CN116693823A - Degradable polymer nano gel microsphere and preparation method and application thereof - Google Patents
Degradable polymer nano gel microsphere and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229920006237 degradable polymer Polymers 0.000 title description 6
- 229920000642 polymer Polymers 0.000 claims abstract description 53
- 239000000178 monomer Substances 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 38
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 28
- 229940079593 drug Drugs 0.000 claims abstract description 27
- -1 vinyl cyclic acetal Chemical class 0.000 claims abstract description 27
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002270 dispersing agent Substances 0.000 claims abstract description 20
- FHTWQMHOTBIHEP-UHFFFAOYSA-N 2-methylidene-4-phenyl-1,3-dioxolane Chemical group O1C(=C)OCC1C1=CC=CC=C1 FHTWQMHOTBIHEP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000004132 cross linking Methods 0.000 claims abstract description 17
- 238000010526 radical polymerization reaction Methods 0.000 claims abstract description 14
- 150000003254 radicals Chemical class 0.000 claims abstract description 14
- 239000003999 initiator Substances 0.000 claims abstract description 13
- 239000012454 non-polar solvent Substances 0.000 claims abstract description 11
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 36
- 229960002897 heparin Drugs 0.000 claims description 36
- 229920000669 heparin Polymers 0.000 claims description 36
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 21
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000002245 particle Substances 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000006185 dispersion Substances 0.000 claims description 9
- 239000011261 inert gas Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- SAPGBCWOQLHKKZ-UHFFFAOYSA-N 6-(2-methylprop-2-enoyloxy)hexyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCCCCOC(=O)C(C)=C SAPGBCWOQLHKKZ-UHFFFAOYSA-N 0.000 claims description 7
- 235000021355 Stearic acid Nutrition 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 7
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 7
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 7
- 239000008117 stearic acid Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 6
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
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- 239000012876 carrier material Substances 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- XOJWAAUYNWGQAU-UHFFFAOYSA-N 4-(2-methylprop-2-enoyloxy)butyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCCOC(=O)C(C)=C XOJWAAUYNWGQAU-UHFFFAOYSA-N 0.000 claims description 2
- BWJUFXUULUEGMA-UHFFFAOYSA-N propan-2-yl propan-2-yloxycarbonyloxy carbonate Chemical compound CC(C)OC(=O)OOC(=O)OC(C)C BWJUFXUULUEGMA-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
The invention relates to a polymer nano gel microsphere, a preparation method and application thereof. The polymer nano gel microsphere is prepared from dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, a dispersing agent, a free radical initiator and a crosslinking monomer in a nonpolar solvent through free radical polymerization reaction; the vinyl cyclic acetal monomer is 2-methylene-4-phenyl-1, 3-dioxolane and/or 5, 6-benzo-2-methylene-1, 3-dioxepane. The main chain of the polymer nano gel microsphere prepared by the invention contains degradable ester groups, so that the problem that the stimulus-responsive nano gel microsphere obtained by free radical polymerization at present cannot be degraded is solved. The obtained polymer nano gel microsphere has the performance of dual response of temperature and pH, can be used for drug loading and responsive release, can be degraded under alkaline conditions, and has good application prospect in the field of biological medicine.
Description
Technical Field
The invention relates to the technical field of stimulus-responsive functional polymers, in particular to a temperature and pH responsive degradable polymer nanogel microsphere, and a preparation method and application thereof.
Background
Polymer nanogels (also known as microgels) are colloidal particles with highly cross-linked internal structures, typically between 1nm and 1um in particle size. Compared with the traditional linear polymer, the polymer nanogel has the advantages of low viscosity, high specific surface area and the like, and has great application potential in various fields of biological medicine, food, petrochemical industry, environmental protection and the like in recent years.
The stimulus-responsive nanogel is a microgel which can be swelled or extruded by a solvent under the change of external environmental conditions (such as temperature, pH, ionic strength and the like), thereby increasing or shrinking the volume, and has good application prospect in the fields of tissue engineering and biological medicine, and has been a research hot spot in the field of high polymers in the past ten years.
At present, the stimulus-responsive nanogel is mainly prepared by a vinyl monomer free radical polymerization technology, a main chain skeleton is a C-C bond, and the degradation performance is poor, which is a great obstacle for the practical application of the nanogel in the fields of tissue engineering and biological medicine.
Disclosure of Invention
Based on the above, the invention aims to overcome the problem of poor degradability faced by the current preparation of stimulus-responsive nanogels by free radical polymerization, and provides a temperature and pH responsive degradable polymer nanogel microsphere and a method for preparing the degradable nanogel microsphere by the free radical polymerization technology.
In order to achieve the above object, the present invention includes the following technical solutions.
A polymeric nanogel microsphere, wherein a repeating structural unit in the polymeric nanogel microsphere has a structure represented by the following formula (I):
wherein R is 1 Is one of the following structures:
R 2 is n-butyl or n-hexyl.
The polymer nano gel microsphere is prepared by a free radical polymerization reaction of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, a dispersing agent, a free radical initiator and a crosslinking monomer in a nonpolar solvent;
the vinyl cyclic acetal monomer is 2-methylene-4-phenyl-1, 3-dioxolane and/or 5, 6-benzo-2-methylene-1, 3-dioxepane.
The invention also provides a method for preparing the degradable polymer nanogel microsphere by a free radical polymerization technology, which comprises the following technical scheme.
The preparation process of polymer nanometer gel microsphere includes the following steps:
adding the dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, a dispersing agent, a free radical initiator and a crosslinking monomer into a nonpolar solvent, and reacting under an inert gas atmosphere to obtain the modified polyvinyl alcohol.
The invention also provides application of the polymer nano gel microsphere, which comprises the following technical scheme.
The polymer nano gel microsphere is used as a carrier material in the preparation of pH and/or temperature responsive release drugs.
The invention also provides a pH and/or temperature responsive release medicament, which comprises the following technical scheme.
A pH and/or temperature responsive release drug prepared from a pharmaceutically active ingredient and pharmaceutically acceptable excipients, wherein the excipients comprise the polymer nanogel microspheres.
Wherein the active pharmaceutical ingredient is a hydrophilic drug such as heparin.
A nano gel microsphere medicine loaded with heparin is prepared from the polymer nano gel microsphere and heparin.
In some of these embodiments, the mass ratio of the polymeric nanogel microspheres to heparin is 4-6:1.
the invention also provides a preparation method of the heparin-loaded nanogel microsphere drug, which comprises the following steps:
dispersing the polymer nano gel microsphere in tetrahydrofuran to obtain nano gel microsphere dispersion liquid, dissolving heparin in water, dripping the solution into the nano gel microsphere dispersion liquid, stirring the solution in an open mode to volatilize the tetrahydrofuran completely, centrifuging the solution, and freeze-drying the solution to obtain the heparin-loaded nano gel microsphere drug.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, by using a free radical dispersion polymerization method, dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer and crosslinking monomer as reaction raw materials, and copolymerizing in a nonpolar solvent under the combined action of a dispersing agent and a free radical initiator, the polymer nanogel microsphere with a main chain containing degradable ester groups is prepared, and the problem that the stimulus-responsive nanogel microsphere obtained by free radical polymerization at present cannot be degraded is solved. The obtained polymer nano gel microsphere has the performance of dual response of temperature and pH, can be used for drug loading and responsive release, can be degraded under alkaline conditions, and has good application prospect in the field of biological medicine.
Drawings
FIG. 1 is a Fourier transform infrared absorption spectrum of the nanogel microsphere prepared in example 1.
FIG. 2 is a scanning electron microscope image of the nanogel microspheres prepared in example 1.
FIG. 3 is a graph of dynamic light scattering particle size for the water-dispersed nano-nanospheres of example 1 at different pH and temperature.
FIG. 4 is a scanning electron microscope image of the nanogel microspheres prepared in example 1 after hydrolysis under alkaline conditions.
FIG. 5 is a graph showing the drug release profile of heparin-loaded nanogel microspheres prepared in example 2 at 37℃and at different pH values.
FIG. 6 is a scanning electron microscope image of the nanogel microspheres prepared in example 3.
FIG. 7 is a scanning electron microscope image of the nanogel microspheres prepared in example 4.
FIG. 8 is a scanning electron microscope image of the nanogel microspheres prepared in example 5.
Detailed Description
The technical scheme of the invention is further described by the following specific examples. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements or modules listed but may alternatively include additional steps not listed or inherent to such process, method, article, or device.
In the present invention, the term "plurality" means two or more. "and/or", describes an association relationship of an association object, and indicates that there may be three relationships, for example, a and/or B, and may indicate: a exists alone, A and B exist together, and B exists alone. The character "/" generally indicates that the context-dependent object is an "or" relationship.
In one embodiment of the present invention, the present invention provides a polymer nanogel microsphere, in which the repeating structural unit has a structure represented by the following formula (I):
wherein R is 1 Is one of the following structures:
R 2 is n-butyl or n-hexyl.
In one embodiment of the present invention, the present invention provides a polymer nanogel microsphere prepared from dimethylaminoethyl methacrylate, a vinyl cyclic acetal monomer, a dispersant, a free radical initiator and a crosslinking monomer by free radical polymerization in a nonpolar solvent;
the vinyl cyclic acetal monomer is 2-methylene-4-phenyl-1, 3-dioxolane and/or 5, 6-benzo-2-methylene-1, 3-dioxepane.
According to the invention, the vinyl cyclic acetal monomer, the dimethylaminoethyl methacrylate and the crosslinking monomer are subjected to free radical dispersion copolymerization in a nonpolar solvent to prepare the polymer nanogel microsphere with the main chain containing the degradable ester group, so that the problem that the stimulus-responsive nanogel microsphere obtained by free radical polymerization at present cannot be degraded is solved. The polymethyl methacrylate chain segment in the polymer nanogel microsphere can generate phase transition along with the change of temperature and/or pH, and can generate the transition of hydrophilic and hydrophobic properties, so that the volume change of the polymer nanogel microsphere can be caused, and the prepared polymer nanogel microsphere has the dual response properties of temperature and pH and can be used for loading and responsive release of medicines. Meanwhile, the copolymer of the dimethylaminoethyl methacrylate and the vinyl cyclic acetal monomer can insert degradable ester groups into the main chain of the polymer, so that the polymer is endowed with good degradation performance, the polymer can be degraded under alkaline conditions, and the problem that the stimulus-responsive polymer nanogel microsphere obtained by free radical polymerization can not be degraded at present is solved, so that the polymer has an expected potential application prospect in the field of biological medicine.
The vinyl cyclic acetal monomer adopted by the invention is 2-methylene-4-phenyl-1, 3-dioxolane (MPDL) and/or 5, 6-benzo-2-methylene-1, 3-dioxacycloheptane (BMDO), the two vinyl cyclic acetal monomers both contain benzene rings, the introduction of benzene ring side groups has a stabilizing effect on generated free radicals, the ring opening efficiency of the monomer is high, the side reaction is less, and the 100% ring opening efficiency can be realized under the condition of free radical polymerization. In addition, the dimethylaminoethyl methacrylate has a low glass transition temperature (Tg), which is not beneficial to the maintenance of the morphology of the self-assembly body in the polymerization process, the Tg of the phenyl ring side groups in MPDL and BMDO can be improved, and the stability of the obtained polymer nanogel microsphere particles can be enhanced by introducing a crosslinking agent (crosslinking monomer).
In addition, as the vinyl cyclic acetal monomer is sensitive to active protons and is easy to react with a solvent in a side way, so that the copolymerization reaction efficiency of the vinyl cyclic acetal monomer and dimethylaminoethyl methacrylate is influenced, and the acquisition of the polymer nanogel microsphere is influenced.
In some embodiments of the invention, the crosslinking monomer is selected from one or both of 1, 6-hexanediol dimethacrylate and 1, 4-butanediol dimethacrylate.
In some embodiments of the invention, the dispersant is stearic acid.
In some embodiments of the invention, the non-polar solvent is n-heptane.
In some embodiments of the invention, the initiator is selected from one or more of azobisisobutyronitrile, azobisisoheptonitrile, diisopropyl peroxydicarbonate.
In some embodiments of the invention, the molar ratio of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer and crosslinking monomer is 3 to 7:1:0.1 to 0.5, more preferably 4 to 6:1:0.2 to 0.4, more preferably 4.8 to 5.2:1:0.3-0.35. The amount of the crosslinking agent can affect the synthesis of the polymer, and when the amount is too low, the stability of the obtained polymer nanogel microsphere cannot be maintained, and when the amount is too high, crosslinking gelation occurs in the polymerization process, and the polymer nanogel microsphere cannot be obtained. The molar ratio of the dimethylaminoethyl methacrylate, the vinyl cyclic acetal monomer and the crosslinking monomer is within the above preferred range, which is favorable for obtaining the polymer nanogel microspheres and improving the stability of the obtained polymer nanogel microspheres.
In some embodiments of the invention, the mass ratio of the dimethylaminoethyl methacrylate to the dispersant is 1:0.02 to 0.1, more preferably 1:0.04 to 0.06, more preferably 1:0.05. the particle size of the temperature and pH responsive degradable polymer nanogel microsphere can be adjusted by adding the dispersing agent, and the particle size is reduced along with the increase of the content of the dispersing agent within a certain range.
In some embodiments of the invention, the molar ratio of vinyl cyclic acetal monomer to free radical initiator is 1:0.05 to 0.1, more preferably 1:0.06 to 0.09, more preferably 1:0.08.
in some embodiments of the invention, the polymer nanogel microspheres have a particle size of 200nm to 600nm.
In some embodiments of the invention, the polymer nanogel microspheres have a particle size of 300nm to 500nm.
In one embodiment of the present invention, the present invention provides a method for preparing the degradable polymeric nanogel microspheres by a free radical polymerization technique, comprising the steps of: adding the dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, a dispersing agent, a free radical initiator and a crosslinking monomer into a nonpolar solvent, and reacting under an inert gas atmosphere to obtain the modified polyvinyl alcohol.
In some of these embodiments, the temperature of the reaction is 80 ℃ to 100 ℃ and the time of the reaction is 4 hours to 10 hours. At the preferable temperature, the ring-opening polymerization of the vinyl cyclic acetal monomer is facilitated, and the reaction conversion rate is improved.
In some of these embodiments, the temperature of the reaction is from 85 ℃ to 95 ℃ and the time of the reaction is from 6h to 9h.
In one embodiment of the invention, the invention also provides the application of the polymer nanogel microsphere as a carrier material in the preparation of pH and/or temperature responsive release drugs.
In one embodiment of the present invention, the present invention provides a pH and/or temperature responsive release drug prepared from a pharmaceutically active ingredient and pharmaceutically acceptable excipients, including the polymeric nanogel microspheres.
In some embodiments, the pharmaceutically active ingredient is a hydrophilic drug.
In some embodiments, the pharmaceutically active ingredient is heparin.
In one embodiment of the invention, the invention provides a heparin-loaded nanogel microsphere drug prepared from raw and auxiliary materials comprising the polymer nanogel microsphere and heparin.
In some of these embodiments, the mass ratio of the polymeric nanogel microspheres to heparin is 4-6:1.
in one embodiment of the present invention, the present invention provides a method for preparing the heparin-loaded nanogel microsphere drug, comprising the steps of:
dispersing the polymer nano gel microsphere in tetrahydrofuran to obtain nano gel microsphere dispersion liquid, dissolving heparin in water, dripping the solution into the nano gel microsphere dispersion liquid, stirring the solution in an open mode to volatilize the tetrahydrofuran completely, centrifuging the solution, and freeze-drying the solution to obtain the heparin-loaded nano gel microsphere drug.
The following are specific examples. The starting materials used in the examples below, unless otherwise specified, are all commercially available from conventional sources; the processes used, unless otherwise specified, are all conventional in the art. The room temperature or room temperature refers to 25.+ -. 5 ℃ unless otherwise specified.
EXAMPLE 1 Synthesis and characterization of temperature and pH responsive degradable nanogel microspheres
1. Synthesis of temperature and pH responsive degradable nanogel microspheres
2g (12.7 mmol) of dimethylaminoethyl methacrylate, 0.4g (2.5 mmol) of vinylcyclic acetal monomer (2-methylene-4-phenyl-1, 3-dioxolane, MPDL), 0.1g of dispersant stearic acid, 32.4mg (0.2 mmol) of Azobisisobutyronitrile (AIBN), 0.2g (0.8 mmol) of 1, 6-hexanediol dimethacrylate and 10mL of n-heptane were added and reacted at 90℃for 8 hours under an inert gas atmosphere. And (3) centrifuging to obtain 2.6g of nano gel microspheres.
The reaction formula is as follows:
wherein R is 1 Is that(. Representing the site of attachment), R 2 Is n-hexyl.
2. Test characterization
(1) The obtained nanogel microsphere was subjected to infrared spectrum characterization as shown in FIG. 1 at 1785cm -1 The characteristic absorption peak of the stretching vibration of C=O bond in the MPDL unit appears, at 1720cm -1 The characteristic absorption peak of the stretching vibration of C=O bond in the dimethylaminoethyl methacrylate unit shows that the MPDL and the dimethylaminoethyl methacrylate realize copolymerization.
(2) The obtained nanogel microsphere is subjected to scanning electron microscope characterization, and as shown in figure 2, the nanogel microsphere prepared in the embodiment is spherical and has the particle size of 400nm.
(3) Dispersing the obtained nano gel microsphere in water, and measuring the particle size of the nano gel microsphere at different pH values and different temperatures by using dynamic light scattering. As shown in fig. 3, the particle size decreases with increasing temperature in the test range, indicating that the polydimethylaminoethyl methacrylate segment undergoes a phase transition from hydrophilic to hydrophobic, and the microsphere volume shrinks; also, as pH increases, the phase transition temperature is lower, since as pH increases, deprotonation of the amino group occurs resulting in greater hydrophobicity and thus lower phase transition temperature.
(4) 10mg of the obtained nanogel microspheres were dispersed in 1mL of sodium hydroxide solution at pH 10 and stirred for 6h. The obtained sample is observed by a scanning electron microscope, and as shown in fig. 4, the result shows that the morphology of the gel microsphere becomes irregular granules, and the size is 60-100nm, which indicates that the nano gel microsphere is degraded.
EXAMPLE 2 preparation of heparin-loaded nanogel microspheres and drug Release
1. Preparation of heparin-loaded nanogel microspheres
100mg of the nanogel microsphere prepared in example 1 is taken and dispersed in 10mL of tetrahydrofuran to obtain a nanogel microsphere dispersion, 20mg of heparin is dissolved in 2mL of water, and the mixture is added dropwise into the nanogel microsphere dispersion, and the mixture is stirred for 24 hours with an opening to completely volatilize the tetrahydrofuran. Centrifuging to separate supernatant and nanometer gel microsphere, and freeze drying to obtain nanometer gel microsphere loaded with heparin. The heparin content in the supernatant was determined by uv absorption spectroscopy and the heparin loading in the nanogel microspheres was calculated to be 13.2% (method reference int.j. Nanomedia., 2016,11,6149-6159).
2. Heparin release rates of nanogel microspheres at different pH
50mg of the prepared heparin-loaded nanogel microsphere is taken and stirred and dispersed in 1mL of PBS buffer with specific pH at 37 ℃; the release rate was calculated by measuring the heparin content released in the solution by UV-Vis spectrometry standard curve method by pipetting 10uL of supernatant with a pipette and diluting to 1mL at different time periods.
As shown in fig. 5, the time required for heparin to reach 50% release rate was 21h (ph=6), 12.5h (ph=7) and 7.5h (ph=8), respectively, with increasing pH, i.e. the higher the pH, the faster the release rate of heparin, since the higher the pH, the higher the degree of deprotonation of the amino group, the more hydrophobic, the more advantageous the release of hydrophilic heparin. The degradable nano gel microsphere prepared by the invention can be used as a carrier of hydrophilic drugs such as heparin and the like for preparing pH and/or temperature responsive release drugs, and can realize the effect of different drug release speeds at different pH and/or temperature.
Example 3 Synthesis and characterization of temperature and pH responsive degradable nanogel microspheres
2g (12.7 mmol) of dimethylaminoethyl methacrylate, 0.4g (2.5 mmol) of vinylcyclic acetal monomer (5, 6-benzo-2-methylene-1, 3-dioxacycloheptane, BMDO), 0.1g of dispersant stearic acid, 32.4mg (0.2 mmol) of azobisisobutyronitrile and 0.2g (0.8 mmol) of 1, 6-hexanediol dimethacrylate were added to 10mL of n-heptane and reacted at 90℃under an inert gas atmosphere for 8 hours. And (3) centrifuging to obtain 2.6g of nano gel microspheres.
The reaction formula is as follows:
wherein R is 1 Is that(. Representing the site of attachment), R 2 Is n-hexyl.
The obtained nanogel microsphere is subjected to scanning electron microscope characterization, and as shown in fig. 6, the nanogel microsphere prepared in the embodiment is spherical and has the particle size of 400nm.
EXAMPLE 4 Synthesis and characterization of temperature and pH responsive degradable nanogel microspheres
2g (12.7 mmol) of dimethylaminoethyl methacrylate, 0.4g (2.5 mmol) of vinylcyclic acetal monomer (2-methylene-4-phenyl-1, 3-dioxolane, MPDL), 0.05g of dispersant stearic acid, 32.4mg (0.2 mmol) of Azobisisobutyronitrile (AIBN), 0.2g (0.8 mmol) of 1, 6-hexanediol dimethacrylate and 10mL of n-heptane were added and reacted at 90℃for 8 hours under an inert gas atmosphere. And (3) centrifuging to obtain 2.5g of nano gel microspheres.
The obtained nanogel microsphere is subjected to scanning electron microscope characterization, and as shown in fig. 7, the nanogel microsphere prepared in the embodiment is spherical and has the particle size of 500nm.
EXAMPLE 5 Synthesis and characterization of temperature and pH responsive degradable nanogel microspheres
2g (12.7 mmol) of dimethylaminoethyl methacrylate, 0.4g (2.5 mmol) of vinylcyclic acetal monomer (2-methylene-4-phenyl-1, 3-dioxolane, MPDL), 0.2g of dispersant stearic acid, 32.4mg (0.2 mmol) of Azobisisobutyronitrile (AIBN), 0.2g (0.8 mmol) of 1, 6-hexanediol dimethacrylate and 10mL of n-heptane were added and reacted at 90℃for 8 hours under an inert gas atmosphere. And (3) centrifuging to obtain 2.4g of nano gel microspheres.
The obtained nanogel microsphere is subjected to scanning electron microscope characterization, and as shown in fig. 8, the nanogel microsphere prepared in the embodiment is spherical and has the particle size of 300nm.
Comparative example 1 Synthesis of temperature and pH responsive degradable nanogel microspheres
2g (12.7 mmol) of dimethylaminoethyl methacrylate, 0.4g (2.5 mmol) of vinyl cyclic acetal monomer (2-methylene-4-phenyl-1, 3-dioxolane, MPDL), 0.1g (0.2 mmol) of dispersant stearic acid, 32.4mg (0.2 mmol) of azobisisobutyronitrile and 0.64g (2.5 mmol) of 1, 6-hexanediol dimethacrylate were added to 10mL of n-heptane, and the reaction was carried out at 90℃for 2 hours under an inert gas atmosphere, so that gelation could not be continued.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (17)
1. The polymer nanogel microsphere is characterized in that a repeated structural unit in the polymer nanogel microsphere has a structure shown in the following formula (I):
wherein R is 1 Is one of the following structures:
R 2 is n-butyl or n-hexyl.
2. The polymer nano gel microsphere is characterized by being prepared from dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, a dispersing agent, a free radical initiator and a crosslinking monomer through free radical polymerization reaction in a nonpolar solvent;
the vinyl cyclic acetal monomer is 2-methylene-4-phenyl-1, 3-dioxolane and/or 5, 6-benzo-2-methylene-1, 3-dioxepane.
3. The polymer nanogel microsphere of claim 2 wherein the crosslinking monomer is selected from one or both of 1, 6-hexanediol dimethacrylate and 1, 4-butylene glycol dimethacrylate; and/or the number of the groups of groups,
the dispersing agent is stearic acid; and/or the number of the groups of groups,
the nonpolar solvent is n-heptane; and/or the number of the groups of groups,
the initiator is selected from one or more of azodiisobutyronitrile, azodiisoheptonitrile and diisopropyl peroxydicarbonate.
4. The polymeric nanogel microsphere of claim 2 or 3 wherein the molar ratio of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer and crosslinking monomer is 3-7:1:0.1-0.5.
5. The polymeric nanogel microsphere of claim 4 wherein the molar ratio of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer and crosslinking monomer is 4-6:1:0.2-0.4.
6. The polymer nanogel microsphere of claim 2 or 3, wherein the mass ratio of dimethylaminoethyl methacrylate to the dispersant is 1:0.02-0.1; and/or the number of the groups of groups,
the molar ratio of the vinyl cyclic acetal monomer to the free radical initiator is 1:0.05-0.1.
7. The polymer nanogel microsphere according to claim 6, wherein the mass ratio of dimethylaminoethyl methacrylate to the dispersant is 1:0.04-0.06; and/or the number of the groups of groups,
the molar ratio of the vinyl cyclic acetal monomer to the free radical initiator is 1:0.06-0.09.
8. A polymer nanogel microsphere according to any one of claims 1 to 3, characterized in that it has a particle size of 200nm to 600nm.
9. A method for preparing the polymer nanogel microsphere according to any one of claims 1 to 8, comprising the steps of: adding the dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, a dispersing agent, a free radical initiator and a crosslinking monomer into a nonpolar solvent, and reacting under an inert gas atmosphere to obtain the modified polyvinyl alcohol.
10. The method for preparing polymer nanogel microspheres according to claim 9, wherein the reaction temperature is 80-100 ℃ and the reaction time is 4-10 h.
11. Use of the polymeric nanogel microspheres according to any one of claims 1-8 as a carrier material in the preparation of a pH and/or temperature responsive release drug.
12. The pH and/or temperature responsive release medicine is characterized in that the medicine is prepared from a medicine active ingredient and pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise the polymer nanogel microspheres.
13. The pH and/or temperature responsive release drug of claim 12, wherein the pharmaceutically active ingredient is a hydrophilic drug.
14. The pH and/or temperature responsive release drug of claim 13, wherein the pharmaceutically active ingredient is heparin.
15. A heparin-loaded nanogel microsphere drug, characterized in that it is prepared from the polymer nanogel microsphere according to any one of claims 1-8 and heparin raw and auxiliary materials.
16. The heparin-loaded nanogel microsphere drug of claim 15, wherein the mass ratio of polymer nanogel microsphere to heparin is 4-6:1.
17. a method for preparing the heparin-loaded nanogel microsphere drug of claim 15 or 16, comprising the steps of:
dispersing the polymer nano gel microsphere in tetrahydrofuran to obtain nano gel microsphere dispersion liquid, dissolving heparin in water, dripping the solution into the nano gel microsphere dispersion liquid, stirring the solution in an open mode to volatilize the tetrahydrofuran completely, centrifuging the solution, and freeze-drying the solution to obtain the heparin-loaded nano gel microsphere drug.
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