PH-temperature dual-responsive core-shell structure microgel as well as preparation method and application thereof
By introducing citonic acid or mesconic acid into the core or shell layer in the polymerization process of PNIPAM microgels, the problem of limited acid monomer binding in the prior art is solved, and a microgel with dual responsiveness and excellent encapsulation performance is prepared.
Patent Information
- Application Number
- CN202510115721.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-24
- Publication Date
- 2025-06-27
AI Technical Summary
The acid monomer introduced in the prior art contains only one carboxyl group, resulting in limited binding of drug molecules to it, which seriously limits its application in the fields of biomedicine and other fields.
Citricacin or mesconic acid is introduced into the core or shell layer respectively during PNIPAM polymerization. These dibasic acids have two carboxyl groups, increasing the possibility of drug binding and adjusting the collapse ratio and minimum critical dissolution temperature (LCST) of the microgel by adjusting the pH.
The prepared pH-temperature dual-responsive core-shell structure microgel has better drug binding ability and stability, and LCST can be adjusted to close to human temperature, suitable for encapsulation materials in the field of biomedical science.
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Figure CN120209220A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of gel materials, and particularly relates to a pH-temperature dual-responsive core-shell structured microgel and a preparation method and application thereof. Background Art
[0002] Poly(N-isopropylacrylamide) (PNIPAM) microgels have received extensive attention due to their temperature-responsive properties and biocompatibility, etc. When the temperature is higher than the lower critical solution temperature (LCST) (32 °C), the PNIPAM polymer chains become hydrophobic, thereby expelling the water in the body and causing the particles to shrink. By introducing other functional monomers during the polymerization process, PNIPAM microgels can be made responsive to pH, ions, light, magnetism, glucose, etc., which expands the applications of PNIPAM-based microgels in the biomedical and industrial fields. For example, introducing acrylic acid or methacrylic acid monomers during the polymerization process can obtain microgels with dual pH and temperature responsiveness. When pH > pKa, the carboxyl groups of the acid monomers are deprotonated, which can enhance the charge density around the polymer chains, thereby causing the network structure inside the microgel to expand.
[0003] More importantly, it has been found in research that the position of the copolymerized olefin carboxylic acid in the microgel structure also affects the swelling behavior of the microgel, and thus affects the ability to stabilize emulsions.
[0004] However, the introduced such acid monomers only contain one carboxyl group, resulting in limited binding of drug molecules to them, which severely limits their applications in the biomedical and other fields. Summary of the Invention
[0005] The purpose of this part is to outline some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this part, as well as in the abstract and title of the specification of this application, to avoid obscuring the purpose of this part, the abstract, and the title of the invention, and such simplifications or omissions cannot be used to limit the scope of the present invention.
[0006] In view of the above and / or problems existing in the prior art, the present invention is proposed.
[0007] Therefore, the purpose of the present invention is to overcome the deficiencies in the prior art and provide a preparation method for a pH-temperature dual-responsive core-shell structured microgel.
[0008] To solve the above technical problems, the present invention provides the following technical solution: A preparation method for a pH-temperature dual-responsive core-shell structured microgel, including,
[0009] Introducing citraconic acid or mesaconic acid into the core or shell layer during the PNIPAM polymerization process to obtain a pH-temperature dual-responsive core-shell structured microgel.
[0010] As a preferred embodiment of the preparation method of the present invention, it includes:
[0011] Dissolve citraconic acid or mesaconic acid, N-isopropylacrylamide, and a crosslinking agent in water, stir in an inert atmosphere, and when reaching a preset temperature, add an initiator to carry out the reaction;
[0012] Add the mixed N-isopropylacrylamide, surfactant, aqueous solution of crosslinking agent, and initiator solution to the above reaction system and continue the reaction;
[0013] Dialyze the product obtained from the reaction using a dialysis bag, and then perform vacuum rotary evaporation to collect the sample, obtaining PNIPAM microgels with citraconic acid or mesaconic acid in the core.
[0014] As a preferred embodiment of the preparation method of the present invention, the mass ratio of citraconic acid or mesaconic acid, N-isopropylacrylamide, surfactant, and crosslinking agent is (15 - 25):100:(0 - 5):(3 - 7).
[0015] As a preferred embodiment of the preparation method of the present invention, the crosslinking agent is N,N'-methylenebisacrylamide, the surfactant is sodium dodecyl sulfate, and the initiator is potassium persulfate.
[0016] As a preferred embodiment of the preparation method of the present invention, during the stirring in an inert atmosphere, the stirring temperature is 20 - 25°C and the stirring time is 30 - 50 min; when reaching the preset temperature, add an initiator to carry out the reaction, where the preset temperature is 65 - 75°C and the reaction time is 2 - 3 h.
[0017] As a preferred embodiment of the preparation method of the present invention, when adding the mixed N-isopropylacrylamide, surfactant, aqueous solution of crosslinking agent, and initiator solution to the above reaction system, the mass ratio of N-isopropylacrylamide to the crosslinking agent is 100:3 - 7; during the continued reaction, the reaction time is 2 - 3 h.
[0018] As a preferred embodiment of the preparation method of the present invention, the molecular weight cut-off of the dialysis bag is 3500 - 10000 Da, and the rotary evaporation temperature is 45 - 65°C.
[0019] As a preferred embodiment of the preparation method of the present invention, it further includes:
[0020] Dissolve N-isopropylacrylamide, surfactant and crosslinking agent in water, stir under an inert atmosphere, and when the preset temperature is reached, add an initiator to react. Among them, the mass ratio of N-isopropylacrylamide to the crosslinking agent is 100:(3-7), the crosslinking agent is N,N'-methylenebisacrylamide, the surfactant is sodium dodecyl sulfate, the initiator is potassium persulfate, the stirring temperature is 20-25°C, the stirring time is 30-50 minutes, the preset temperature is 65-75°C, and the reaction time is 2-3 h;
[0021] Add the mixed citraconic acid or mesaconic acid, N-isopropylacrylamide, aqueous solution of N,N'-methylenebisacrylamide and initiator solution to the above reaction system and continue the reaction. Among them, the mass ratio of citraconic acid or mesaconic acid, N-isopropylacrylamide to the crosslinking agent is (15-25):100:(3-7), and the reaction time is 2-3 h;
[0022] Dialyze the product obtained by the reaction using a dialysis bag, and then perform vacuum rotary evaporation to collect the sample. Among them, the molecular weight cut-off of the dialysis bag is 3500-10000 Da, and the rotary evaporation temperature is 45-65°C.
[0023] Another object of the present invention is to overcome the deficiencies in the prior art and provide a pH-temperature dual-responsive core-shell structured microgel.
[0024] Another object of the present invention is to overcome the deficiencies in the prior art and provide an application of a pH-temperature dual-responsive core-shell structured microgel in the preparation of encapsulating materials applied to the biomedical field.
[0025] Advantages of the present invention:
[0026] (1) The present invention provides a pH- and temperature-dual-responsive microgel and its preparation method and application. During the polymerization of PNIPAM, citraconic acid and mesaconic acid are introduced into the core and shell layers respectively. Citraconic acid and mesaconic acid are dibasic acids and are isomers of each other; the introduced citraconic acid and mesaconic acid and their positions will affect the swelling behavior and collapse ratio of the microgel. Changing the pH value can adjust the LCST (adjustment range 32°C-40°C) and surface charge density; by measuring the dynamic interfacial tension and the air-water interface compression curve, it is also revealed that citraconic acid and mesaconic acid and their positions play an important role in the stability ability at the interface and the particle-particle interaction. The rheometer is also used to prove that citraconic acid and mesaconic acid and their positions have an impact on the rheological behavior and phase transition of the microgel.
[0027] (2) In the process of polymerization of the method of the present invention, isomeric dibasic acids (citraconic acid and mesaconic acid) are respectively introduced into the core and the shell to prepare core-shell PNIPAM microgels with dual pH and temperature responsiveness of acids in the core and the shell. Having two carboxyl groups makes it easier to bind to small drug molecules. Changing the pH can adjust the collapse ratio and LCST of the microgels (closer to human body temperature). At the same time, the microgels have good stability, uniformity and swelling properties, and can be used as excellent encapsulation materials in the fields of biomedicine and the like. Description of the Drawings
[0028] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings. Among them:
[0029] Figure 1 It is a scanning electron microscope characterization diagram of the microgels prepared in the embodiments of the present invention.
[0030] Figure 2 It is a particle size characterization diagram of the microgels prepared in the embodiments of the present invention tested by a Zeta potential and nanoparticle size analyzer, proving that the particle size of the prepared microgels has dual responsiveness to pH and temperature.
[0031] Figure 3 It is a Zeta potential characterization diagram of the microgels prepared in the embodiments of the present invention tested by a Zeta potential and nanoparticle size analyzer, proving that the Zeta potential of the prepared microgels has dual responsiveness to pH and temperature.
[0032] Figure 4 It is a schematic diagram of the synthesis of core-shell PNIPAM microgels with citraconic acid or mesaconic acid in the core.
[0033] Figure 5 It is a schematic diagram of the synthesis of core-shell PNIPAM microgels with citraconic acid or mesaconic acid in the shell. Detailed Embodiments
[0034] In order to make the above objects, features and advantages of the present invention more obvious and understandable, the following will describe the detailed embodiments of the present invention in conjunction with the embodiments of the specification.
[0035] In the following description, many specific details are set forth in order to fully understand the present invention. However, the present invention can also be implemented in other ways different from those described herein. Those skilled in the art can make similar generalizations without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.
[0036] Secondly, the so-called "one embodiment" or "embodiment" herein refers to a specific feature, structure or characteristic that may be included in at least one implementation manner of the present invention. The "in one embodiment" appearing in different places in this specification does not all refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments.
[0037] In the embodiments of the present invention, N-isopropylacrylamide and citraconic acid are purchased from Tokyo Chemical Industry Co., Ltd., N,N'-methylenebisacrylamide is purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. and mesaconic acid is purchased from Shanghai Macklin Biochemical Co., Ltd.
[0038] Example 1
[0039] This example relates to a preparation method of a core-shell PNIPAM microgel with dual pH and temperature responsiveness with citraconic acid in the core. The schematic diagram is as Figure 4 shown, and includes the following steps:
[0040] Step 1. Dissolve 0.32 g of citraconic acid, 1.51 g of N-isopropylacrylamide, 0.02 g of sodium dodecyl sulfate and 0.05 g of N,N'-methylenebisacrylamide in 98 mL of water, stir under an inert atmosphere, and when the preset temperature of 70 °C is reached, add 0.03 g of potassium persulfate for reaction.
[0041] Step 2. Add 2.52 g of N-isopropylacrylamide, 0.08 g of N,N'-methylenebisacrylamide aqueous solution and 0.04 g of potassium persulfate 50 mL solution mixed well into the reaction system of the above step, and continue the reaction.
[0042] Step 3. Dialyze the product obtained from the reaction using a dialysis bag with a cut-off molecular weight of 3500 Da, and then perform vacuum rotary evaporation to collect the sample (rotary evaporation temperature 60 °C) to obtain a PNIPAM microgel with citraconic acid in the core (as Figure 1 shown in a).
[0043] Step 4. Characterize the particle size and Zeta potential of the prepared microgel using a Zeta potential and nanoparticle size analyzer (as Figure 2 shown in a and 3).
[0044] Example 2
[0045] This example relates to a preparation method of a core-shell PNIPAM microgel with dual pH and temperature responsiveness with mesaconic acid in the core. The schematic diagram is as Figure 4 shown, and includes the following steps:
[0046] Step 1. Dissolve 0.32 g of itaconic acid, 1.51 g of N-isopropylacrylamide, 0.02 g of sodium dodecyl sulfate, and 0.05 g of N,N'-methylenebisacrylamide in 98 mL of water, stir under an inert atmosphere, and when the preset temperature of 70 °C is reached, add 0.03 g of potassium persulfate for reaction.
[0047] Step 2. Add 2.52 g of N-isopropylacrylamide, 0.08 g of N,N'-methylenebisacrylamide aqueous solution, and 0.04 g of potassium persulfate 50 mL solution that are mixed well into the reaction system of the above step, and continue the reaction.
[0048] Step 3. Dialyze the product obtained from the reaction using a dialysis bag with a molecular weight cut-off of 3500 Da, and then perform vacuum rotary evaporation to collect the sample (rotary evaporation temperature 60 °C) to obtain PNIPAM microgels with itaconic acid in the core (as Figure 1 shown in b).
[0049] Step 4. Characterize the particle size and Zeta potential of the prepared microgels using a Zeta potential and nanoparticle size analyzer (as Figure 2 shown in b and 3).
[0050] Example 3
[0051] This example relates to a preparation method of core-shell PNIPAM microgels with pH and temperature dual responsiveness and citraconic acid in the shell. The schematic diagram is as Figure 5 shown, and it includes the following steps:
[0052] Step 1. Dissolve 1.51 g of N-isopropylacrylamide, 0.02 g of sodium dodecyl sulfate, and 0.05 g of N,N'-methylenebisacrylamide in 98 mL of water, stir under an inert atmosphere, and when the preset temperature of 70 °C is reached, add 0.03 g of potassium persulfate for reaction.
[0053] Step 2. Add 0.32 g of citraconic acid, 2.52 g of N-isopropylacrylamide, 0.08 g of N,N'-methylenebisacrylamide aqueous solution, and 0.04 g of potassium persulfate 50 mL solution that are mixed well into the reaction system of the above step, and continue the reaction.
[0054] Step 3. Dialyze the product obtained from the reaction using a dialysis bag with a molecular weight cut-off of 3500 Da, and then perform vacuum rotary evaporation to collect the sample (rotary evaporation temperature 60 °C) to obtain PNIPAM microgels with citraconic acid in the shell (as Figure 1 shown in c).
[0055] Step 4. Characterize the particle size and Zeta potential of the prepared microgels using a Zeta potential and nanoparticle size analyzer (as Figure 2as shown in c and 3).
[0056] Example 4
[0057] This example relates to a method for preparing a core-shell PNIPAM microgel with dual pH and temperature responsiveness of mesaconic acid in the shell layer. The schematic diagram is as shown in Figure 5 shown, and includes the following steps:
[0058] Step 1. Dissolve 1.51 g of N-isopropylacrylamide, 0.02 g of sodium dodecyl sulfate, and 0.05 g of N,N'-methylenebisacrylamide in 98 mL of water, stir in an inert atmosphere, and when the preset temperature reaches 70 °C, add 0.03 g of potassium persulfate for reaction.
[0059] Step 2. Add a mixed aqueous solution of 0.32 g of mesaconic acid, 2.52 g of N-isopropylacrylamide, 0.08 g of N,N'-methylenebisacrylamide, and 0.04 g of potassium persulfate in 50 mL to the reaction system in the above step, and continue the reaction.
[0060] Step 3. Dialyze the product obtained from the reaction using a dialysis bag with a molecular weight cut-off of 3500 Da, and then perform vacuum rotary evaporation to collect the sample (rotary evaporation temperature 60 °C) to obtain a PNIPAM microgel with mesaconic acid in the shell layer (as shown in Figure 1 d).
[0061] Step 4. Characterize the particle size and Zeta potential of the prepared microgel using a Zeta potential and nanoparticle size analyzer (as shown in Figure 2 d and 3).
[0062] Comparative Example 1
[0063] Step 1. Dissolve 1.51 g of N-isopropylacrylamide, 0.02 g of sodium dodecyl sulfate, and 0.05 g of N,N'-methylenebisacrylamide in 98 mL of water, stir in an inert atmosphere, and when the preset temperature reaches 70 °C, add 0.03 g of potassium persulfate for reaction.
[0064] Step 2. Add a mixed aqueous solution of 2.52 g of N-isopropylacrylamide, 0.08 g of N,N'-methylenebisacrylamide, and 0.04 g of potassium persulfate in 50 mL to the reaction system in the above step, and continue the reaction.
[0065] Step 3. Dialyze the product obtained from the reaction using a dialysis bag with a molecular weight cut-off of 3500 Da, and then perform vacuum rotary evaporation to collect the sample (rotary evaporation temperature 60 °C) to obtain a pure PNIPAM microgel.
[0066] Compared with the core-shell PNIPAM microgels prepared in Examples 1-4, the LCST of this microgel is around 32 °C. Changing the pH cannot regulate the collapse ratio and LCST of the microgel, and its binding force with small molecule drugs is weak, which limits its wide application in the biomedical field.
[0067] Comparative Example 2
[0068] Step 1. Dissolve 94.9 mol% of N-isopropylacrylamide, 0.1 mol% of fumaric acid, and 5 mol% of N,N'-methylenebisacrylamide in 490 mL of water, stir under an inert atmosphere, and when the preset temperature of 70 °C is reached, add 5 mL of sodium dodecyl sulfate with a concentration of 0.4 mM and 5 mL of potassium persulfate with a concentration of 2 mM to react.
[0069] Step 2. Dialyze the product obtained from the reaction using a dialysis bag to obtain poly(N-isopropylacrylamide-co-fumaric acid) microgels.
[0070] Compared with the core-shell PNIPAM microgels prepared in Examples 1-4, the LCST of the microgels prepared by this one-step synthesis method is similar to that of PNIPAM, and the particle size is not sensitive to pH value changes. Although fumaric acid is also a short-chain dibasic acid, the reaction rate is quite different when polymerizing with N-isopropylacrylamide. Fumaric acid mainly polymerizes on the surface of the microgel, resulting in the particle size being insensitive to pH value changes.
[0071] Therefore, the microgels prepared by the stepwise synthesis method proposed in the present invention can regulate whether the acid is in the core or the shell, and PNIPAM-based microgels with controllable LCST and dual temperature and pH responsiveness can be prepared according to actual needs.
[0072] It should be noted that the above examples are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered within the scope of the present invention.
Claims
1. A method for preparing a pH-temperature dual-responsive core-shell structure microgel, characterized in that: include, During the polymerization process of PNIPAM, citraconic acid or mesaconic acid was introduced into the core or shell layer to prepare pH-temperature dual responsive core-shell structure microgels.
2. The preparation method according to claim 1, characterized in that: include, Dissolve citraconic acid or mesaconic acid, N-isopropylacrylamide, surfactant and crosslinking agent in water, stir under an inert atmosphere, and add initiator to react when the preset temperature is reached; Adding the mixed N-isopropylacrylamide, crosslinking agent aqueous solution and initiator solution into the above reaction system to continue the reaction; The product obtained by the reaction is dialyzed using a dialysis bag, and then the sample is collected by vacuum rotary evaporation to obtain a PNIPAM microgel with citraconic acid or mesaconic acid in the core.
3. The preparation method according to claim 2, characterized in that: The mass ratio of the citraconic acid or mesaconic acid, N-isopropylacrylamide, surfactant and crosslinking agent is (15-25):100:(0-5):(3-7).
4. The preparation method according to claim 3, characterized in that: The cross-linking agent is N,N'-methylenebisacrylamide, the surfactant is sodium dodecyl sulfate, and the initiator is potassium persulfate.
5. The preparation method according to claim 2, characterized in that: The stirring is performed under an inert atmosphere, wherein the stirring temperature is 20-25° C. and the stirring time is 30-50 min; when the preset temperature is reached, an initiator is added to react, wherein the preset temperature is 65-75° C. and the reaction time is 2-3 h.
6. The preparation method according to claim 2 or 5, characterized in that: The mixed N-isopropylacrylamide, crosslinking agent aqueous solution, surfactant and initiator solution are added to the reaction system, wherein the mass ratio of N-isopropylacrylamide to the crosslinking agent is 100:3-7; and the reaction is continued, wherein the reaction time is 2-3 hours.
7. The preparation method according to claim 6, characterized in that: The molecular weight cut-off of the dialysis bag is 3500-10000Da, and the rotary evaporation temperature is 45-65°C.
8. The preparation method according to claim 1, characterized in that: Also includes, Dissolve N-isopropylacrylamide and a crosslinking agent in water, stir under an inert atmosphere, and when the preset temperature is reached, add an initiator to react, wherein the mass ratio of N-isopropylacrylamide to the crosslinking agent is 100:(3-7), the crosslinking agent is N,N'-methylenebisacrylamide, the surfactant is sodium dodecyl sulfate, the initiator is potassium persulfate, the stirring temperature is 20-25°C, the stirring time is 30-50 minutes, the preset temperature is 65-75°C, and the reaction time is 2-3h; Add the mixed citraconic acid or mesaconic acid, N-isopropylacrylamide, N,N'-methylenebisacrylamide aqueous solution and initiator solution into the above reaction system and continue the reaction, wherein the mass ratio of citraconic acid or mesaconic acid, N-isopropylacrylamide and crosslinking agent is (15-25):100:(3-7), and the reaction time is 2-3h; The product obtained by the reaction is dialyzed using a dialysis bag, and then a sample is collected by vacuum rotary evaporation, wherein the molecular weight cutoff of the dialysis bag is 3500-10000Da, and the rotary evaporation temperature is 45-65°C.
9. The pH-temperature dual responsive core-shell structure microgel prepared by the preparation method according to any one of claims 1 to 8.
10. Use of the pH-temperature dual responsive core-shell structure microgel according to claim 9 in preparing encapsulation materials for use in the biomedical field.