CN109550050B - Melanin-loaded molybdenum dioxide drug-loaded compound and preparation and application thereof - Google Patents
Melanin-loaded molybdenum dioxide drug-loaded compound and preparation and application thereof Download PDFInfo
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- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a melanin-loaded molybdenum dioxide drug-loaded compound, and preparation and application thereof, wherein the drug-loaded compound comprises MoO2The nano-sheet, the modification unit mPEG-DSPE, melanin and adriamycin. The preparation method comprises the following steps: (1) ammonium molybdate, ultrapure water, hydrochloric acid, cyclohexane and oleylamine are mixed and dispersed for reaction to obtain MoO2(ii) a (2) Modifying PEG to obtain MoO2-PEG; (3) loading melanin to obtain MoO2-PEG-Mel; (4) loading model drug DOX to obtain MoO2-PEG-Mel-DOX, useful for the synergistic treatment of breast cancer tumors. The preparation method is simple to operate, experiment conditions are easy to control, and the method has the prospect of industrial implementation.
Description
Technical Field
The invention belongs to the technical field of drug-loaded nano materials, and particularly relates to a melanin-loaded molybdenum dioxide nano drug-loaded compound, and a preparation method and application thereof.
Background
Malignant tumors are a serious threat to human health and life, the incidence and mortality of tumors are increasing in recent years, and tumor therapy has become a major challenge in the current medical research field. At present, the treatment means of tumors mainly comprises surgical excision, radiotherapy and chemical drug therapy, and some tumors also utilize methods such as gene therapy, biological therapy and the like as adjuvant therapy. Chemotherapy drugs, as a means of systemic treatment, are effective against the invasion and metastasis of tumor cells, and thus chemotherapy dominates the overall treatment of tumors. However, the traditional chemotherapeutic drugs still have certain limitations, such as poor water solubility, short remission period, slow excretion, obvious toxic and side effects, cross-drug resistance and the like. The therapeutic efficacy of such chemical agents remains to be improved. In addition, compared with the traditional radiotherapy, the photothermal therapy has the advantages of better micro-invasiveness and better treatment effect.
The appearance of nanotechnology provides a new idea for designing antitumor drugs. The nanotechnology is combined with multidisciplinary cross cooperation, and the method has wide application prospects in the aspects of tumor imaging, tumor diagnosis, tumor targeted therapy and the like. The nano-sheet drug delivery system has the advantages of easy surface targeted modification, long circulation and retention time, easy penetration into cells, slow release and controlled release and the like, and can overcome the defects of poor biological selectivity, low utilization rate, poor stability, short drug action time, serious adverse reaction and the like of the existing small-molecule drug preparation.
Notably, the microenvironment at the tumor site is slightly warmer than normal tissue (1-2℃. higher than normal), slightly acidic pH (slightly lower than normal) and excessive cell proliferation with high enzyme concentration, which can reduce the therapeutic effect of cytotoxic drugs. Based on these characteristics, some temperature or pH responsive drug delivery vehicles, commonly referred to as "smart nanocarriers", can be synthesized because they can undergo rapid, abrupt and reversible structural/property changes at the tumor site to cope with small changes in the surrounding environment.
The molybdenum dioxide nano material has low cost and wide optical absorption, and has photothermal treatment, pH response and drug loading capacity, so that the molybdenum dioxide nano material has great potential in application in biological medicine. At present, research on a molybdenum dioxide-based controlled release system further enhances the photo-thermal treatment effect, and meanwhile, in the research combined with chemotherapy, a drug-loading system with double responses of near infrared light and pH is realized, so that the related research on improving the treatment effect and reducing toxic and side effects gradually draws wide attention of students.
Melanin is a natural biological pigment, is almost distributed in all organisms, has wide physiological functions, is a good target for photoacoustic imaging and photothermal therapy, and can be well chelated with metals and medicines. Melanin is also a good scavenger for oxygen free radicals, and can be used for antioxidation, anti-aging, anti-radiation, anti-ultraviolet, etc. In addition, melanin also has physiological functions of resisting virus, regulating immunity, resisting tumor, etc. The melanin is a natural biological pigment, and has good biodegradability and biocompatibility. In view of the special physicochemical properties, the melanin has good application prospect in medical diagnosis and treatment. The melanin has strong absorption in near infrared region, is a good photo-thermal agent, and can be used for photo-thermal treatment and tumor ablation. Melanin can be combined with many drugs as a drug carrier. As a trapping agent, melanin can be used for antioxidation, anti-aging, anti-radiation, etc. In addition, melanin is used for treating diseases associated with melanin deficiency, such as senile dementia, xeroderma pigmentosum, etc.
Wenyan Yin et al developed a photothermal material of molybdenum oxide nanosheets with a photothermal conversion efficiency of 27.3% under 808nm laser irradiation (Yin W, Bao T, Zhang X, et al, biodegradable MoOx nanoparticles with an effective near-isolated photothermal and a photosensitive synthetic cancer therapy [ J ] Nanoscale,2018, 10.).
Disclosure of Invention
The invention aims to solve the technical problem of providing a melanin-loaded molybdenum dioxide nano drug-loaded compound, a preparation method and application thereof, and overcomes the defect of low photo-thermal conversion efficiency of a molybdenum oxide material.
The invention relates to a melanin-loaded molybdenum dioxide nano drug-loaded compound, which comprises molybdenum dioxide MoO2The nano-sheet, distearoyl phosphatidyl ethanolamine mPEG-DSPE modified by modifying unit polyethylene glycol, melanin and adriamycin DOX.
The invention also provides a preparation method of the melanin-loaded molybdenum dioxide nano drug-loaded compound, which comprises the following steps:
(1) dispersing ammonium molybdate into ultrapure water, adding hydrochloric acid, performing ultrasonic treatment to obtain ammonium molybdate dispersion liquid, dispersing oleylamine into cyclohexane to obtain oleylamine dispersion liquid, slowly adding the oleylamine dispersion liquid into the ammonium molybdate dispersion liquid, performing magnetic stirring, then reacting, centrifuging and washing to obtain MoO2A material; wherein the mass ratio of ammonium molybdate to oleylamine is 3:2-3:5, and the volume ratio of ultrapure water, hydrochloric acid and cyclohexane is 30:1:10-30:1.5: 13;
(2) MoO obtained in the step (1)2Dispersing into chloroform, performing ice bath ultrasonic treatment, adding mPEG-DSPE, stirring at room temperature overnight, performing rotary evaporation, washing and centrifuging to obtain MoO2-a PEG material; wherein, MoO2The mass ratio of the mPEG-DSPE to the mPEG-DSPE is 1:5-1: 10;
(3) MoO obtained in the step (2)2Dispersing PEG into ultrapure water, sonicating, adding melanin, continuing sonicating, stirring overnight at room temperature, centrifuging and washing to obtain MoO2-PEG-Mel; wherein the melanin is in contact with MoO2-the mass ratio of PEG is 1:5 to 1: 10;
(4) MoO obtained in the step (3)2mixing-PEG-Mel with model drug DOX in ultrapure water, stirring overnight at room temperature, centrifuging and washing to obtain load blackMolybdenum dioxide nano drug-loaded composite MoO of pigment2-PEG-Mel-DOX; wherein, MoO2The mass ratio of the PEG-Mel to the DOX is 1:1-1: 3.
The concentration of the hydrochloric acid in the step (1) is 1 mol/L.
The pH value of the ammonium molybdate dispersion liquid in the step (1) is 5.0-5.5.
The ultrasonic treatment time in the step (1) is 5-10 min; the magnetic stirring time is 0.5-1 h.
The technological parameters of the reaction in the step (1) are as follows: the reaction temperature is 180 ℃ and 260 ℃, and the reaction time is 12-15 h.
The washing process conditions in the step (1) are as follows: washing with chloroform and ethanol alternately for 3-5 times.
The washing process conditions in the steps (2), (3) and (4) are as follows: washing with ultrapure water for 3-5 times.
The time of ice bath ultrasonic treatment in the step (2) is 100-200 min. The purpose of ice bath ultrasound is to process large nanosheets into small fragments, reducing particle size.
The ultrasonic treatment time in the step (3) is 10-15 min.
The time for continuing the ultrasonic treatment in the step (3) is 0.5-1 h.
The invention further provides application of the melanin-loaded molybdenum dioxide nano drug-loaded compound in the fields of tumor targeting and cooperative treatment.
The drug-loaded nano compound MoO prepared by the invention2-PEG-Mel-DOX for drug release assay comprising:
(1) preparing a DOX phosphoric acid buffer solution and an acetic acid buffer solution, detecting a maximum absorption value in an ultraviolet spectrophotometer, and fitting DOX standard curves in two pH environments;
(2) adding MoO2Dissolving the PEG-Mel-DOX drug-loaded composite material in a buffer solution, placing the buffer solution in two dialysis bags, respectively placing the dialysis bags in two pH values, oscillating for a certain time, sampling at different time points, and supplementing the buffer solution to obtain a pH response drug release curve.
(3) Adding MoO2-PEG-Mel-DOX medicine carrying composite material is dissolved in acetic acidAnd (3) placing the saline buffer solution into a dialysis bag, then respectively irradiating with different powers for a certain time, sampling at different time points, and supplementing a buffer solution to obtain a photothermal response drug release curve.
The pH value of the phosphoric acid buffer solution in the step (1) is 7-7.5; the pH value of the acetic acid buffer solution is 5-6.
And (2) in the step (1), the concentration of the DOX standard curve is 0.005-0.08 mg/mL.
The two pH values in the step (2) are respectively as follows: phosphoric acid buffer solution with pH value of 7-7.4, acetic acid buffer solution with pH value of 5-6; the oscillation time is 24h-72h, and the volume is 10-15 mL.
MoO required for drug release in the step (2)2The weight of the-PEG-Mel-DOX drug-loaded composite material is 0.5-4 mg.
MoO required for drug release in the step (3)2The PEG-Mel-DOX drug-loaded composite material is 0.5-4 mg, and the pH value of the acetic acid buffer solution is 5-6; the wavelength of the laser is 808nm, and the irradiation power is 1.0-3.0W/cm2Irradiating for 1-5 min; the oscillation time is 24h-72h, and the volume is 10-15 mL.
According to the invention, the PEG is used for modifying the molybdenum dioxide, so that the effect of increasing the stability of the medicine-carrying compound is achieved. After the drug-loaded complex enters cells through an endocytic pathway through irradiation of near infrared light, endosome membrane is unstable due to local heating caused by photothermal effect, so that the drug and the carrier thereof are promoted to escape from endosome. The effect that most anticancer drugs should be rapidly released into the cytosol is achieved. Thereby greatly improving the curative effect of the medicine. The invention constructs a synergistic treatment system of chemotherapy and photothermal treatment, and further improves the photothermal conversion efficiency of the photothermal material molybdenum dioxide by loading melanin with good biocompatibility.
Advantageous effects
(1) The method is simple, mild in reaction condition, easy to operate and has an industrial implementation prospect.
(2) MoO of the invention2the-PEG-Mel-DOX drug-loaded composite material has high drug loading capacity, can be slowly released for a long time, and has pH and near infrared light dual-response conveying capacityThe release rate is high in a low pH value environment, and the preparation is suitable for a microenvironment of tumor tissues; and generates hyperpyrexia under the irradiation of laser with lower power, and has the potential of long-acting and slow-release of tumors.
(3) The nano-particles obtained by the invention have better water dispersibility and biocompatibility, and have the prospect of being applied to tumor targeting and cooperative treatment.
(4) MoO of the invention2The melanin loaded in the PEG-Mel-DOX medicine-carrying composite material can realize the enhancement of the photo-thermal treatment effect of the melanin on breast cancer cells, and the photo-thermal conversion efficiency can reach 69.1%.
Drawings
FIG. 1 is a TEM spectrum of molybdenum dioxide nanosheets of example 1;
FIG. 2 shows MoO in example 12、MoO2-PEG、MoO2-PEG-Mel、MoO2-a uv spectrum of PEG-Mel-DOX;
FIG. 3 shows MoO in example 12、PEG、MoO2-PEG、Mel、MoO2-PEG-Mel、DOX、MoO2-an infrared spectrum of PEG-Mel-DOX;
FIG. 4 shows MoO in example 12、MoO2-PEG、MoO2-PEG-Mel、MoO2-Zeta potential change of PEG-Mel-DOX;
FIG. 5 shows MoO in example 12Hydrodynamic diameter variation of the PEG material;
FIG. 6 shows MoO in example 22In vitro drug release behavior of PEG-Mel-DOX under different conditions.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Example 1
(1) Dispersing 3g of ammonium molybdate into 30ml of ultrapure water, then adding 1ml of hydrochloric acid (the concentration is 1mol/L), carrying out ultrasonic treatment for five minutes, dispersing 2g of oleylamine into 10ml of cyclohexane, slowly adding the oleylamine dispersion into the ammonium molybdate dispersion, carrying out magnetic stirring for half an hour, reacting the product at 200 ℃ for 15 hours, collecting the product after the reaction is finished, centrifuging, washing with trichloromethane and ethanol, and collecting to obtain the molybdenum dioxide material.
(2) And (2) dispersing the molybdenum dioxide material prepared in the step (1) into 50ml of chloroform solution, then carrying out ice-bath ultrasonic treatment on the solution for 150 minutes, processing large nanosheet layers into small fragments, and reducing the particle size. After the ultrasonic treatment, 500mg of mPEG-DSPE was added, stirred at room temperature overnight, chloroform was evaporated by rotary evaporation to give a dark brown dried substance, and the product was washed with ultrapure water and collected by centrifugation to give MoO2-a PEG material.
(3) MoO prepared in the step (2)2-the PEG material was dispersed in 50ml of ultrapure water and sonicated for ten minutes, after which the mixture was mixed in a mass ratio of 10: 1, carrying out ultrasonic treatment on the mixed solution for half an hour, stirring at room temperature overnight, centrifuging to collect a product, washing with ultrapure water, and collecting the product to obtain MoO2-PEG-Mel。
(4) MoO obtained in the step (3)2Mixing PEG-Mel and model drug DOX at a mass ratio of 1:1 in ultrapure water, stirring at room temperature overnight, centrifuging, washing with ultrapure water for multiple times, and collecting product, namely melanin-loaded molybdenum dioxide nano drug-loaded compound MoO2-PEG-Mel-DOX。
The supernatant was collected by centrifugation and the absorbance of the supernatant was measured,
the final product MoO of this example was added2And (3) dispersing the-PEG-Mel-DOX into ultrapure water, shooting a TEM, and observing the morphology as shown in figure 1, wherein the nanosheet material with uniform morphology is successfully prepared.
The structure of each stage of the product of this example was confirmed, and the MoO before and after drug loading was measured2、MoO2-PEG、MoO2-PEG-Mel、MoO2The ultraviolet absorbances and the ultraviolet spectrum changes of the four materials of-PEG-Mel-DOX are shown in figure 2, and the characteristic peak of melanin at 270nm can be knownThe characteristic peak of DOX at 480nm proves the successful loading of melanin and DOX.
Further MoO before and after drug loading2、MoO2-PEG、MoO2-PEG-Mel、MoO2The four materials of-PEG-Mel-DOX are subjected to infrared characterization, the change of an infrared spectrum is shown in figure 3, and 1067cm can be known-1And 958cm-1Successful loading of PEG was noted, passing through 1705cm-1And 1607cm-1Successful loading of melanin was noted, passing through 1577cm-1And 1620cm-1The successful loading of DOX is known.
Performing physical and chemical property test on the synthesized product, and measuring MoO before and after drug loading2、MoO2-PEG、MoO2-PEG-Mel、MoO2The potential changes of the four materials of-PEG-Mel-DOX, and the results are shown in FIG. 4, the potential before and after the material changes, which helps to prove the successful preparation of the material at different stages, and meanwhile, a larger absolute value shows that the dispersibility of the material is good.
Further on MoO2The hydrodynamic diameter result of the PEG material subjected to DLS detection is shown in FIG. 5, and the particle size of the material is 160 +/-10 nm, which accords with the EPR effect, is beneficial to passive targeting aggregation of the material in a tumor region, and can prove that the material is successfully synthesized.
Example 2
MoO of the invention2-method for performing drug release experiments with PEG-Mel-DOX drug loaded system:
(1) preparing a DOX phosphoric acid buffer solution and an acetic acid buffer solution, detecting the maximum absorption value in an ultraviolet spectrophotometer, and fitting DOX standard curves under two pH environments (5.8 and 7.4);
(2) 5mg of MoO2Dissolving the PEG-Mel-DOX drug-loaded composite material in 5mL of buffer solution, placing the solution in two dialysis bags, placing the dialysis bags in buffer solutions with pH 5.8 and pH 7.0 respectively, shaking, sampling at different time points, supplementing fresh buffer solution, and obtaining a pH response drug release curve.
(3) Mixing 5mgMoO2The PEG-Mel-DOX drug-loaded composite materials are respectively dissolved in 5mL of buffer solutions (5.8 and 7.4) with different pH values, placed in dialysis bags, and then respectively used808nm 1W/cm2The test piece is placed in a shaking table to be oscillated for 5min, sampling and detection are carried out at different time points, and buffer solution is supplemented, so that a photothermal response drug release curve is obtained.
The release curves of DOX under two pH environments and with or without laser irradiation are shown in figure 6, it can be seen that the release under different pH conditions has significant difference, the photothermal effect can significantly improve the release of the drug, the pH of the tumor tissue is lower than that of the normal tissue cells, and the release of the drug-loaded material just meets the characteristic. The drug-loaded composite material is shown to be a pH/light multiple stimulation response type drug carrier which can be used for treating tumors.
Comparative example 1
Wenyan Yin et al developed a photothermal material of molybdenum oxide nanosheets with a photothermal conversion efficiency of 27.3% under 808nm laser irradiation (Yin W, Bao T, Zhang X, et al, biodegradable MoOx nanoparticles with an effective near-isolated photothermal and a photosensitive synthetic cancer therapy [ J ] Nanoscale,2018, 10.).
In the invention, the preparation of the molybdenum oxide nanosheet layer is modified, and the melanin is loaded to further enhance the photothermal effect of the material, so that the photothermal conversion efficiency can reach 69.1%, and the treatment effect of the material on tumors is further enhanced.
Claims (9)
1. A melanin-loaded molybdenum dioxide nano drug-loaded compound comprises molybdenum dioxide MoO2The nano-sheet, distearoyl phosphatidyl ethanolamine mPEG-DSPE modified by modifying unit polyethylene glycol, melanin Mel and adriamycin DOX;
the preparation method of the melanin-loaded molybdenum dioxide nano drug-loaded compound comprises the following steps:
(1) dispersing ammonium molybdate into ultrapure water, adding hydrochloric acid, performing ultrasonic treatment to obtain ammonium molybdate dispersion liquid, dispersing oleylamine into cyclohexane to obtain oleylamine dispersion liquid, slowly adding the oleylamine dispersion liquid into the ammonium molybdate dispersion liquid, performing magnetic stirring, then reacting, centrifuging and washing to obtain MoO2A material; wherein the mass ratio of ammonium molybdate to oleylamine is 3:2-3:5, ultrapure water, hydrochloric acid and cyclohexaneThe volume ratio of the alkane is 30:1:10-30:1.5:13, and the technological parameters of the reaction are as follows: the reaction temperature is 180 ℃ and 260 ℃, and the reaction time is 12-15 h;
(2) MoO obtained in the step (1)2Dispersing into chloroform, performing ice bath ultrasonic treatment, adding mPEG-DSPE, stirring at room temperature overnight, performing rotary evaporation, washing and centrifuging to obtain MoO2-a PEG material; wherein, MoO2The mass ratio of the mPEG-DSPE to the mPEG-DSPE is 1:5-1: 10;
(3) MoO obtained in the step (2)2Dispersing PEG into ultrapure water, sonicating, adding melanin, continuing sonicating, stirring overnight at room temperature, centrifuging and washing to obtain MoO2-PEG-Mel; wherein the melanin is in contact with MoO2-the mass ratio of PEG is 1:5 to 1: 10;
(4) MoO obtained in the step (3)2mixing-PEG-Mel with model drug DOX in ultrapure water, stirring overnight at room temperature, centrifuging, and washing to obtain melanin-loaded molybdenum dioxide nano drug-loaded compound MoO2-PEG-Mel-DOX; wherein, MoO2The mass ratio of the PEG-Mel to the DOX is 1:1-1: 3.
2. A method of preparing the melanin-loaded molybdenum dioxide drug-loaded nanocomposite of claim 1, comprising:
(1) dispersing ammonium molybdate into ultrapure water, adding hydrochloric acid, performing ultrasonic treatment to obtain ammonium molybdate dispersion liquid, dispersing oleylamine into cyclohexane to obtain oleylamine dispersion liquid, slowly adding the oleylamine dispersion liquid into the ammonium molybdate dispersion liquid, performing magnetic stirring, then reacting, centrifuging and washing to obtain MoO2A material; wherein the mass ratio of ammonium molybdate to oleylamine is 3:2-3:5, the volume ratio of ultrapure water, hydrochloric acid and cyclohexane is 30:1:10-30:1.5:13, and the technological parameters of the reaction are as follows: the reaction temperature is 180 ℃ and 260 ℃, and the reaction time is 12-15 h;
(2) MoO obtained in the step (1)2Dispersing into chloroform, performing ice bath ultrasonic treatment, adding mPEG-DSPE, stirring at room temperature overnight, performing rotary evaporation, washing and centrifuging to obtain MoO2-a PEG material; wherein, MoO2The mass ratio of the mPEG-DSPE to the mPEG-DSPE is 1:5-1: 10;
(3) MoO obtained in the step (2)2Dispersing PEG into ultrapure water, sonicating, adding melanin, continuing sonicating, stirring overnight at room temperature, centrifuging and washing to obtain MoO2-PEG-Mel; wherein the melanin is in contact with MoO2-the mass ratio of PEG is 1:5 to 1: 10;
(4) MoO obtained in the step (3)2mixing-PEG-Mel with model drug DOX in ultrapure water, stirring overnight at room temperature, centrifuging, and washing to obtain melanin-loaded molybdenum dioxide nano drug-loaded compound MoO2-PEG-Mel-DOX; wherein, MoO2The mass ratio of the PEG-Mel to the DOX is 1:1-1: 3.
3. The method of claim 2, wherein: the concentration of the hydrochloric acid in the step (1) is 1 mol/L; the pH of the ammonium molybdate dispersion is 5.0 to 5.5.
4. The method of claim 2, wherein: the ultrasonic treatment time in the step (1) is 5-10 min; the magnetic stirring time is 0.5-1 h.
5. The method of claim 2, wherein: the washing process conditions in the step (1) are as follows: washing with chloroform and ethanol alternately for 3-5 times.
6. The method of claim 2, wherein: the washing process conditions in the steps (2), (3) and (4) are as follows: washing with ultrapure water for 3-5 times.
7. The method of claim 2, wherein: the time of ice bath ultrasonic treatment in the step (2) is 100-200 min.
8. The method of claim 2, wherein: the ultrasonic treatment time in the step (3) is 10-15 min; the continuous ultrasonic treatment time is 0.5-1 h.
9. The application of the melanin-loaded molybdenum dioxide nano drug-loaded compound in the preparation of tumor-targeted and synergistic therapeutic drugs according to claim 1.
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