点的水分散液的浓度为0.2-2mg/mL。In the preparation method of the present invention, in the step (2), the concentration of the aqueous dispersion of the stannous sulfide quantum dots is 0.2-2 mg/mL.
本发明制备方法中，所述步骤(2)中，所述搅拌的速度为600-1200转/分钟。In the preparation method of the present invention, in the step (2), the stirring speed is 600-1200 rpm.
本发明制备方法中，所述步骤(3)中，所述搅拌的速度为600-1200转/ 分钟。In the preparation method of the present invention, in the step (3), the stirring speed is 600-1200 rpm.
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.
本发明第二方面提供的基于硫化亚锡量子点的递药***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 quantum dot-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 large-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量子点的电镜图；1 is an electron micrograph of a stannous sulfide quantum dot 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量子点的光热效果测量升温曲线图；2 is a graph showing the photothermal effect measurement temperature rise of the stannous sulfide quantum dots coated with folic acid-modified polyethylene glycol on the surface of Example 1 of the present invention;
图3为本发明实施例1的基于硫化亚锡量子点的递药***的Zeta电位；3 is a zeta potential of a stannous sulfide quantum dot-based 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量子点的递药***的药物负载量结果图。4 is a graph showing the results of drug loading of a stannous sulfide quantum dot-based delivery system according to an embodiment 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.
具体地，第一方面，本发明提供了一种基于硫化亚锡量子点的递药***，包括硫化亚锡量子点，包覆在所述硫化亚锡量子点表面的叶酸修饰的聚乙二 醇，以及负载在所述硫化亚锡量子点上的抗癌药物。Specifically, in a first aspect, the present invention provides a stannous sulfide quantum dot based drug delivery system comprising a stannous sulfide quantum dot, a folic acid modified polyethylene glycol coated on the surface of the stannous sulfide quantum dot And an anticancer drug loaded on the stannous sulfide quantum dots.
硫化亚锡是一种层间通过范德华力结合的二维材料，制备硫化亚锡量子点所需的原料无毒并且在地球上的含量十分丰富，且硫化亚锡量子点药物负载率高，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 quantum dots are non-toxic and rich in content on the earth, and the stannous sulfide quantum dot drug loading rate 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.
本发明实施方式中，所述硫化亚锡量子点的尺寸小于或等于10nm。可选地，所述硫化亚锡量子点的尺寸为1-10nm。进一步可选地，所述硫化亚锡量子点的尺寸为1-5nm。进一步可选地，所述硫化亚锡量子点的尺寸为5-10nm。进一步可选地，所述硫化亚锡量子点的尺寸为1nm、2nm、3nm、4nm、5nm、6nm、7nm、8nm、9nm或10nm。可选地，对所述硫化亚锡量子点的层数不做特殊限制。In an embodiment of the invention, the size of the stannous sulfide quantum dots is less than or equal to 10 nm. Optionally, the stannous sulfide quantum dots have a size of 1-10 nm. Further optionally, the stannous sulfide quantum dots have a size of 1-5 nm. Further optionally, the stannous sulfide quantum dots have a size of 5-10 nm. Further optionally, the size of the stannous sulfide quantum dots is 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm or 10 nm. Alternatively, the number of layers of the stannous sulfide quantum dots is not particularly limited.
选择适合的尺寸能够保证递药***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***无法进入肿瘤部位的问题。选择较小尺寸可以增大硫化亚锡量子点的比表面积，从而增强其光热效果和药物负载率。Choosing the right size can ensure that the drug delivery system has a better passive enrichment effect at the tumor site, and avoids the problem that the delivery system cannot enter the tumor site due to excessive size. Selecting a smaller size increases the specific surface area of the stannous quantum dots, thereby enhancing their photothermal effect and drug loading rate.
本发明实施方式中，可选地，所述硫化亚锡量子点与所述叶酸修饰的聚乙二醇的质量比为1∶0.5-20。进一步地，两者的质量比可为1∶1-10。进一步地，两者的质量比可为1∶10-20。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量子点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量子点表面。In an embodiment of the invention, optionally, the mass ratio of the stannous sulfide quantum dots to the folic acid modified polyethylene glycol is 1:0.5-20. Further, the mass ratio of the two may be 1:1-10. Further, the mass ratio of the two may be 1:10-20. 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 quantum dots 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 quantum dots by electrostatic attraction.
本发明实施方式中，可选地，所述递药***中，所述硫化亚锡量子点与所 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。这里的质量比实际上为负载在所述硫化亚锡量子点上的所述抗癌药物的质量(负载量)。当然，可以根据实际情况，通过调节投料比来控制最终的负载量，如可以使负载量为50％-220％。In an embodiment of the present invention, optionally, in the drug delivery system, the mass ratio of the stannous sulfide quantum dots to the anticancer drug is 1:1 to 2.5, and the mass ratio is 1:1-2. . The mass ratio here is actually the mass (loading amount) of the anticancer drug loaded on the stannous sulfide quantum dot. Of course, the final load can be controlled by adjusting the feed ratio according to the actual situation, for example, the load can be 50%-220%.
本发明实施方式中，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 an embodiment of the present invention, optionally, the anticancer drug includes doxorubicin, and may also include other anticancer drugs.
本发明实施方式中，所述抗癌药物负载在所述硫化亚锡量子点上，所述叶酸修饰的聚乙二醇包覆在所述负载有抗癌药物的硫化亚锡量子点表面，或者，所述叶酸修饰的聚乙二醇没有完全包裹所述硫化亚锡量子点，所述抗癌药物通过所述叶酸修饰的聚乙二醇之间的空隙负载在所述硫化亚锡量子点上。In an embodiment of the invention, the anticancer drug is supported on the stannous sulfide quantum dot, and the folic acid modified polyethylene glycol is coated on the surface of the stannous sulfide quantum dot loaded with the anticancer drug, or The folic acid-modified polyethylene glycol does not completely encapsulate the stannous sulfide quantum dots, and the anticancer drug is supported on the stannous sulfide quantum dots by a space between the folic acid-modified polyethylene glycols .
本发明第一方面提供的基于硫化亚锡量子点的递药***，其硫化亚锡量子点载体成本低易制备，且具有良好的光热效果，从而使得该递药***兼具硫化亚锡量子点的光热杀死肿瘤和化疗药物的化疗***的功效，对于癌症治疗具有极高的临床价值。The stannous sulfide quantum dot-based delivery system provided by the first aspect of the invention has low cost and easy preparation of the stannous sulfide quantum dot carrier, and has good photothermal effect, so that the delivery system has both stannous sulfide quantum. The efficacy of the photothermal heat killing tumor and chemotherapy drugs for the treatment of tumors 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量子点的递药***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 a stannous sulfide quantum dot, 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5℃-10℃水浴超声8-12小时，随后离心收集沉淀，烘干，得到硫化亚锡量子点；(1) After grinding the stannous sulfide block for 20-60 minutes, disperse in an organic solvent, and sonicate in a water bath at 5 ° C - 10 ° C for 8-12 hours, then collect the precipitate by centrifugation and dry to obtain a stannous sulfide quantum dot. ;
(2)将所述硫化亚锡量子点分散于水中，得到硫化亚锡量子点的水分散液，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量子点；(2) Dispersing the stannous sulfide quantum dots in water to obtain an aqueous dispersion of stannous sulfide quantum dots, 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 quantum dot 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量子点分散于水 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量子点的递药***，所述基于硫化亚锡量子点的递药***包括硫化亚锡量子点，包覆在所述硫化亚锡量子点表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡量子点上的抗癌药物。(3) Dispersing the stannous sulfide quantum dots coated with the 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 quantum dot delivery system, the stannous sulfide quantum dot-based delivery system comprising stannous sulfide quantum dots, folic acid-modified polyethylene glycol coated on the surface of the stannous sulfide quantum dots, and a load in the chamber An anticancer drug on a stannous quantum dot.
上述制备方法中，所述步骤(1)中，所述有机溶剂包括异丙醇和氮甲基吡咯烷酮中的一种或两种。可选地，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 nitromethylpyrrolidone. Alternatively, the mass concentration of the stannous sulfide after grinding in the organic solvent is from 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5-10℃。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5-10℃，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量子点尺寸更小，更均一，获得所需尺寸的硫化亚锡量子点的产率高。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 5-10 °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 5-10 ° C during the ultrasonic process, and when the temperature rises, the ice pack can be used for cooling. By combining the probe ultrasound with water bath ultrasound, the resulting stannous sulfide quantum dots are smaller and more uniform in size, resulting in a higher yield of stannous sulfide quantum dots of the desired size.
本发明制备方法中，可选地，水浴超声的温度保持在5-10℃。水浴温度过高会导致硫化亚锡量子点降解，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。可选地，将所述分散液于10℃水浴超声8-12小时。In the preparation method of the present invention, optionally, the temperature of the water bath ultrasonication is maintained at 5-10 °C. If the temperature of the water bath is too high, the stannous sulfide quantum dots will be degraded. The temperature range adopted by the present 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. Alternatively, the dispersion was sonicated in a 10 ° C water bath for 8-12 hours.
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13000-16000转/分钟的转速离心0.5-1h，取上清液，然后将所述上清液以17000-25000转/分钟的转速离心0.5-1h，收集沉淀。可选地，将所述经超声后的分散液以15000转/分钟的转速离心0.5-1h，取上清液，然后将所述上清液以 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量子点，第二步的高速离心分离即获得所需尺寸的硫化亚锡量子点。In the above preparation method, in the step (1), the specific operation of collecting the precipitate by centrifugation is: firstly, centrifuging at a rotational speed of 1,300-16,000 rpm for 0.5-1 h, taking the supernatant, and then the supernatant. The mixture was centrifuged at 17,000-25,000 rpm for 0.5-1 h, and the precipitate was collected. Optionally, the ultrasonicated dispersion is centrifuged at 15,000 rpm for 0.5-1 h, the supernatant is taken, and then the supernatant is centrifuged at 20000 rpm for 0.5-1 h, and collected. precipitation. The first step of low-speed centrifugation is to separate and remove the larger portion of the stannous sulfide quantum dots, and the second step of high-speed centrifugation to obtain the desired size of stannous sulfide quantum dots.
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.
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，所述硫化亚锡量子点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 quantum dots 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，步骤(2)中，所述硫化亚锡量子点与所述叶酸修饰的聚乙二醇的质量比为1∶0.5-20。可选地，两者的质量比可为1∶1-10。进一步地，两者的质量比可为1∶10-20。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, in the step (2), the mass ratio of the stannous sulfide quantum dots to the folic acid-modified polyethylene glycol is 1:0.5-20. Alternatively, the mass ratio of the two may be 1:1-10. Further, the mass ratio of the two may be 1:10-20. 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。可选地，以18000-20000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. Alternatively, after centrifugation at a speed of 18,000-20000 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，所述硫化亚锡量子点与所述抗癌药物的投料比为1∶0.5-3。进一步可选地，所述硫化亚锡量子点与所述抗癌药物的投料比为1∶1-3当然也可以过量加入，如硫化亚锡量子点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 ratio of the stannous sulfide quantum dots to the anticancer drug is 1:0.5-3. Further, optionally, the ratio of the stannous sulfide quantum dots to the anticancer drug is 1:1 to 3, and may be excessively added, for example, the mass ratio of the stannous sulfide quantum dots 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量子点的递药***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 quantum dot-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 large-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.
实施例1Example 1
一种基于硫化亚锡量子点的递药***的制备方法，包括以下步骤：A method for preparing a delivery system based on stannous sulfide quantum dots, 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，探头超声的探头功率为360w，探头超声过程中保持温度为5-10℃，期间当温度升高时，使用冰袋进行降温；再将分散液于水浴超声8小时，得到经超声后的分散液，水浴超声的温度保持在5-10℃，当水浴温度升高，通过换水以保证水浴温度在5-10℃范围内；将经超声后的分散液离心后，以15000转/分钟的转速离心0.5h，取上清液，然后将上清液以20000转/分钟的转速离心0.5h，收集沉淀，烘干， 得到硫化亚锡量子点；(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 with a probe for 5 hours, and the probe ultrasonic power of the probe is 360 W, the probe During the ultrasonic process, the temperature is maintained at 5-10 ° C. During the temperature increase, the ice pack is used to cool down; then the dispersion is ultrasonicated in a water bath for 8 hours to obtain the ultrasonic dispersion, and the temperature of the ultrasonic bath is maintained at 5-10. °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 5-10 °C; after centrifuging the ultrasonicated dispersion, centrifuging at 15,000 rpm for 0.5 h, taking the supernatant, then The supernatant was centrifuged at 20000 rpm for 0.5 h, and the precipitate was collected and dried to obtain a stannous sulfide quantum dot;
(2)将硫化亚锡量子点分散于水中，得到浓度为0.5mg/mL的硫化亚锡量子点的水分散液，再按照硫化亚锡量子点与叶酸修饰的聚乙二醇(FA-PEG-NH 2)的质量比为1∶2，向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20000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量子点； (2) dispersing the stannous sulfide quantum dots in water to obtain an aqueous dispersion of stannous sulfide quantum dots at a concentration of 0.5 mg/mL, followed by stannous sulfide quantum dots and folic acid modified polyethylene glycol (FA-PEG) The mass ratio of -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 20,000 rpm for 0.5 hour to collect the precipitate. a stannous sulfide quantum dot 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量子点分散于水中，并按照硫化亚锡量子点与抗癌药物的投料比为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20000转/分钟的转速离心0.5h，收集沉淀，即得到基于硫化亚锡量子点的递药***，基于硫化亚锡量子点的递药***包括硫化亚锡量子点，包覆在硫化亚锡量子点表面的叶酸修饰的聚乙二醇，以及负载在硫化亚锡量子点上的抗癌药物。(3) Dispersing the stannous sulfide quantum dots of the obtained surface coated with folic acid-modified polyethylene glycol in water, and adding the anticancer drug Azomycin according to the ratio of the stannous sulfide quantum dots to the anticancer drug 1:2 After stirring at 800 rpm for 24 hours, and then centrifuging at 20000 rpm for 0.5 h, the precipitate was collected to obtain a stannous sulfide quantum dot-based delivery system, and a stannous sulfide quantum dot-based delivery system. These include stannous sulfide quantum dots, folic acid-modified polyethylene glycol coated on the surface of stannous sulfide quantum dots, and anticancer drugs loaded on stannous sulfide quantum dots.
图1为本发明实施例1制备得到的硫化亚锡量子点的电镜图，从图中可以看出，所得硫化亚锡量子点的长宽尺寸小于10nm。1 is an electron micrograph of a stannous sulfide quantum dot prepared in Example 1 of the present invention. As can be seen from the figure, the obtained stannous sulfide quantum dot has a length to width dimension of less than 10 nm.
实施例2Example 2
一种基于硫化亚锡量子点的递药***的制备方法，包括以下步骤：A method for preparing a delivery system based on stannous sulfide quantum dots, 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8小时，探头超声的探头功率为150w，探头超声过程中保持温度为10℃，期间当温度升高时，使用冰袋进行降温；再将分散液于水浴超声12小时，得到经超声后的分散液，水浴超声的温度保持在5-10℃，当水浴温度升高，通过换水以保证水浴温度在 5-10℃范围内；将经超声后的分散液离心后，以13000转/分钟的转速离心1h，取上清液，然后将上清液以18000转/分钟的转速离心1h，收集沉淀，烘干，得到硫化亚锡量子点；(1) After grinding the stannous sulfide block for 40 minutes, it was dispersed in nitromethylpyrrolidone to obtain a dispersion having a concentration of 1 mg/mL; the above dispersion was ultrasonicated with a probe for 8 hours, and the probe ultrasonic power of the probe was 150 W. During the ultrasonic process of the probe, the temperature is kept at 10 °C. During the temperature increase, the ice pack is used to cool down. Then the dispersion is ultrasonicated in a water bath for 12 hours to obtain the ultrasonic dispersion. The temperature of the ultrasonic bath is kept at 5-10 °C. When the temperature of the water bath rises, the water bath temperature is adjusted to be in the range of 5-10 ° C; after the ultrasonic dispersion is centrifuged, centrifuge at 13,000 rpm for 1 h, the supernatant is taken, and then the upper liquid is taken. The supernatant was centrifuged at 18,000 rpm for 1 h, and the precipitate was collected and dried to obtain a stannous sulfide quantum dot;
(2)将硫化亚锡量子点分散于水中，得到浓度为1.0mg/mL的硫化亚锡量子点的水分散液，再按照硫化亚锡量子点与叶酸修饰的聚乙二醇(FA-PEG-NH 2)的质量比为1∶2.5，向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18000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量子点； (2) dispersing the stannous sulfide quantum dots in water to obtain an aqueous dispersion of stannous sulfide quantum dots at a concentration of 1.0 mg/mL, followed by stannous sulfide quantum dots and folic acid modified polyethylene glycol (FA-PEG) The mass ratio of -NH 2 ) was 1:2.5, and folic acid-modified polyethylene glycol was added to the aqueous dispersion, and the mixture was stirred at 800 rpm for 16 hours, and then centrifuged at 18,000 rpm for 1 hour to collect a precipitate. Obtaining a stannous sulfide quantum dot 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量子点分散于水中，并按照硫化亚锡量子点与抗癌药物的投料比为1∶1加入抗癌药物阿霉素，以800转/分钟搅拌24小时后，然后以18000转/分钟的转速离心1h，收集沉淀，即得到基于硫化亚锡量子点的递药***，基于硫化亚锡量子点的递药***包括硫化亚锡量子点，包覆在硫化亚锡量子点表面的叶酸修饰的聚乙二醇，以及负载在硫化亚锡量子点上的抗癌药物。(3) Dispersing the stannous sulfide quantum dots of the obtained surface coated with folic acid-modified polyethylene glycol in water, and adding the anticancer drug Azomycin according to the ratio of the stannous sulfide quantum dots to the anticancer drug After stirring at 800 rpm for 24 hours, and then centrifuging at 18,000 rpm for 1 h, the precipitate was collected to obtain a stannous sulfide quantum dot-based delivery system, and the stannous sulfide quantum dot-based delivery system included Stannous sulfide quantum dots, folic acid-modified polyethylene glycol coated on the surface of stannous sulfide quantum dots, and anticancer drugs loaded on stannous sulfide quantum dots.
实施例3Example 3
一种基于硫化亚锡量子点的递药***的制备方法，包括以下步骤：A method for preparing a delivery system based on stannous sulfide quantum dots, comprising the steps of:
(1)将硫化亚锡块体研磨60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4小时，探头超声的探头功率为600w，探头超声过程中保持温度为5-10℃，期间当温度升高时，使用冰袋进行降温；再将分散液于水浴超声10小时，得到经超声后的分散液，水浴超声的温度保持在5-10℃，当水浴温度升高，通过换水以保证水浴温度在 5-10℃范围内；将经超声后的分散液离心后，以16000转/分钟的转速离心0.5h，取上清液，然后将上清液以25000转/分钟的转速离心0.5h，收集沉淀，烘干，得到硫化亚锡量子点；(1) After grinding the stannous sulfide block for 60 minutes, it was dispersed in nitromethylpyrrolidone to obtain a dispersion having a concentration of 1 mg/mL; the above dispersion was ultrasonicated by a probe for 4 hours, and the probe ultrasonic power of the probe was 600 W. During the ultrasonic process of the probe, the temperature is kept at 5-10 °C. During the temperature increase, the ice pack is used to cool down; then the dispersion is sonicated in a water bath for 10 hours to obtain the ultrasonic dispersion, and the temperature of the ultrasonic bath is kept at 5- 10 ° C, when the temperature of the water bath rises, by changing the water to ensure that the temperature of the water bath is in the range of 5-10 ° C; after centrifugation of the ultrasonicated dispersion, centrifugation at 16000 rpm for 0.5 h, the supernatant is taken. Then, the supernatant was centrifuged at 25,000 rpm for 0.5 h, and the precipitate was collected and dried to obtain a stannous sulfide quantum dot;
(2)将硫化亚锡量子点分散于水中，得到浓度为2.0mg/mL的硫化亚锡量子点的水分散液，再按照硫化亚锡量子点与叶酸修饰的聚乙二醇(FA-PEG-NH 2)的质量比为1∶10，向水分散液中加入叶酸修饰的聚乙二醇，以1000转/分钟搅拌10小时后，再以20000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量子点； (2) dispersing the stannous sulfide quantum dots in water to obtain an aqueous dispersion of stannous sulfide quantum dots at a concentration of 2.0 mg/mL, followed by stannous sulfide quantum dots and folic acid modified polyethylene glycol (FA-PEG) The mass ratio of -NH 2 ) was 1:10, and folic acid-modified polyethylene glycol was added to the aqueous dispersion, and the mixture was stirred at 1000 rpm for 10 hours, and then centrifuged at 20000 rpm for 0.5 hour to collect a precipitate. a stannous sulfide quantum dot 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量子点分散于水中，并按照硫化亚锡量子点与抗癌药物的投料比为1∶3加入抗癌药物阿霉素，以800转/分钟搅拌24小时后，然后以18000转/分钟的转速离心1h，收集沉淀，即得到基于硫化亚锡量子点的递药***，基于硫化亚锡量子点的递药***包括硫化亚锡量子点，包覆在硫化亚锡量子点表面的叶酸修饰的聚乙二醇，以及负载在硫化亚锡量子点上的抗癌药物。(3) Dispersing the stannous sulfide quantum dots of the obtained surface coated with the folic acid-modified polyethylene glycol in water, and adding the anticancer drug Azomycin according to the ratio of the stannous sulfide quantum dots to the anticancer drug 1:3 After stirring at 800 rpm for 24 hours, and then centrifuging at 18,000 rpm for 1 h, the precipitate was collected to obtain a stannous sulfide quantum dot-based delivery system, and the stannous sulfide quantum dot-based delivery system included Stannous sulfide quantum dots, folic acid-modified polyethylene glycol coated on the surface of stannous sulfide quantum dots, and anticancer drugs loaded on stannous sulfide quantum dots.
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量子点超声分散于水中，得到硫化亚锡量子点浓度为0.1mg/mL的分散液，将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10分钟后关闭激光电源，降温10分钟，循环6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量子点具有良好的光热效应。 The stannous sulfide quantum dot 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 stannous sulfide quantum dot concentration of 0.1 mg/mL, and the dispersion was obtained. In the cuvette, a laser with a power density of 1 W/cm 2 and a wavelength of 808 nm was used to vertically illuminate the cuvette, and the temperature of the dispersion was measured by an infrared thermometer. After 10 minutes of irradiation, the laser power was turned off and the temperature was lowered for 10 minutes. After 6 cycles, a temperature rise-down curve as shown in Fig. 2 was obtained. It can be seen from the temperature rise-down curve of FIG. 2 that the stannous sulfide quantum dots 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量子点的递药***分散于水中，得到硫化亚锡量子点浓度为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量子点的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 quantum dot-based delivery system prepared in Example 1 of the present invention in water to obtain a dispersion of stannous sulfide quantum dot concentration of 0.1 mg/mL, and measuring the zeta potential of the dispersion; The zeta potential of the stannous sulfide quantum dots 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量子点超声分散于水中，得到硫化亚锡量子点浓度为0.1mg/mL的分散液，分别按阿霉素与硫化亚锡量子点的投料质量比为0.5∶1、1∶1、2∶1、3∶1向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量子点的投料比为3∶1时，负载量(即形成的递药***中，阿霉素与硫化亚锡量子点的质量比)约为220％，当进一步提高阿霉素的加入量时，负载率不再显著增加，因此将阿霉素与硫化亚锡量子点的投料比控制在1∶1-3较合适。The stannous sulfide quantum dots coated with the folic acid-modified polyethylene glycol prepared in the first embodiment of the present invention were ultrasonically dispersed in water to obtain a dispersion of stannous sulfide quantum dots having a concentration of 0.1 mg/mL, respectively. The ratio of the mass ratio of the doxorubicin to the stannous sulfide quantum dots was 0.5:1, 1:1, 2:1, 3:1, and the doxorubicin was added to the dispersion, and the mixture was stirred for 24 hours. The doxorubicin loading rate was as shown in Fig. 4. It is shown that when the ratio of doxorubicin to stannous sulfide quantum dots is 3:1, the loading amount (that is, the mass ratio of doxorubicin to stannous sulfide quantum dots in the formed delivery system) is about 220%. When the addition amount of doxorubicin is further increased, the loading rate is no longer significantly increased, so it is suitable to control the dosing ratio of doxorubicin to stannous sulfide quantum dots at 1:1-3.
(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。The first group: PBS (phosphate buffered saline solution) was injected into the mice by intratumoral injection to observe the tumor growth.
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。 The second group: the tumor site of the mouse was irradiated with a laser with a power density of 1 W/cm 2 and a wavelength of 808 nm, and the tumor growth was observed.
第三组：将100μg/mL的硫化亚锡量子点的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。 The third group: 100 μg / mL of stannous sulfide quantum dot in PBS (phosphate buffered saline solution) dispersion was injected into the mouse by intratumoral injection, and the power density was 1 W/cm 2 and the wavelength was 808 nm. The laser was used to irradiate the tumor site of the mouse to observe the tumor growth.
第四组：将本发明实施例1制备的基于硫化亚锡量子点的递药***的PBS分散液(其中硫化亚锡量子点的浓度为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。The fourth group: the PBS dispersion of the stannous sulfide quantum dot-based delivery system prepared in Example 1 of the present invention (in which the concentration of stannous sulfide quantum dots is 100 μg/mL) is injected into the mouse by intratumoral injection. In vivo, observe tumor growth.
第五组：将本发明实施例1制备的基于硫化亚锡量子点的递药***的PBS分散液(其中硫化亚锡量子点的浓度为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。 The fifth group: the PBS dispersion of the stannous sulfide quantum dot-based delivery system prepared in Example 1 of the present invention (in which the concentration of stannous sulfide quantum dots 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.
小鼠经过本发明实施例的基于硫化亚锡量子点的递药***的治疗之后，肿瘤大小得到了很明显的控制。14天后，第一组的肿瘤大小是第三组的5倍左右，第一组的肿瘤大小是第五组的10倍左右。这是由于本发明实施例的基于硫化亚锡量子点的递药***，其硫化亚锡量子点载体具有良好的光热效果，载药量高，从而使得该递药***兼具硫化亚锡量子点的光热杀死肿瘤和化疗药物的化疗***的功效。Tumor size was clearly controlled after treatment of the mice based on the stannous sulfide quantum dot-based delivery system of the present invention. After 14 days, the tumor size of the first group was about 5 times that of the third group, and the tumor size of the first group was about 10 times that of the fifth group. This is because the stannous sulfide quantum dot-based delivery system of the embodiment of the present invention has a good photothermal effect and a high drug loading amount, so that the delivery system has the stannous sulfide quantum. The point of photothermal kills the efficacy of chemotherapy and chemotherapy for tumors and chemotherapy drugs.
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 (20)

  1. 一种基于硫化亚锡量子点的递药***，其中，包括硫化亚锡量子点，包覆在所述硫化亚锡量子点表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡量子点上的抗癌药物。A tellurization system based on stannous sulfide quantum dots, comprising stannous sulfide quantum dots, folic acid-modified polyethylene glycol coated on the surface of the stannous sulfide quantum dots, and supported on the stannous sulfide Anticancer drugs on quantum dots.
  2. 如权利要求1所述的递药***，其中，所述硫化亚锡量子点的尺寸小于或等于10nm。The drug delivery system of claim 1 wherein said stannous sulfide quantum dots have a size of less than or equal to 10 nm.
  3. 如权利要求2所述的递药***，其中，所述硫化亚锡量子点的尺寸为1-10nm。The delivery system of claim 2 wherein said stannous sulfide quantum dots have a size of from 1 to 10 nm.
  4. 如权利要求3所述的递药***，其中，所述硫化亚锡量子点的尺寸为1-5nm。The delivery system of claim 3 wherein said stannous sulfide quantum dots have a size of from 1 to 5 nm.
  5. 如权利要求3所述的递药***，其中，所述硫化亚锡量子点的尺寸为5-10nm。The delivery system of claim 3 wherein said stannous sulfide quantum dots have a size of 5-10 nm.
  6. 如权利要求1所述的递药***，其中，所述硫化亚锡量子点与所述叶酸修饰的聚乙二醇的质量比为1∶0.5-20。The delivery system of claim 1 wherein the mass ratio of said stannous sulfide quantum dots to said folic acid modified polyethylene glycol is 1: 0.5-20.
  7. 如权利要求6所述的递药***，其中，所述硫化亚锡量子点与所述叶酸修饰的聚乙二醇的质量比可为1∶1-10。The drug delivery system of claim 6 wherein the mass ratio of said stannous sulfide quantum dots to said folic acid modified polyethylene glycol is from 1: 1 to 10.
  8. 如权利要求6所述的递药***，其中，所述硫化亚锡量子点与所述叶酸修饰的聚乙二醇的质量比可为1∶10-20。The drug delivery system of claim 6 wherein the mass ratio of said stannous sulfide quantum dots to said folic acid modified polyethylene glycol is from 1:10 to 20.
  9. 如权利要求1所述的递药***，其中，所述递药***中，所述硫化亚锡量子点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 a mass ratio of said stannous sulfide quantum dots to said anticancer drug in said delivery system is from 1:1 to 2.5.
  10. 如权利要求1所述的递药***，其中，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量子点表面。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 an amide bond and a polyethylene glycol. In combination, the folic acid-modified polyethylene glycol is adsorbed on the surface of the stannous sulfide quantum dots by electrostatic attraction.
  11. 如权利要求1所述的递药***，其中，所述抗癌药物包括阿霉素。The delivery system of claim 1 wherein said anticancer drug comprises doxorubicin.
  12. 一种基于硫化亚锡量子点的递药***的制备方法，其中，包括以下步骤：A preparation method of a stannous sulfide quantum dot-based delivery system, comprising the following steps:
    (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5℃-10℃水浴超声8-12小时，随后离心收集沉淀，烘干，得到硫化亚锡量子点；(1) After grinding the stannous sulfide block for 20-60 minutes, disperse in an organic solvent, and sonicate in a water bath at 5 ° C - 10 ° C for 8-12 hours, then collect the precipitate by centrifugation and dry to obtain a stannous sulfide quantum dot. ;
    (2)将所述硫化亚锡量子点分散于水中，得到硫化亚锡量子点的水分散液，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量子点；(2) Dispersing the stannous sulfide quantum dots in water to obtain an aqueous dispersion of stannous sulfide quantum dots, 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 quantum dot 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量子点分散于水中，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量子点的递药***，所述基于硫化亚锡量子点的递药***包括硫化亚锡量子点，包覆在所述硫化亚锡量子点表面的叶酸修饰的聚乙二醇，以及负载在所述硫化亚锡量子点上的抗癌药物。(3) Dispersing the stannous sulfide quantum dots coated with the 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 quantum dot delivery system, the stannous sulfide quantum dot-based delivery system comprising stannous sulfide quantum dots, folic acid-modified polyethylene glycol coated on the surface of the stannous sulfide quantum dots, and a load in the chamber An anticancer drug on a stannous quantum dot.
  13. 如权利要求12所述的制备方法，其中，所述步骤(1)中，所述有机溶剂包括异丙醇和氮甲基吡咯烷酮中的一种或两种。The production method according to claim 12, wherein in the step (1), the organic solvent comprises one or both of isopropanol and nitromethylpyrrolidone.
  14. 如权利要求12所述的制备方法，其中，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 12, wherein in the step (1), 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.
  15. 如权利要求14所述的制备方法，其中，所述探头超声过程中的温度 为5-10℃。The production method according to claim 14, wherein the temperature of the probe during the ultrasonic process is 5 - 10 °C.
  16. 如权利要求12所述的制备方法，其中，所述步骤(1)中，所述离心收集沉淀的具体操作为：先以13000-16000转/分钟的转速离心0.5-1h，取上清液，然后将所述上清液以17000-25000转/分钟的转速离心0.5-1h，收集沉淀。The preparation method according to claim 12, wherein in the step (1), the specific operation of collecting the precipitate by centrifugation is: firstly, centrifuging at a rotational speed of 1,300-16,000 rpm for 0.5-1 h, and taking the supernatant. The supernatant was then centrifuged at 17,000-25,000 rpm for 0.5-1 h and the precipitate was collected.
  17. 如权利要求12所述的制备方法，其中，所述步骤(2)中，所述硫化亚锡量子点的水分散液的浓度为0.2-2mg/mL。The production method according to claim 12, wherein in the step (2), the aqueous dispersion of the stannous sulfide quantum dots has a concentration of 0.2 to 2 mg/mL.
  18. 如权利要求12所述的制备方法，其中，所述步骤(2)中，所述搅拌的速度为600-1200转/分钟。The production method according to claim 12, wherein in the step (2), the stirring speed is 600 to 1200 rpm.
  19. 如权利要求12所述的制备方法，其中，所述步骤(3)中，所述搅拌的速度为600-1200转/分钟。The production method according to claim 12, wherein in the step (3), the stirring speed is 600 to 1200 rpm.
  20. 如权利要求12所述的制备方法，其中，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。The preparation method according to claim 12, wherein in the step (2) and the step (3), the specific operation of collecting the precipitate by centrifugation is: after centrifuging at a speed of 15,000-20000 rpm for 0.5-1 h, The precipitate was collected.
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