CN112972366A - Injectable photothermal chemotherapy sensitization drug-loaded hydrogel and preparation method thereof - Google Patents
Injectable photothermal chemotherapy sensitization drug-loaded hydrogel and preparation method thereof Download PDFInfo
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- CN112972366A CN112972366A CN202110134054.7A CN202110134054A CN112972366A CN 112972366 A CN112972366 A CN 112972366A CN 202110134054 A CN202110134054 A CN 202110134054A CN 112972366 A CN112972366 A CN 112972366A
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Abstract
The invention discloses an injectable photothermal chemotherapy sensitization drug-loaded hydrogel and a preparation method thereof. The invention relates to an injectable photothermal chemotherapy sensitization drug-loaded hydrogel which comprises the following raw materials: injectable hydrogels and drug-loaded nanomicelles; the injectable hydrogel is synthetic phospholipid with temperature-sensitive characteristic, and the drug-loaded nano-micelle comprises nano-particles with photo-thermal conversion effect. The loading and long-term release of hydrophilic anticancer drugs and hydrophobic anticancer drugs are realized by taking the injectable photothermal chemotherapy sensitization drug-loaded hydrogel as a carrier, after intratumoral administration, the retention time in tumors is prolonged, the multiple long-acting killing effect of the thermochemical chemotherapy on the tumors is realized, the anti-tumor effect is enhanced, and the toxic and side effects of the drugs on normal tissues are reduced.
Description
Technical Field
The invention belongs to the technical field of nano biomedicine, and particularly relates to an injectable photothermal chemotherapy sensitization drug-loaded hydrogel and a preparation method thereof.
Background
The intratumoral injection is used as a non-intravenous administration mode in tumor treatment, and directly delivers the anti-tumor drug to a focus, so that the concentration of the drug at a tumor part can be greatly improved, the distribution of the drug in normal tissues/organs is obviously reduced, the advantages of enhanced curative effect, reduced toxicity, minimally invasive property and the like are achieved, and the injection is widely applied to clinical tumor treatment. Although chemotherapy drugs can enhance local drug concentration after being injected into tumor, most chemotherapy drugs lack long-term retention capability in tumor, and are diffused to the whole body under the condition of tumor blood flow scouring and dilution, so that the advantages of high local drug concentration and low whole body drug concentration which are special in an injection mode in tumor are greatly reduced, and the potential of chemotherapy cannot be fully exerted. In addition, with the development of technology and the continuous and deep understanding of tumors, people gradually recognize that for malignant tumors, single-mode treatment means such as chemotherapy, radiotherapy, surgery and the like are difficult to achieve ideal treatment effects. Therefore, the concept of multi-mode combined tumor complex therapy is in force. For example, in the field of primary liver cancer treatment, chemotherapy and thermotherapy are commonly used, and hepatic artery chemoembolization (TACE) and radiofrequency ablation (RFA) are clinically used for treatment, but both treatment methods have certain defects, the tumor radical treatment rate is not high, and certain recurrence risk exists. However, the comprehensive treatment of RFA and TACE can obviously improve the complete necrosis rate of the tumor, obtain more exact clinical curative effect and reduce the recurrence risk of the postoperative tumor. The multifunctional nano drug-carrying system provides an effective platform for the combined use of thermotherapy and chemotherapy, and the combined use of thermotherapy and chemotherapy based on the novel nano drug-carrying system is becoming a research hotspot of tumor treatment. Nevertheless, there are some drawbacks to combination therapies based on photothermal chemotherapy: (1) the stability of the photothermal conversion performance is poor; (2) the laser power used for photothermal therapy is too high; (3) the drug release behavior in photothermal chemotherapy treatment is not controllable.
Disclosure of Invention
The invention aims to provide an injectable photothermal chemotherapy sensitization drug-loaded hydrogel and a preparation method thereof aiming at the defects of the prior art.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: an injectable photothermal chemotherapy sensitization drug-loaded hydrogel comprises the following preparation raw materials: injectable hydrogels and drug-loaded nanomicelles; the injectable hydrogel is synthetic phospholipid with temperature-sensitive characteristic, and the drug-loaded nano-micelle comprises nano-particles with photo-thermal conversion effect.
The injectable hydrogel is a synthetic polymer with temperature-sensitive property, is liquid in a normal state, is convenient to inject in vivo on one hand, and is converted into a gel state from a liquid state after near-infrared laser irradiation when reaching a focus position for photothermal chemotherapy combined treatment on the other hand, and wraps the drug-carrying nano micelle, so that the drugs in the drug-carrying nano micelle can be controllably and slowly released.
The nano particles with the photothermal conversion effect can absorb heat generated by near infrared light through plasma resonance or energy transition, so that local high temperature is caused, tumor cells are finally killed, and meanwhile, due to the photothermal conversion effect of the nano particles, the drugs in the injectable photothermal chemotherapy sensitization drug-loaded hydrogel can be controllably and slowly released: after the irradiation of the near infrared light, the release of the medicine is obviously improved, and after the irradiation of the near infrared laser light source is stopped, the release of the medicine becomes gentle again.
As a preferred embodiment of the present invention, the injectable hydrogel includes at least one of poloxamer block copolymer, PNIPAM copolymer, polyethylene glycol/polyester block copolymer; the nano particles with the photo-thermal conversion effect are at least one of nano gold, nano gold derivatives, nano graphene and black phosphorus.
More preferably, the injectable hydrogel is a combination of a poloxamer block copolymer and a PNIPAM copolymer; the weight ratio of the poloxamer block copolymer to the PNIPAM copolymer is 1-2: 1-2, more preferably, the weight ratio of poloxamer block copolymer to PNIPAM copolymer is 1: 1.
The composition of the poloxamer block copolymer and the PNIPAM copolymer can slowly release the loaded medicine at the photothermal conversion temperature of 45 ℃.
As a preferred embodiment of the present invention, the nanogold derivative is a polydopamine-coated modified nanogold particle.
The nano gold particles are a photosensitive material, have good biocompatibility, and can absorb specific light to realize the conversion of light energy to heat energy. The SPR absorption peak of the poly-dopamine coated and modified nano-gold particles is positioned in a near-infrared region, so that near-infrared light can be quickly converted into heat energy, the release of a medicament is promoted, and meanwhile, local short-time high-temperature stimulation can effectively eliminate tumors and realize the synergistic effect of photothermal chemotherapy.
As a preferred embodiment of the present invention, the preparation method of the gold nanoparticle coated and modified with polydopamine comprises the following steps:
the first step is as follows: heating the tetrachloroauric acid solution to boiling, adding the sodium citrate solution while stirring and heating, continuously stirring until the solution is boiled and kept for 20-30min, and cooling to room temperature;
the second step is that: and (3) adding a dopamine solution into the solution cooled to room temperature in the first step, then adjusting the pH value to 8-8.5 by using alkali, stirring for 30-60min, centrifuging, and washing to obtain the poly-dopamine-coated nano gold particles.
In a preferred embodiment of the present invention, in the first step, the concentration of the tetrachloroauric acid solution is 0.5mM, the concentration of the sodium citrate solution is 2mM, the concentration of the dopamine solution is 1mM, and the alkali is 1mol/L NaOH solution.
And as a preferred embodiment of the invention, in the second step, centrifuging at 15000rpm for 20min, discarding the supernatant, washing the bottom precipitate with distilled water, and then centrifuging again to obtain the poly-dopamine-coated gold nanoparticles.
As a preferred embodiment of the invention, the weight ratio of the injectable hydrogel to the drug-loaded nanomicelle is 20-40: 1-2.
More preferably, the injectable hydrogel and drug-loaded nanomicelle are in a weight ratio of 30: 2. The injectable hydrogel and the drug-loaded nano-micelle have the best controllable and slow release effect of the drug in the weight ratio.
As a preferred embodiment of the invention, the drug-loaded nano-micelle further comprises the following raw materials in parts by weight: 30-150 parts of liposome and 100-200 parts of chemotherapy drug; the chemotherapeutic drug comprises at least one of hydrophilic chemotherapeutic drug and hydrophobic chemotherapeutic drug; the nano particles with the photo-thermal conversion effect account for 5 to 30 parts by weight. Preferably, the nano particles having the photo-thermal conversion effect are 25 parts by weight.
As a preferred embodiment of the present invention, the liposome is a synthetic phospholipid; the liposome is at least one of dipalmitoyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol, dipalmitoyl sphingomyelin and distearoyl phosphatidylcholine; more preferably, the liposome is a combination of dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, dipalmitoyl sphingomyelin, and distearoylphosphatidylcholine; the weight ratio of dipalmitoyl phosphatidylcholine to dipalmitoyl phosphatidylglycerol to dipalmitoyl sphingomyelin to distearoyl phosphatidylcholine is 2-10:2-10:1-6: 1-4.
More preferably, the weight ratio of dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, dipalmitoyl sphingomyelin and distearoylphosphatidylcholine is 5:5:3: 2.
As a preferred embodiment of the present invention, the hydrophilic chemotherapeutic agent is at least one of doxorubicin, dexamethasone, and fingolimod; the hydrophobic chemotherapeutic drug is at least one of curcumin, tripterine, prednisolone, paclitaxel and docetaxel; the weight parts of the hydrophilic chemotherapeutic drug and the hydrophobic chemotherapeutic drug are respectively 50-100 and 50-100.
More preferably, the hydrophilic chemotherapeutic is doxorubicin and the hydrophobic chemotherapeutic is curcumin; 100 parts by weight of hydrophobic chemotherapeutic drugs; the weight portion of the hydrophilic chemotherapeutic drug is 100.
As a preferred embodiment of the invention, the preparation method of the drug-loaded nano-micelle comprises the following steps:
(1) dissolving liposome and hydrophobic chemotherapeutic medicine with organic solvent, and removing the organic solvent to form a medicine-carrying liposome film;
(2) and (2) forming a mixed solution by using the hydrophilic chemotherapeutic drug, the nano particles with the photo-thermal conversion effect and water, then dropwise adding the mixed solution into a drug-loaded liposome film, carrying out ultrasonic treatment, and carrying out dialysis treatment to obtain the drug-loaded nano micelle.
In the drug-loaded nano micelle prepared by the invention, the nano particles with the photo-thermal conversion effect and the lipid exist in the same shell layer, and under the irradiation of infrared laser, the nano particles with the photo-thermal conversion effect generate heat to enable the temperature-sensitive liposome in the same layer to generate phase transformation, so that the drug has better controllable release effect.
As a preferred embodiment of the present invention, the organic solvent is dimethyl sulfoxide.
In the second step, the mixed solution is dripped into a drug-loaded liposome film and is subjected to ultrasonic treatment for 30-45min in an ice bath, then the obtained mixed solution is transferred to a dialysis bag, and is subjected to dialysis in ultrapure water for 2-3 days and then is subjected to freeze drying at-80 ℃ to obtain the drug-loaded nano micelle.
In addition, the invention also claims a preparation method of the injection photothermal chemotherapy sensitization drug-loaded hydrogel, which comprises the following steps:
and completely dissolving the drug-loaded nano-micelle and the injectable hydrogel in water to obtain the injectable photothermal chemotherapy sensitization drug-loaded hydrogel.
Compared with the prior art, the invention has the beneficial effects that: the invention provides an injectable photothermal chemotherapy sensitization drug-loaded hydrogel which has the characteristic of photo-thermal induced drug synchronous release and realizes the tumor inhibition effect of precise cooperation of thermal therapy and chemotherapy under the irradiation of near-infrared laser. The loading and long-term release of the hydrophilic anticancer drug and the hydrophobic anticancer drug are realized by taking the injectable photothermal chemotherapy sensitization drug-loaded hydrogel as a carrier, the retention time in tumor is prolonged after intratumoral administration, the anti-tumor effect is enhanced by multiple long-acting killing effects of the thermochemical chemotherapy on the tumor, and the toxic and side effects of the drugs on normal tissues are reduced.
Drawings
Fig. 1 is a photo-thermal effect diagram of an injectable photo-thermal chemotherapy sensitization drug-loaded hydrogel prepared in example 1 of the invention.
Fig. 2 is a slow release diagram in vitro of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in example 1 of the invention.
Fig. 3 is a slow release diagram in vitro of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in example 2 of the invention.
FIG. 4 is an in vitro sustained release diagram of the temperature-sensitive drug-loaded nano-micelle prepared in comparative example 1 of the present invention.
Fig. 5 is a graph showing the drug release effect of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in example 1 of the invention under 808nm near-infrared laser irradiation.
Fig. 6 is a graph showing the therapeutic effect of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in example 1 of the present invention on liver cancer tumors.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
The invention relates to an embodiment of an injectable photothermal chemotherapy sensitization drug-loaded hydrogel and a preparation method thereof, and the preparation method of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel comprises the following specific steps:
step 1: preparation of poly-dopamine coated nano-gold particles
Heating 25mL of 0.5mM tetrachloroauric acid solution to boiling, adding an equal volume of 2mM sodium citrate solution while stirring and heating, continuing to stir until the solution is boiled, keeping the solution for 20-30min, cooling to room temperature, adding 50mL of 1mM dopamine solution to obtain a mixed solution, adjusting the pH value of the mixed solution to 8-8.5 by using a 1mol/L NaOH solution, and stirring for 30-60 min. And after the reaction is completed, centrifuging the solution at the rotating speed of 15000rpm for 20min, removing the supernatant, washing the bottom precipitate with distilled water, and then centrifuging again to obtain the poly-dopamine-coated nano gold particles.
Step 2: preparation of nanomicelles
50mg of Dipalmitoylphosphatidylcholine (DPPC), 50mg of Dipalmitoylphosphatidylglycerol (DPPG), 30mg of dipalmitoyl sphingomyelin (DPSP), 20mg of Distearoylphosphatidylcholine (DSPC) and 100mg of curcumin were weighed out and dissolved in 15ml of dichloromethane, and then dichloromethane was removed by rotary evaporation to form a drug-loaded liposome membrane for use. Weighing 100mg of adriamycin and dissolving the adriamycin into 25ml of the polydopamine-coated nano-gold solution prepared in the step 1, then dropwise adding the obtained mixed solution into a container filled with a drug-loaded liposome film, carrying out ultrasonic treatment for 30-45min in ice bath, then transferring the obtained mixed solution into a dialysis bag, dialyzing with ultrapure water for 2-3 days, and carrying out freeze drying at-80 ℃ to obtain the temperature-sensitive drug-loaded nano-micelle.
And step 3: preparation of injectable photothermal chemotherapy sensitization drug-loaded hydrogel
Weighing 100mg of temperature-sensitive drug-loaded nano-micelle, 750mg of poloxamer block copolymer and 750mg of PNIPAM copolymer, dissolving in 16ml of ultrapure water, and magnetically stirring at normal temperature until the copolymer is completely dissolved to obtain the injectable photothermal chemotherapy sensitization drug-loaded hydrogel.
Example 2
The invention relates to an embodiment of an injectable photothermal chemotherapy sensitization drug-loaded hydrogel and a preparation method thereof, and the preparation method of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel comprises the following specific steps:
step 1: the preparation of the polydopamine-coated gold nanoparticles was the same as that of the polydopamine-coated gold nanoparticles of example 1.
Step 2: preparation of nanomicelles
10mg of Dipalmitoylphosphatidylcholine (DPPC), 10mg of Dipalmitoylphosphatidylglycerol (DPPG), 5mg of dipalmitoyl sphingomyelin (DPSP), 5mg of Distearoylphosphatidylcholine (DSPC) and 50mg of curcumin were weighed out and dissolved in 15ml of dichloromethane, and then dichloromethane was removed by rotary evaporation to form a drug-loaded liposome film for use. Weighing 50mg of adriamycin to dissolve in 5ml of the polydopamine-coated nanogold solution prepared in the step 1, then dropwise adding the obtained mixed solution into a container filled with a drug-loaded liposome film, carrying out ultrasonic treatment for 30-45min in ice bath, then transferring the obtained mixed solution into a dialysis bag, dialyzing with ultrapure water for 2-3 days, and carrying out freeze drying at-80 ℃ to obtain the temperature-sensitive drug-loaded nano micelle.
And step 3: preparation of injectable photothermal chemotherapy sensitization drug-loaded hydrogel
Weighing 50mg of temperature-sensitive drug-loaded nano-micelle, 500mg of poloxamer block copolymer and 500mg of PNIPAM copolymer, dissolving in 5ml of ultrapure water, and magnetically stirring at normal temperature until the copolymer is completely dissolved to obtain the injectable photothermal chemotherapy sensitization drug-loaded hydrogel.
Example 3
The invention relates to an embodiment of an injectable photothermal chemotherapy sensitization drug-loaded hydrogel and a preparation method thereof, and the preparation method of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel comprises the following specific steps:
step 1: the preparation of the polydopamine-coated gold nanoparticles was the same as that of the polydopamine-coated gold nanoparticles of example 1.
Step 2: preparation of nanomicelles
30mg of Dipalmitoylphosphatidylcholine (DPPC), 30mg of Dipalmitoylphosphatidylglycerol (DPPG), 18mg of dipalmitoyl sphingomyelin (DPSP), 12mg of Distearoylphosphatidylcholine (DSPC) and 75mg of curcumin were weighed out and dissolved in 15ml of dichloromethane, and then dichloromethane was removed by rotary evaporation to form a drug-loaded liposome film for use. Weighing 75mg of adriamycin to dissolve in 22ml of the polydopamine-coated nanogold solution prepared in the step 1, then dropwise adding the obtained mixed solution into a container filled with a drug-loaded liposome film, carrying out ultrasonic treatment for 30-45min in ice bath, then transferring the obtained mixed solution into a dialysis bag, dialyzing with ultrapure water for 2-3 days, and carrying out freeze drying at-80 ℃ to obtain the temperature-sensitive drug-loaded nano micelle.
And step 3: preparation of injectable photothermal chemotherapy sensitization drug-loaded hydrogel
Weighing 75mg of temperature-sensitive drug-loaded nano-micelle, 1000mg of poloxamer block copolymer and 1000mg of PNIPAM copolymer, dissolving in 20ml of ultrapure water, and magnetically stirring at normal temperature until the copolymer is completely dissolved to obtain the injectable photothermal chemotherapy sensitization drug-loaded hydrogel.
Comparative example 1
Step 1: preparation of poly-dopamine coated nano-gold particles
Heating 25mL of 0.5mM tetrachloroauric acid solution to boiling, adding an equal volume of 2mM sodium citrate solution while stirring and heating, continuing to stir until the solution is boiled, keeping the solution for 20-30min, cooling to room temperature, adding 50mL of 1mM dopamine solution to obtain a mixed solution, adjusting the pH value of the mixed solution to 8-8.5 by using a 1mol/L NaOH solution, and stirring for 30-60 min. And after the reaction is completed, centrifuging the solution at the rotating speed of 15000rpm for 20min, removing the supernatant, washing the bottom precipitate with distilled water, and then centrifuging again to obtain the poly-dopamine-coated nano gold particles.
Step 2: preparation of nanomicelles
50mg of Dipalmitoylphosphatidylcholine (DPPC), 50mg of Dipalmitoylphosphatidylglycerol (DPPG), 30mg of dipalmitoyl sphingomyelin (DPSP), 20mg of Distearoylphosphatidylcholine (DSPC) and 100mg of curcumin were weighed out and dissolved in 15ml of dichloromethane, and then dichloromethane was removed by rotary evaporation to form a drug-loaded liposome membrane for use. Weighing 100mg of adriamycin and dissolving the adriamycin into 25ml of the polydopamine-coated nano-gold solution prepared in the step 1, then dropwise adding the obtained mixed solution into a container filled with a drug-loaded liposome film, carrying out ultrasonic treatment for 30-45min in ice bath, then transferring the obtained mixed solution into a dialysis bag, dialyzing with ultrapure water for 2-3 days, and carrying out freeze drying at-80 ℃ to obtain the temperature-sensitive drug-loaded nano-micelle.
Test example 1: testing of photothermal effects
The injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in the example 1 is added at the power of 1.0w/cm2And irradiating under laser with the wavelength of 808nm to test the photo-thermal effect of the injectable photo-thermal chemotherapy sensitization drug-loaded hydrogel.
Fig. 1 is a photo-thermal effect diagram of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in example 1 of the invention, and it can be seen from fig. 1 that the temperature of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel gradually rises with the extension of the illumination time, and the temperature exceeds 45 ℃, so that the injectable photothermal chemotherapy sensitization drug-loaded hydrogel has good photo-thermal conversion performance.
Test example 2: drug Release Performance test
Testing the drug release performance without illumination: 1mL of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in the example 1 and the example 2 is respectively placed in dialysis bags, then is respectively placed in 10mL of EP tubes, then is supplemented with 9mL of PBS, is placed in a 120rpm shaking table at 37 ℃ and 120rpm, is periodically centrifuged to take supernatant, and is used for measuring the content of adriamycin and curcumin in the supernatant.
Fig. 2 is an in vitro sustained release diagram of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in example 1 of the invention. Fig. 3 is an in vitro sustained release diagram of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in example 2 of the invention. It can be seen from fig. 2 and 3 that the cumulative release amount of curcumin was 48% and 52% and the cumulative release amount of doxorubicin was 65% and 68% after 48 hours, and the release curves of both became flat after 12 hours, indicating that the injectable hydrogel had a slow sustained drug release effect. FIG. 4 is an in vitro sustained release diagram of the temperature-sensitive drug-loaded nano-micelle prepared in comparative example 1 of the present invention. As can be seen from fig. 4, the cumulative release amount of curcumin is 68% and the cumulative release amount of doxorubicin is 79% after 48 hours, compared with the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in example 1 and example 2, the drug release amount of comparative example 1 at the same time point is higher than that of example 1 and example 2, because the protection of the hydrogel layer is lacked in comparative example 1, and the drug is directly released to the release medium at the same time point, so that the release amount is far higher than that of example 1 and example 2. The excessively high drug release amount not only does not meet the requirement of long-acting slow release of a drug-carrying system, but also easily causes the local drug concentration to be excessively high to generate side effects and drug resistance.
Testing the drug release performance under 808nm near infrared irradiation: 1mL of the injectable photothermal chemotherapy sensitization drug loaded hydrogel prepared in example 1 was placed in a 10mL EP tube, then 9mL of PBS was added, and then a near infrared laser light source (lambda: 808nm, 1.0W/cm) was used2) Irradiating for 10min, centrifuging to obtain supernatant, and measuring the content of adriamycin and curcumin in the supernatant.
Fig. 5 is a graph showing the drug release effect of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in example 1 of the invention under 808nm near-infrared laser irradiation. The results of fig. 5 show that after the injectable photothermal chemotherapy sensitization drug-loaded hydrogel is irradiated by a near-infrared laser light source with the wavelength of 808nm, the release of two drugs is improved obviously, and after the near-infrared laser light source with the wavelength of 808nm stops irradiating, the release of the two drugs becomes gentle, which proves that the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared by the invention has the photothermal regulation 'on-demand' drug release characteristic.
Test example 3: test of therapeutic Effect on H22 liver cancer tumor
The average volume of 24H 22 liver cancer tumors is 100-150mm3The male Balb/c nude mice are randomly divided into 4 groups according to 6 mice per group, and 50 mu LPBS, adriamycin and curcumin, the photothermal chemotherapy sensitization drug-loaded hydrogel capable of being injected into the tumors of the 4 groups of tumor-loaded mice, the photothermal chemotherapy sensitization drug-loaded hydrogel capable of being injected in the example 1 and the photothermal chemotherapy sensitization drug-loaded hydrogel capable of being injected in the example 1 under the near infrared laser irradiation of 808nm are respectively injected into the tumors of the 4 groups of tumor-loaded mice in an intratumoral injection mode.
Fig. 6 is a graph showing the treatment effect of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared in example 1 on liver cancer tumors. As shown in fig. 6, the tumors of mice in the chemotherapy and photothermal therapy combined treatment group (the injectable photothermal chemotherapy sensitization drug-loaded hydrogel drug prepared in example 1 under 808nm near-infrared laser irradiation) are completely inhibited, and the treatment effect is obviously superior to that of other experimental groups, which indicates that the injectable photothermal chemotherapy sensitization drug-loaded hydrogel prepared by the invention can significantly prolong the drug release time, and significantly enhance the treatment effect on H22 liver cancer tumors by the chemotherapy and photothermal combined treatment of H22 liver cancer tumors.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The utility model provides an injectable photothermal chemotherapy sensitization medicine carrying hydrogel which characterized in that, the injectable photothermal chemotherapy sensitization medicine carrying hydrogel includes following preparation raw materials: injectable hydrogels and drug-loaded nanomicelles; the injectable hydrogel is synthetic phospholipid with temperature-sensitive characteristic, and the drug-loaded nano-micelle comprises nano-particles with photo-thermal conversion effect.
2. The injectable photothermal chemotherapy sensitization drug loaded hydrogel according to claim 1, wherein the injectable hydrogel comprises at least one of poloxamer block copolymers, PNIPAM copolymers, polyethylene glycol/polyester block copolymers; the nano particles with the photo-thermal conversion effect are at least one of nano gold, nano gold derivatives, nano graphene and black phosphorus.
3. The injectable photothermal chemotherapy sensitization drug-loaded hydrogel according to claim 2, wherein the nanogold derivative is a polydopamine-coated modified nanogold particle.
4. The injectable photothermal chemotherapy sensitization drug-loaded hydrogel according to claim 3, wherein the preparation method of the poly-dopamine coated modified nano-gold particles comprises the following steps:
the first step is as follows: heating the tetrachloroauric acid solution to boiling, adding the sodium citrate solution while stirring and heating, continuously stirring until the solution is boiled and kept for 20-30min, and cooling to room temperature;
the second step is that: and (3) adding a dopamine solution into the solution cooled to room temperature in the first step, then adjusting the pH value to 8-8.5 by using alkali, stirring for 30-60min, centrifuging, and washing to obtain the poly-dopamine-coated nano gold particles.
5. The injectable photothermal chemotherapy sensitization drug-loaded hydrogel according to claim 1, wherein the weight ratio of the injectable hydrogel to the drug-loaded nanomicelle is 20-40: 1-2.
6. The injectable photothermal chemotherapy sensitization drug-loaded hydrogel according to claim 1, wherein the drug-loaded nano micelle further comprises the following raw materials in parts by weight: 30-150 parts of liposome and 100-200 parts of chemotherapy drug; the chemotherapeutic drug comprises at least one of hydrophilic chemotherapeutic drug and hydrophobic chemotherapeutic drug; the nano particles with the photo-thermal conversion effect account for 0.005-0.3 weight part.
7. The injectable photothermal chemotherapy sensitization drug-loaded hydrogel according to claim 6, wherein the liposome is at least one of dipalmitoyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol, dipalmitoyl sphingomyelin, distearoyl phosphatidylcholine; more preferably, the liposome is a combination of dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine, the weight ratio of dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine being 2-10:2-10:1-6: 1-4.
8. The injectable photothermal chemotherapy sensitization drug-loaded hydrogel according to claim 6, wherein the hydrophilic chemotherapeutic drug is at least one of doxorubicin, dexamethasone, and fingolimod; the hydrophobic chemotherapeutic drug is at least one of curcumin, tripterine, prednisolone, paclitaxel and docetaxel; the weight parts of the hydrophilic chemotherapeutic drug and the hydrophobic chemotherapeutic drug are respectively 50-100 and 50-100.
9. The injectable photothermal chemotherapy sensitization drug-loaded hydrogel according to claim 6, wherein the preparation method of the drug-loaded nano-micelle comprises the following steps:
(1) dissolving liposome and hydrophobic chemotherapeutic medicine with organic solvent, and removing the organic solvent to form a medicine-carrying liposome film;
(2) and (2) forming a mixed solution by using the hydrophilic chemotherapeutic drug, the nano particles with the photo-thermal conversion effect and water, then dropwise adding the mixed solution into a drug-loaded liposome film, carrying out ultrasonic treatment, and carrying out dialysis treatment to obtain the drug-loaded nano micelle.
10. The preparation method of the injectable photothermal chemotherapy sensitization drug-loaded hydrogel according to any one of claims 1 to 9, which comprises the following steps:
and completely dissolving the drug-loaded nano-micelle and the injectable hydrogel in water to obtain the injectable photothermal chemotherapy sensitization drug-loaded hydrogel.
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