WO2024221222A1 - Degradable polymer nanogel microsphere, and preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a polymer nanogel microsphere, and a preparation method therefor and a use thereof. The polymer nanogel microsphere is prepared by free radical polymerization reaction of dimethylaminoethyl methacrylate, a vinyl cyclic acetal monomer, a dispersant, a free radical initiator and a crosslinking monomer in a non-polar solvent, wherein the vinyl cyclic acetal monomer is 2-methylene-4-phenyl-1,3-dioxolane and/or 5,6-benzo-2-methylene-1,3-dioxepane. A backbone of the polymer nanogel microsphere prepared by the present invention contains a degradable ester group, overcoming the problem that the current stimuli-responsive nanogel microspheres obtained by means of free radical polymerization cannot be degraded. The prepared polymer nanogel microsphere has temperature and pH dual-response performance, can be used for drug loading and responsive release, can be degraded under an alkaline condition, and has a good application prospect in the field of biomedicine.

Description

Degradable polymer nanogel microspheres and preparation method and application thereof Technical Field

The invention relates to the technical field of stimulus-responsive functional polymers, and in particular to temperature- and pH-responsive degradable polymer nanogel microspheres and a preparation method and application thereof.

Background Art

Polymer nanogel (also known as microgel) is a kind of colloidal particle with highly cross-linked internal structure, and its particle size is usually between 1nm and 1um. Compared with traditional linear polymers, polymer nanogel has the advantages of low viscosity and high specific surface area. In recent years, it has shown great application potential in many fields such as biomedicine, food, petrochemical and environmental protection.

Stimuli-responsive nanogels refer to a type of microgel that can expand or shrink in volume due to swelling or solvent extrusion inside the nanogels when external environmental conditions change (such as temperature, pH, ionic strength, etc.). Because of their good application prospects in tissue engineering and biomedicine, they have been a research hotspot in the polymer field over the past decade.

Currently, stimulus-responsive nanogels are mainly prepared through free radical polymerization technology of vinyl monomers. The main chain skeleton is C-C bond and has poor degradation performance, which is a major obstacle to its practical application in tissue engineering and biomedicine.

Summary of the invention

Based on this, the purpose of the present invention is to overcome the problem of poor degradability currently faced by the preparation of stimulus responsive nanogels by free radical polymerization, and to provide a temperature and pH responsive degradable polymer nanogel microsphere, as well as a method for preparing the degradable nanogel microsphere by free radical polymerization technology.

In order to achieve the above-mentioned object of the invention, the present invention includes the following technical solutions.

A polymer nanogel microsphere, wherein the repeating structural unit in the polymer nanogel microsphere has a structure shown in the following formula (I):

Wherein, _R1 is one of the following structures:

_R2 is n-butyl or n-hexyl.

A polymer nanogel microsphere is prepared by free radical polymerization of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, dispersant, free radical initiator and crosslinking monomer in a non-polar 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 present invention also provides a method for preparing the degradable polymer nanogel microspheres by free radical polymerization technology, which includes the following technical scheme.

A method for preparing polymer nanogel microspheres comprises the following steps:

The dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, dispersant, free radical initiator and crosslinking monomer are added into a non-polar solvent and reacted under an inert gas atmosphere to obtain the product.

The present invention also provides the application of the polymer nanogel microspheres, including the following technical solutions.

The polymer nanogel microspheres are used as carrier materials in the preparation of pH and/or temperature responsive release drugs.

The present invention also provides a pH and/or temperature responsive drug release, including the following technical solutions.

A pH and/or temperature responsive release drug is prepared from active drug ingredients and adjuvants acceptable in drugs, wherein the adjuvants include the polymer nanogel microspheres.

Wherein, the active pharmaceutical ingredient is a hydrophilic drug, such as heparin.

A heparin-loaded nanogel microsphere medicine is prepared from raw and auxiliary materials including the polymer nanogel microsphere and heparin.

In some of the embodiments, the mass ratio of the polymer nanogel microspheres to heparin is 4-6:1.

The present invention also provides a method for preparing the heparin-loaded nanogel microsphere drug, comprising the following steps:

The polymer nanogel microspheres are dispersed in tetrahydrofuran to obtain a nanogel microsphere dispersion, the heparin is dissolved in water, and then added dropwise to the nanogel microsphere dispersion, stirred in an open air to completely volatilize the tetrahydrofuran, centrifuged, and freeze-dried to obtain the heparin-loaded nanogel microsphere drug.

Compared with the prior art, the present invention has the following beneficial effects:

The present invention adopts a free radical dispersion polymerization method, uses dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer and crosslinking monomer as reaction raw materials, and copolymerizes in a non-polar solvent under the joint action of a dispersant and a free radical initiator to prepare a polymer nanogel microsphere with a degradable ester group in the main chain, which overcomes the problem that the stimulus-responsive nanogel microsphere obtained by free radical polymerization cannot be degraded. The obtained polymer nanogel microsphere has the performance of dual response to temperature and pH, and can be used for medicine It can load and responsively release substances, and can degrade under alkaline conditions, which has good application prospects in the field of biomedicine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a Fourier transform infrared absorption spectrum of the nanogel microspheres prepared in Example 1.

FIG. 2 is a scanning electron microscope image of the nanogel microspheres prepared in Example 1.

FIG3 is a dynamic light scattering particle size diagram of the water-dispersible nanospheres of Example 1 at different pH and temperature.

FIG. 4 is a scanning electron micrograph of the nanogel microspheres prepared in Example 1 after hydrolysis under alkaline conditions.

FIG5 is a graph showing the drug release curves of the heparin-loaded nanogel microspheres prepared in Example 2 at 37° C. and 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.

FIG8 is a scanning electron microscope image of the nanogel microspheres prepared in Example 5.

DETAILED DESCRIPTION

The technical scheme of the present invention is further illustrated by specific examples below. Those skilled in the art should understand that the examples are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

The terms "include" and "have" and any variations thereof are intended to cover non-exclusive inclusions. For example, a process, method, device, product or apparatus comprising a series of steps is not limited to the listed The present invention does not include the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to these processes, methods, products or devices.

In the present invention, the term "multiple" refers to two or more than two. "And/or" describes the association relationship of associated objects, indicating that three relationships may exist. For example, A and/or B can represent the following three situations: A exists alone, A and B exist at the same time, and B exists alone. The character "/" generally indicates that the associated objects are in an "or" relationship.

In one embodiment of the present invention, the present invention provides a polymer nanogel microsphere, wherein the repeating structural unit in the polymer nanogel microsphere has a structure shown in the following formula (I):

Wherein, _R1 is one of the following structures:

_R2 is n-butyl or n-hexyl.

In one embodiment of the present invention, the present invention provides a polymer nanogel microsphere, which is prepared by free radical polymerization of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, dispersant, free radical initiator and crosslinking monomer in a non-polar 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 present invention prepares polymer nanogel microspheres with degradable ester groups in the main chain by free radical dispersion copolymerization of vinyl cyclic acetal monomers, dimethylaminoethyl methacrylate and crosslinking monomers in a non-polar solvent, thereby overcoming the problem that the stimulus responsive nanogel microspheres currently obtained by free radical polymerization cannot be degraded. The polydimethylaminoethyl methacrylate chain segments in the polymer nanogel microspheres undergo phase transition with changes in temperature and/or pH, and undergo a transition in hydrophilic and hydrophobic properties, thereby causing a volume change of the polymer nanogel microspheres, so that the prepared polymer nanogel microspheres have dual-responsive properties of temperature and pH, and can be used for drug loading and responsive release. At the same time, the copolymerization of dimethylaminoethyl methacrylate and vinyl cyclic acetal monomers can insert a degradable ester group into the polymer main chain, giving the polymer good degradation performance, and the polymer can be degraded under alkaline conditions, overcoming the problem that the stimulus responsive polymer nanogel microspheres currently obtained by free radical polymerization cannot be degraded, thereby making it have a foreseeable potential application prospect in the field of biomedicine.

The vinyl cyclic acetal monomers used in the present invention are 2-methylene-4-phenyl-1,3-dioxolane (MPDL) and/or 5,6-benzo-2-methylene-1,3-dioxepane (BMDO). Both of these vinyl cyclic acetal monomers contain benzene rings. The introduction of benzene ring side groups has a stabilizing effect on the generated free radicals. The monomers have high ring-opening efficiency and few side reactions, and can achieve 100% ring-opening efficiency under free radical polymerization conditions. In addition, the glass transition temperature (Tg) of dimethylaminoethyl methacrylate is low, which is not conducive to maintaining the morphology of the self-assembly during the polymerization process. The benzene ring side groups in MPDL and BMDO can increase their Tg, and the introduction of a cross-linking agent (cross-linking monomer) can enhance the stability of the resulting polymer nanogel microsphere particles.

In addition, since vinyl cyclic acetal monomers are sensitive to active protons and are prone to side reactions with solvents, thereby affecting the efficiency of their copolymerization with dimethylaminoethyl methacrylate and the acquisition of polymer nanogel microspheres, the use of non-polar solvents for dispersion polymerization in the reaction system of the present invention can effectively avoid the above problems, achieve very excellent reaction results, and efficiently obtain stable and degradable polymer nanogel microspheres.

In some embodiments of the present invention, the cross-linking monomer is selected from one or both of 1,6-hexanediol dimethacrylate and 1,4-butanediol dimethacrylate.

In some embodiments of the present invention, the dispersant is stearic acid.

In some embodiments of the present invention, the non-polar solvent is n-heptane.

In some embodiments of the present invention, the initiator is selected from one or more of azobisisobutyronitrile, azobisisoheptanenitrile, and diisopropyl peroxydicarbonate.

In some embodiments of the present invention, the molar ratio of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer and crosslinking monomer is 3-7:1:0.1-0.5, more preferably 4-6:1:0.2-0.4, and more preferably 4.8-5.2:1:0.3-0.35. The amount of crosslinking agent used will affect the synthesis of the polymer. If the amount is too low, the stability of the obtained polymer nanogel microspheres cannot be maintained. If the amount is too high, crosslinking and gelation will occur during the polymerization process, and polymer nanogel microspheres cannot be obtained. The molar ratio of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer and crosslinking monomer is within the above preferred range, which is conducive to the acquisition of polymer nanogel microspheres and to improving the stability of the obtained polymer nanogel microspheres.

In some embodiments of the present invention, the mass ratio of the dimethylaminoethyl methacrylate to the dispersant is 1:0.02-0.1, more preferably 1:0.04-0.06, and more preferably 1:0.05. The particle size of the temperature and pH responsive degradable polymer nanogel microspheres of the present invention can be adjusted by the amount of dispersant added. Within a certain range, the particle size decreases as the content of the dispersant increases.

In some embodiments of the present invention, the molar ratio of the vinyl cyclic acetal monomer to the free radical initiator is 1:0.05-0.1, more preferably 1:0.06-0.09, and more preferably 1:0.08.

In some embodiments of the present invention, the particle size of the polymer nanogel microspheres is 200nm-600nm.

In some embodiments of the present invention, the particle size of the polymer nanogel microspheres is 300nm-500nm.

In one embodiment of the present invention, the present invention provides a method for preparing the degradable polymer nanogel microspheres by free radical polymerization technology, comprising the following steps: adding the dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, dispersant, free radical initiator and cross-linking monomer to a non-polar solvent, and reacting under an inert gas atmosphere to obtain.

In some embodiments, the reaction temperature is 80° C.-100° C., and the reaction time is 4 h-10 h. The preferred temperature is conducive to the ring-opening polymerization of the vinyl cyclic acetal monomer and improves the reaction conversion rate.

In some embodiments, the reaction temperature is 85° C.-95° C., and the reaction time is 6 h-9 h.

In one embodiment of the present invention, the present invention also provides the use of the polymer nanogel microspheres as carrier materials 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, which is prepared from a drug active ingredient and an excipient acceptable in the drug, wherein the excipient includes the polymer 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 present invention, the present invention provides a heparin-loaded nanogel microsphere drug, which is prepared from raw materials and auxiliary materials including the polymer nanogel microsphere and heparin.

In some of the embodiments, the mass ratio of the polymer 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 following steps:

The polymer nanogel microspheres are dispersed in tetrahydrofuran to obtain a nanogel microsphere dispersion, the heparin is dissolved in water, and then added dropwise to the nanogel microsphere dispersion, and stirred in an open air to make the tetrahydrofuran The hydrofuran is completely volatilized, centrifuged and freeze-dried to obtain the heparin-loaded nanogel microsphere drug.

The following are specific examples. The raw materials used in the following examples, unless otherwise specified, can all be obtained from conventional commercial sources; the processes used, unless otherwise specified, all adopt conventional processes in the art. Unless otherwise specified, room temperature or normal temperature refers to 25±5°C.

Example 1 Synthesis and characterization of temperature and pH responsive degradable nanogel microspheres

1. Synthesis of Temperature- and pH-responsive Degradable Nanogel Microspheres

2 g (12.7 mmol) of dimethylaminoethyl methacrylate, 0.4 g (2.5 mmol) of vinyl cyclic acetal monomer (2-methylene-4-phenyl-1,3-dioxolane, MPDL), 0.1 g of stearic acid as a dispersant, 32.4 mg (0.2 mmol) of azobisisobutyronitrile, and 0.2 g (0.8 mmol) of 1,6-hexanediol dimethacrylate were added to 10 mL of n-heptane, and reacted at 90° C. for 8 h under an inert gas atmosphere. After centrifugation, 2.6 g of nanogel microspheres were obtained.

The reaction formula is as follows:

Among them, _R1 is (* indicates the connection site), _R2 is n-hexyl.

2. Test Characterization

(1) The obtained nanogel microspheres were characterized by infrared spectroscopy. As shown in FIG1 , a characteristic absorption peak of the stretching vibration of the C=O bond in the MPDL unit appeared at 1785 cm ^-1 , and a characteristic absorption peak of the stretching vibration of the C=O bond in the dimethylaminoethyl methacrylate unit appeared at 1720 cm ^-1 , indicating that MPDL and dimethylaminoethyl methacrylate were copolymerized.

(2) The obtained nanogel microspheres were characterized by scanning electron microscopy. As shown in FIG. 2 , the nanogel microspheres prepared in this example were spherical in shape with a particle size of ∼400 nm.

(3) The obtained nanogel microspheres were dispersed in water, and the particle size at different pH and temperature was measured by dynamic light scattering. As shown in Figure 3, within the test range, the particle size decreased with increasing temperature, indicating that the poly(dimethylaminoethyl methacrylate) chain segment underwent a phase transition from hydrophilic to hydrophobic, and the volume of the microspheres shrank; and as the pH increased, the phase transition temperature became lower, because as the pH increased, the amino group was deprotonated, resulting in stronger hydrophobicity, which led to a lower phase transition temperature.

(4) 10 mg of the obtained nanogel microspheres were dispersed in 1 mL of sodium hydroxide solution at pH 10 and stirred for 6 h. The obtained sample was observed by scanning electron microscopy, as shown in FIG4 . The results showed that the morphology of the gel microspheres became irregular particles with a size of 60-100 nm, indicating that the nanogel microspheres were degraded.

Example 2 Preparation and drug release of heparin-loaded nanogel microspheres

1. Preparation of heparin-loaded nanogel microspheres

100 mg of the nanogel microspheres prepared in Example 1 were dispersed in 10 mL of tetrahydrofuran to obtain a nanogel microsphere dispersion. 20 mg of heparin was dissolved in 2 mL of water and added dropwise to the nanogel microsphere dispersion. The mixture was stirred in an open container for 24 h to allow the tetrahydrofuran to completely evaporate. The supernatant and nanogel microspheres were separated by centrifugation. The gel microspheres were freeze-dried to obtain nanogel microspheres loaded with heparin. The heparin content in the supernatant was determined by ultraviolet absorption spectroscopy, and the heparin loading in the nanogel microspheres was calculated to be 13.2% (Method 2 Reference: Int. J. Nanomed., 2016, 11, 6149-6159).

2. Heparin release rate of nanogel microspheres at different pH

Take 50 mg of the prepared heparin-loaded nanogel microspheres and disperse them in 1 mL of PBS buffer with a specific pH at 37°C with stirring; use a pipette to draw 10 uL of the supernatant and dilute it to 1 mL at different time periods, and determine the heparin content released in the solution by the UV-Vis spectral standard curve method to calculate the release rate.

The test results are shown in Figure 5. As the pH increases, the time required for heparin to reach a 50% release rate is 21h (pH = 6), 12.5h (pH = 7) and 7.5h (pH = 8), that is, the higher the pH, the faster the release rate of heparin. This is because the higher the pH, the higher the degree of amino deprotonation, the stronger the hydrophobicity, and the more conducive to the release of hydrophilic heparin. This shows that the degradable nanogel microspheres prepared by the present invention can be used as a carrier of hydrophilic drugs such as heparin to prepare pH and/or temperature responsive release drugs, and can achieve the effect of different drug release rates at different pH and/or temperatures.

Example 3 Synthesis and characterization of temperature and pH responsive degradable nanogel microspheres

2 g (12.7 mmol) of dimethylaminoethyl methacrylate, 0.4 g (2.5 mmol) of vinyl cycloacetal monomer (5,6-benzo-2-methylene-1,3-dioxepane, BMDO), 0.1 g of stearic acid as a dispersant, 32.4 mg (0.2 mmol) of azobisisobutyronitrile, and 0.2 g (0.8 mmol) of 1,6-hexanediol dimethacrylate were added to 10 mL of n-heptane and reacted at 90° C. for 8 h under an inert gas atmosphere. After centrifugation, 2.6 g of nanogel microspheres were obtained.

The reaction formula is as follows:

Among them, _R1 is (* indicates the connection site), _R2 is n-hexyl.

The obtained nanogel microspheres were characterized by scanning electron microscopy. As shown in FIG6 , the nanogel microspheres prepared in this example were spherical in shape and had a particle size of ˜400 nm.

Example 4 Synthesis and characterization of temperature and pH responsive degradable nanogel microspheres

2g (12.7mmol) of dimethylaminoethyl methacrylate, 0.4g (2.5mmol) of vinyl cyclic acetal monomer (2-methylene-4-phenyl-1,3-dioxolane, MPDL), 0.05g of stearic acid as a dispersant, 32.4mg (0.2mmol) of azobisisobutyronitrile, and 0.2g (0.8mmol) of 1,6-hexanediol dimethacrylate were added to 10mL of n-heptane, and reacted at 90°C for 8h under an inert gas atmosphere. After centrifugation, 2.5g of nanogel microspheres were obtained.

The obtained nanogel microspheres were characterized by scanning electron microscopy. As shown in FIG. 7 , the nanogel microspheres prepared in this example were spherical in shape with a particle size of ˜500 nm.

Example 5 Synthesis and characterization of temperature and pH responsive degradable nanogel microspheres

2 g (12.7 mmol) of dimethylaminoethyl methacrylate, 0.4 g (2.5 mmol) of vinyl cyclic acetal monomer (2-methylene-4-phenyl-1,3-dioxolane, MPDL), and 0.2 g of stearic acid as a dispersant were added. 32.4 mg (0.2 mmol) of azobisisobutyronitrile and 0.2 g (0.8 mmol) of 1,6-hexanediol dimethacrylate were added to 10 mL of n-heptane and reacted at 90° C. for 8 h under an inert gas atmosphere. After centrifugation, 2.4 g of nanogel microspheres were obtained.

The obtained nanogel microspheres were characterized by scanning electron microscopy. As shown in FIG8 , the nanogel microspheres prepared in this example were spherical in shape with a particle size of ˜300 nm.

Comparative Example 1 Synthesis of Temperature and pH Responsive Degradable Nanogel Microspheres

2 g (12.7 mmol) of dimethylaminoethyl methacrylate, 0.4 g (2.5 mmol) of vinyl cyclic acetal monomer (2-methylene-4-phenyl-1,3-dioxolane, MPDL), 0.1 g of stearic acid as a dispersant, 32.4 mg (0.2 mmol) of azobisisobutyronitrile, and 0.64 g (2.5 mmol) of 1,6-hexanediol dimethacrylate were added to 10 mL of n-heptane and reacted at 90 °C for 2 h under an inert gas atmosphere. The system gelled and could not proceed further.

The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the attached claims.

Claims (17)

A polymer nanogel microsphere, characterized in that the repeating structural unit in the polymer nanogel microsphere has a structure shown in the following formula (I):
Wherein, _R1 is one of the following structures: _R2 is n-butyl or n-hexyl. A polymer nanogel microsphere, characterized in that it is prepared by free radical polymerization of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, dispersant, free radical initiator and crosslinking monomer in a non-polar 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 polymer nanogel microspheres according to claim 2, characterized in that the cross-linking monomer is selected from one or both of 1,6-hexanediol dimethacrylate and 1,4-butanediol dimethacrylate; and/or, The dispersant is stearic acid; and/or, The non-polar solvent is n-heptane; and/or, The initiator is selected from azobisisobutyronitrile, azobisisoheptanenitrile, diisopropyl peroxydicarbonate One or more of. The polymer nanogel microspheres according to claim 2 or 3 are characterized in that the molar ratio of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer and cross-linking monomer is 3-7:1:0.1-0.5. The polymer nanogel microspheres according to claim 4 are characterized in that the molar ratio of dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer and cross-linking monomer is 4-6:1:0.2-0.4. The polymer nanogel microspheres according to claim 2 or 3, characterized in that the mass ratio of the dimethylaminoethyl methacrylate to the dispersant is 1:0.02-0.1; and/or, The molar ratio of the vinyl cyclic acetal monomer to the free radical initiator is 1:0.05-0.1. The polymer nanogel microspheres according to claim 6, characterized in that the mass ratio of the dimethylaminoethyl methacrylate to the dispersant is 1:0.04-0.06; and/or, The molar ratio of the vinyl cyclic acetal monomer to the free radical initiator is 1:0.06-0.09. The polymer nanogel microspheres according to any one of claims 1 to 3, characterized in that the particle size is 200nm-600nm. A method for preparing the polymer nanogel microspheres according to any one of claims 1 to 8, characterized in that it comprises the following steps: adding the dimethylaminoethyl methacrylate, vinyl cyclic acetal monomer, dispersant, free radical initiator and crosslinking monomer to a non-polar solvent, and reacting under an inert gas atmosphere to obtain the microspheres. The method for preparing polymer nanogel microspheres according to claim 9, characterized in that the reaction temperature is 80°C-100°C, and the reaction time is 4h-10h. Use of the polymer nanogel microspheres according to any one of claims 1 to 8 as carrier materials in the preparation of pH and/or temperature responsive release drugs. A pH and/or temperature responsive release drug, characterized in that it consists of a pharmaceutical active ingredient The polymer nanogel microspheres are prepared by combining the polymer nanogel microspheres with the excipients acceptable in medicine. The pH and/or temperature responsive release drug according to claim 12, characterized in that the active ingredient of the drug is a hydrophilic drug. The pH and/or temperature responsive release drug according to claim 13, characterized in that the active ingredient of the drug is heparin. A heparin-loaded nanogel microsphere drug, characterized in that it is prepared from raw and auxiliary materials including the polymer nanogel microspheres according to any one of claims 1 to 8 and heparin. The heparin-loaded nanogel microsphere drug according to claim 15, characterized in that the mass ratio of the polymer nanogel microspheres to heparin is 4-6:1. A method for preparing the heparin-loaded nanogel microsphere drug according to claim 15 or 16, characterized in that it comprises the following steps: The polymer nanogel microspheres are dispersed in tetrahydrofuran to obtain a nanogel microsphere dispersion, the heparin is dissolved in water, and then added dropwise to the nanogel microsphere dispersion, stirred in an open air to completely volatilize the tetrahydrofuran, centrifuged, and freeze-dried to obtain the heparin-loaded nanogel microsphere drug.