Synthesis method of photoresponse type multi-heavy drug loading nanogel
By using polar organic solvents, crosslinking agents, initiators, and polymer molecular monomers in a room temperature non-protected gas environment, the microemulsion system was successfully solved by combining ultrasonic treatment and heating and distillation steps, the nanogel size and morphology were unstable. The problem is that stable and hydrophilic photoresponsive multi-load drug nanogels have good modification and application potential.
Patent Information
- Application Number
- CN202411287930.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-13
- Publication Date
- 2024-12-13
AI Technical Summary
In the prior art, the nanogel prepared in a room temperature non-protective gas environment has unstable size and morphology, making it difficult to achieve stable nanogel preparation.
The microemulsion system is prepared by polar organic solvents, crosslinkers, initiators, and polymer molecular monomers. Through ultrasonic treatment, heating and distillation, cleaning and vacuum freeze-drying steps, stable photoresponsive multi-load drug nanocoagulation is prepared. glue.
The nanogel has achieved dimensional and morphological stability, and the preparation method is low-cost and simple. The nanogel has good hydrophilicity and surfactant groups, which is conducive to further modification and application.
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Figure CN119112769A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of nanomaterials, and in particular to a method for synthesizing light-responsive multi-drug-loaded nanogel. Background Art
[0002] At present, hydrogel is a kind of hydrophilic three-dimensional network structure gel. This kind of gel can swell rapidly in water and retain a large volume of water in the swollen state without dissolving. Microspheres are a special type of microparticle dispersion system, with a particle size range of 1nm to 100μm, which can adsorb drugs, pollutants, etc. through electrostatic forces. Hydrogel microspheres have the advantages of both, with a high specific surface area and porosity, which is conducive to the loading and surface modification of small molecules, and have great potential in the field of drug delivery. The premise of its biological application is: it has a certain hydrophilicity and good biosafety, and has active groups on the surface (such as -COOH, -NH2).
[0003] However, in a non-protective gas environment at room temperature, the size and morphology of the nanogels prepared using these traditional methods are unstable.
[0004] Therefore, how to provide a method for synthesizing photoresponsive multi-drug-loaded nanogels that can stabilize the size and morphology of the prepared nanogels has become a technical problem that technicians in this field urgently need to solve. Summary of the invention
[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, one object of the present invention is to provide a method for synthesizing a photoresponsive multi-drug-loaded nanogel, which can stabilize the size and morphology of the prepared nanogel.
[0006] A method for synthesizing a light-responsive multi-drug-loaded nanogel disclosed in the present invention comprises:
[0007] Step (1): preparing a microemulsion system using a polar organic solvent, a crosslinking agent, an initiator, and a polymer molecular monomer;
[0008] Step (2): subjecting the microemulsion system to ultrasonic treatment to obtain a solution;
[0009] Step (3): heating and distilling the solution, and collecting the solid precipitate;
[0010] Step (4): washing and removing impurities from the solid precipitate, and then performing vacuum freeze drying to obtain the nanogel.
[0011] Furthermore, in step (2), the duration of ultrasonic treatment is 5-20 min;
[0012] Furthermore, in step (4), during the cleaning process, a polar organic solvent and distilled water are used for cleaning in a volume ratio of 1:1-1:3;
[0013] Furthermore, in step (4), the impurity removal method is centrifugal treatment.
[0014] Furthermore, the heating distillation in step (3) comprises the following steps: heating the solution in an oil bath at 80°C-120°C until boiling, and stopping after 5mL-40mL of the organic solvent is distilled out.
[0015] Furthermore, in step (1), the initiator used includes any one of azobisisobutyronitrile (AIBN), azobisisoheptanenitrile (AIVN), sodium persulfate, and potassium persulfate;
[0016] Furthermore, in step (1), the initiator is used at a concentration of 1 wt% to 10 wt%.
[0017] Furthermore, in step (1), the polymer molecular monomer used includes any one of methacrylic acid (MAA), N-isopropylacrylamide (NIPAAM), acrylic acid (AA), acrylamide (AAm) and their derivatives;
[0018] Furthermore, in step (1), the amount of polymer molecule monomer used is 0.5-50 mmol.
[0019] Furthermore, in step (1), the polar organic solvent used includes any one of acetonitrile, ethanol, acetone, and ethyl acetate;
[0020] Furthermore, in step (1), the volume of the polar organic solvent is 40-100 mL.
[0021] Furthermore, in step (1), the cross-linking agent used includes any one of N,N'-bis(acryl)cystamine (BAC) and N,N-methylenebisacrylamide (MBA);
[0022] And / or, in step (1), the cross-linking agent is used at a concentration of 5 wt% to 20 wt%.
[0023] Furthermore, the method further comprises: step (5): preserving the nanogel; the preserving the nanogel comprises the following steps:
[0024] The nanogel is dispersed in an organic solvent, and the drug molecules or light-responsive molecules are dissolved in the organic solvent. After centrifugation and washing, the nanogel is dispersed in a buffer solution or physiological saline for storage.
[0025] Furthermore, before the centrifugation in step (5), the following steps are also included: stirring and then standing for 12 hours;
[0026] Furthermore, the washing process uses distilled water for washing.
[0027] Further, the drug molecule in step (5) includes at least one of ibuprofen (IBF), indomethacin (INM), diclofenac potassium (DP), paclitaxel (PTX), doxorubicin (DOX), olsalazine, and methotrexate (MTX);
[0028] Furthermore, the addition ratio of the drug molecules in step (5) is 1wt%-25wt%;
[0029] Further, the photoresponsive molecule in step (5) includes at least one of indocyanine green (ICG), IR-820, IR-780, IR-650 and derivatives thereof;
[0030] Furthermore, the addition ratio of the photoresponsive molecules in step (5) is 1 wt%-25 wt%.
[0031] The synthesis method of the light-responsive multi-drug-loaded nanogel of the present invention can make the size and morphology of the prepared nanogel stable, and the preparation method is low-cost, simple and universal. The prepared nanogel has good hydrophilicity and contains a large number of active groups on its surface, which is conducive to the further modification and application of the nanogel.
[0032] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
[0033] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:
[0034] Figure 1 This is a transmission electron microscope photo of polymethacrylic acid nanogel;
[0035] Figure 2 This is the infrared spectrum of polymethacrylic acid nanogel;
[0036] Figure 3 is the UV absorption spectrum of polymethacrylic acid nanogel;
[0037] Figure 4 is a transmission electron microscopy picture of PMAA_INM:IR-820 nanogel;
[0038] Figure 5 is the infrared spectrum of PMAA_INM:IR-820 nanogel;
[0039] Figure 6is the UV absorption spectrum of PMAA_INM:IR-820 nanogel;
[0040] Figure 7 is a transmission electron microscopy photograph of P(MAA-co-NIPAM)_DOX:ICG nanogel. DETAILED DESCRIPTION
[0041] Embodiments of the present invention are described in detail below, examples of which are shown in the accompanying drawings, wherein the same or similar reference numerals throughout represent the same or similar elements or elements having the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain the present invention, and cannot be understood as limiting the present invention.
[0042] The present invention discloses a method for synthesizing a light-responsive multi-drug-loaded nanogel, comprising:
[0043] Step (1): preparing a microemulsion system using a polar organic solvent, a crosslinking agent, an initiator, and a polymer molecular monomer;
[0044] Step (2): subjecting the microemulsion system to ultrasonic treatment to obtain a solution;
[0045] Step (3): heating and distilling the solution, and collecting the solid precipitate;
[0046] Step (4): washing and removing impurities from the solid precipitate, and then performing vacuum freeze drying to obtain the nanogel.
[0047] The synthesis method of the light-responsive multi-drug-loaded nanogel of the present invention can make the size and morphology of the prepared nanogel stable, and the preparation method is low-cost, simple and universal. The prepared nanogel has good hydrophilicity and contains a large number of active groups on its surface, which is conducive to the further modification and application of the nanogel.
[0048] In addition, the synthesized nanocapsules of the present invention have photoresponsiveness, hydrophilicity, active groups on the surface, controllable particle size, and a method for synthesizing nanogels that can load a variety of drugs. The method is simple to operate, stable, controllable, economical and easy to obtain. The surface active groups are: carboxyl (-COOH), amino (-NH2), etc.; the above-mentioned synthesis reaction is carried out in a glass flask; the temperature of the synthesis reaction is 40-70°C, and the time is 4h-24h. The above-mentioned photoresponsive multi-drug-loaded nanogel can specifically be in the form of nanospheres, hollow nanoshells, etc., and has a porous network structure. In the present invention, a variety of drug molecules and photoresponsive molecules are encapsulated in gel micelles, and a nanogel drug carrier with controllable morphology and size is stably prepared.
[0049] The present application also discloses some embodiments, in which in step (2), the duration of ultrasonic treatment is 5-20 min;
[0050] The present application also discloses some embodiments, in which, in step (4), during the cleaning process, a polar organic solvent and distilled water are used for cleaning in a volume ratio of 1:1-1:3;
[0051] The present application also discloses some embodiments, in which in step (4), the impurity removal method is centrifugal treatment.
[0052] The present application also discloses some embodiments, wherein the heating distillation in step (3) comprises the following steps: heating the solution in an oil bath at 80°C-120°C until boiling, and stopping after 5mL-40mL of the organic solvent is distilled out.
[0053] The present application also discloses some embodiments, in step (1), the initiator used includes any one of azobisisobutyronitrile (AIBN), azobisisoheptanenitrile (AIVN), sodium persulfate, and potassium persulfate;
[0054] The present application also discloses some embodiments, in which in step (1), the concentration of the initiator used is 1 wt%-10 wt%.
[0055] The present application also discloses some embodiments, in step (1), the polymer molecular monomer used includes any one of methacrylic acid (MAA), N-isopropylacrylamide (NIPAAM), acrylic acid (AA), acrylamide (AAm) and their derivatives;
[0056] The present application also discloses some embodiments, in which in step (1), the amount of polymer molecule monomer used is 0.5-50 mmol.
[0057] The present application also discloses some embodiments, in which the polar organic solvent used in step (1) includes any one of acetonitrile, ethanol, acetone, and ethyl acetate;
[0058] The present application also discloses some embodiments, in which in step (1), the volume of the polar organic solvent is 40-100 mL.
[0059] The present application also discloses some embodiments, in step (1), the cross-linking agent used includes any one of N,N'-bis(acryl)cystamine (BAC) and N,N-methylenebisacrylamide (MBA);
[0060] And / or, in step (1), the cross-linking agent is used at a concentration of 5 wt% to 20 wt%.
[0061] The present application also discloses some embodiments, further comprising: step (5): preserving the nanogel; preserving the nanogel comprises the following steps:
[0062] The nanogel is dispersed in an organic solvent, and the drug molecules or light-responsive molecules are dissolved in the organic solvent. After centrifugation and washing, the nanogel is dispersed in a buffer solution or physiological saline for storage.
[0063] The present application also discloses some embodiments, wherein before the centrifugation in step (5), the following steps are further included: stirring and then standing for 12 hours;
[0064] And / or, the washing treatment is performed by washing with distilled water.
[0065] The present application also discloses some embodiments, wherein the drug molecule in step (5) includes at least one of ibuprofen (IBF), indomethacin (INM), diclofenac potassium (DP), paclitaxel (PTX), doxorubicin (DOX), olsalazine, and methotrexate (MTX);
[0066] The present application also discloses some embodiments, wherein the addition ratio of the drug molecules in step (5) is 1wt%-25wt%;
[0067] The present application also discloses some embodiments, wherein the photoresponsive molecule in step (5) comprises at least one of indocyanine green (ICG), IR-820, IR-780, IR-650 and derivatives thereof;
[0068] The present application also discloses some embodiments, in which the addition ratio of the photoresponsive molecules in step (5) is 1 wt%-25 wt%.
[0069] The specific process steps of the method of the present invention are as follows: a microemulsion system is prepared with a polar organic solvent, a crosslinking agent, an initiator, and a polymer molecular monomer. The morphology and size of the nanogel are controlled by controlling the proportion of the crosslinking agent and the initiator in the system and the reaction time of the system. The microemulsion system is ultrasonically stirred for about 5-20 minutes to obtain a clear and transparent solution, and then the solution is heated to boiling in an oil bath at 80°C-120°C, and a certain amount of organic solvent (5mL-40mL) is distilled off to terminate the reaction. The system after the reaction is cooled, and a precipitate is collected by high-speed centrifugation for 5-20 minutes. The precipitate is washed in sequence with a polar organic solvent and distilled water in a volume ratio of 1:1-1:3 and a concentration gradient, and then high-speed centrifugation is performed to remove organic impurities adsorbed in the microspheres. The precipitate is vacuum freeze-dried to obtain the target nanogel. The surface of the prepared nanogel is rich in a large number of active groups, so that it has good hydrophilicity and modifiability. The prepared hydrogel microspheres are dispersed in an organic solvent. One or more drug molecules or photosensitizers are weighed and dissolved in an organic solvent. After stirring overnight, they are centrifuged, washed with distilled water, and then dispersed in a buffer solution or physiological saline for storage.
[0070] Example 1
[0071] Preparation of PMAA hydrogel microspheres
[0072] Hydrogel microspheres were prepared using acetonitrile (40 mL), BAC (55.6 mg, 10 wt%), AIBN (16.7 mg, 3 wt%), and MAA (0.5 mmol). The above materials were added to a flask and ultrasonically stirred for 15 minutes to obtain a clear, colorless, transparent solution. The system oil bath was then heated to 80°C and distilled for about 7 minutes to evaporate about 12.5 mL of acetonitrile. After the reaction was completed, high-speed centrifugation was performed for 10 minutes. The precipitate was washed with acetonitrile and distilled water in turn, and then centrifuged at high speed to remove organic impurities adsorbed in the microspheres. The desired hydrogel microsphere sample was obtained by vacuum freeze-drying the precipitate. Their morphology and particle size were measured using a transmission electron microscope, and the results are shown in FIG. Figure 1 As shown in Figure 2, the particle size of PMAA nanogel is about 250 nm, which indicates that the nanogel particles with uniform particle size were successfully synthesized. The infrared spectrum of the material is shown in Figure 2. Figure 2 , the sample is at 3450cm -1 There is a broad absorption at the -OH stretching vibration: This indicates that the microspheres contain more -COOH groups and have good hydrophilicity. PMAA nanogel samples can be easily dispersed in water. The UV absorption spectrum of this material is shown in Figure 3 ,The spectral results showed that PMAA nanogel particles exhibited scattering absorption in the ,ultraviolet region.
[0073] Example 2
[0074] Preparation of PMAA nanogels loaded with IR-820 and indomethacin PMAA_INM:IR-820
[0075] Hydrogel microspheres were prepared using acetonitrile (40 mL), BAC (55.6 mg, 10 wt%), AIBN (16.7 mg, 3 wt%), and MAA (0.5 mL). The above materials were added to a flask and ultrasonically stirred for 15 minutes to obtain a clear, colorless and transparent solution. The system oil bath was then heated to 80 ° C, distilled for about 7 minutes, and about 12.5 mL of acetonitrile was evaporated. After the reaction was completed, high-speed centrifugation was performed for 10 minutes, and the system was washed twice with acetonitrile to remove impurities in the system. The washed PMAA hydrogel microspheres were dispersed in 40 mL of acetonitrile, and INM (18.3 mg, 0.051 mmol) and IR-820 (44.3 mg, 0.051 mmol) were added to the system and fully dissolved, and stirred at low speed overnight. After centrifugation, the microspheres were washed twice with distilled water and dispersed in PBS buffer for storage. Their morphology and particle size were measured by transmission electron microscopy, and the experimental results are shown in the following figure. Figure 4 As shown in Figure 2, the particle size of PMAA nanogel loaded with two drugs is about 220 nm, which indicates that the drug-loaded nanogel with uniform particle size was successfully synthesized. The infrared spectra of this material as well as IR-820 and INM are shown in Figure 2. Figure 5This result shows that IR-820 and INM are successfully loaded into the hydrogel microspheres. The UV absorption spectra of the material and IR-820 and INM are shown in Figure 6 The spectrum shows that PMAA_INM:IR-820 nanogel has strong absorption in the 700-900nm region. These data indicate that this synthetic method can simply and efficiently prepare photoresponsive multi-drug-loaded nanogels with uniform particle size.
[0076] Example 3
[0077] Preparation of P(MAA-co-NIPAM) hydrogel microspheres dually loaded with photosensitizer indocyanine green (ICG) and anticancer drug doxorubicin (DOX)
[0078] Hydrogel microspheres were prepared using acetonitrile (40 mL), ethanol (20 mL), BAC (120 mg, 20 wt%), AIBN (27.8 mg, 5 wt%), MAA (1 mmol), and NIPAAM (1 mmol). The above materials were added to a flask and ultrasonically stirred for 20 minutes to obtain a clear, colorless and transparent solution. The system oil bath was then heated to 80°C and distilled for about 10 minutes to evaporate about 15 mL of a mixture of acetonitrile and ethanol. After the reaction was completed, high-speed centrifugation was performed for 10 minutes and the system was washed twice with acetonitrile to remove impurities present in the system. The washed P (MAA-co-NIPAM) nanogel was dispersed in 40 mL of acetonitrile, and DOX (0.1 mmol) and ICG (0.1 mmol) were added to the system and fully dissolved, and stirred at a low speed overnight. After centrifugation, the system was washed twice with distilled water, and the microspheres were dispersed in PBS buffer for storage. Their morphology and particle size were measured by transmission electron microscopy, and typical results are shown in FIG. Figure 7 As shown, the particle size of P(MAA-co-NIPAM)_DOX:ICG nanogel is about 300nm, and the particle size is uniform and the dispersibility is good. The results also prove that this synthesis method can simply and effectively prepare a new type of light-responsive multi-drug-loaded nanogel.
[0079] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.
[0080] Although the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.
Claims
1. A method for synthesizing a photoresponsive multi-drug-loaded nanogel, characterized in that: include: Step (1): preparing a microemulsion system using a polar organic solvent, a crosslinking agent, an initiator, and a polymer molecular monomer; Step (2): subjecting the microemulsion system to ultrasonic treatment to obtain a solution; Step (3): heating and distilling the solution, and collecting the solid precipitate; Step (4): washing and removing impurities from the solid precipitate, and then performing vacuum freeze-drying to obtain the nanogel.
2. The method for synthesizing the light-responsive multi-drug-loaded nanogel according to claim 1, characterized in that: In the step (2), the duration of the ultrasonic treatment is 5-20 min; And / or, in the step (4), during the cleaning process, a polar organic solvent and distilled water are used for cleaning in a volume ratio of 1:1-1:3; And / or, in step (4), the impurity removal method is centrifugal treatment.
3. The method for synthesizing the light-responsive multi-drug-loaded nanogel according to claim 1 or 2, characterized in that: The heating distillation in step (3) comprises the following steps: heating the solution in an oil bath at 80°C-120°C until boiling, and stopping after 5mL-40mL of the organic solvent is distilled out.
4. The method for synthesizing the light-responsive multi-drug-loaded nanogel according to claim 1 or 2, characterized in that: In the step (1), the initiator used includes any one of azobisisobutyronitrile (AIBN), azobisisoheptanenitrile (AIVN), sodium persulfate, and potassium persulfate; And / or, in step (1), the initiator is used at a concentration of 1wt% to 10wt%.
5. The method for synthesizing the light-responsive multi-drug-loaded nanogel according to claim 1 or 2, characterized in that: In the step (1), the polymer molecule monomer used includes any one of methacrylic acid (MAA), N-isopropylacrylamide (NIPAAM), acrylic acid (AA), acrylamide (AAm) and their derivatives; And / or, in the step (1), the amount of the polymer molecule monomer used is 0.5-50 mmol.
6. The method for synthesizing the light-responsive multi-drug-loaded nanogel according to claim 1 or 2, characterized in that: In the step (1), the polar organic solvent used includes any one of acetonitrile, ethanol, acetone, and ethyl acetate; And / or, in step (1), the volume of the polar organic solvent is 40-100 mL.
7. The method for synthesizing the light-responsive multi-drug-loaded nanogel according to claim 1 or 2, characterized in that: In the step (1), the cross-linking agent used includes any one of N,N'-bis(acryl)cystamine (BAC) and N,N-methylenebisacrylamide (MBA); And / or, in step (1), the cross-linking agent is used at a concentration of 5 wt% to 20 wt%.
8. The method for synthesizing the light-responsive multi-drug-loaded nanogel according to claim 1 or 2, characterized in that: The method further comprises: step (5): preserving the nanogel; preserving the nanogel comprises the following steps: The nanogel is dispersed in an organic solvent, and the drug molecules or light-responsive molecules are dissolved in the organic solvent. After centrifugation and washing, the nanogel is dispersed in a buffer solution or physiological saline for storage.
9. The method for synthesizing the light-responsive multi-drug-loaded nanogel according to claim 8, characterized in that: Before the centrifugation in step (5), the following steps are also included: stirring and then standing for 12 hours; And / or, the washing treatment adopts distilled water washing.
10. The method for synthesizing the light-responsive multi-drug-loaded nanogel according to claim 8 or 9, characterized in that: The drug molecule in step (5) includes at least one of ibuprofen (IBF), indomethacin (INM), diclofenac potassium (DP), paclitaxel (PTX), doxorubicin (DOX), olsalazine, and methotrexate (MTX); And / or, the addition ratio of the drug molecules in the step (5) is 1wt%-25wt%; And / or, the photoresponsive molecule in step (5) comprises at least one of indocyanine green (ICG), IR-820, IR-780, IR-650 and derivatives thereof; And / or, the addition ratio of the photoresponsive molecules in the step (5) is: 1wt%-25wt%.