Design method of temperature-sensitive PNIPAM hydrogel carrier for drug delivery

Abstract

The invention relates to the field of hydrogel carriers, in particular to a design method of a temperature-sensitive PNIPAM (poly (N-isopropylacrylamide)) hydrogel carrier for drug delivery. Comprising the following steps: respectively constructing a PNIPAM molecular chain model, a cross-linking agent BIS model and a water molecule model through molecular dynamics software, and carrying out structure optimization; constructing an amorphous unit cell model of a PNIPAM hydrogel system by using the constructed PNIPAM molecular chain and a cross-linking agent BIS (N, N-methylene bisacrylamide) according to a certain proportion, and carrying out geometric optimization; constructing PNIPAM cross-linked structures with different cross-linking degrees by using a dynamic cross-linking algorithm; pNIPAM cross-linked structures with different cross-linking degrees are filled with water molecules with different proportions by adopting a density filling method, so that PNIPAM hydrogel structures with different cross-linking degrees and water contents are formed; calculating the mechanical property of the PNIPAM hydrogel by using a molecular dynamics simulation method; the volume of a PNIPAM hydrogel cavity is calculated through an alpha shape method; the drug release process is simulated through the discharge process of water molecules in the PNIPAM hydrogel cavity in the heating process.

Description

Technical Field

[0001] The present invention relates to a design method of a thermosensitive PNIPAM hydrogel carrier for drug delivery, and in particular to a thermosensitive PNIPAM hydrogel carrier for drug delivery designed by using a molecular dynamics simulation method. The carrier has the characteristics of temperature response and adjustable mechanical properties, and can deliver drugs such as mRNA, growth factors, small molecule drugs, and ions. Background Art

[0002] Hydrogel is a three-dimensional water-containing polymer network formed by physical or chemical crosslinking. It is widely used in many fields due to its water absorption and elasticity. In recent years, smart hydrogels that respond to external conditions (such as pH, light, heat, magnetic field, electric field, etc.) have become the focus of research, especially in drug delivery, sensors, tissue engineering and advanced manufacturing technology. Poly (N-isopropylacrylamide) (PNIPAM) is a thermosensitive polymer. The lower critical solution temperature (LCST) of the hydrogel formed by it is about 302-305K, which is close to the human body temperature. It can be used as a smart thermosensitive material in medicine.

[0003] In biomedicine, thermosensitive PNIPAM hydrogel carriers need to have certain mechanical properties, because the carrier needs to play the role of a scaffold and play a certain supporting role in the human body; at the same time, it needs to play the role of a carrier, and have a cavity to carry certain drug small molecules to the designated location to play a therapeutic role. Due to its unique thermosensitive properties, PNIPAM hydrogel behaves as a liquid when it is below LCST and as a gel when it is above LCST, which can play the role of a scaffold and drug carrier in the body.

[0004] Traditional PNIPAM hydrogels have poor mechanical properties and cannot play a good role as a scaffold. Therefore, preparing PNIPAM hydrogels with excellent mechanical properties is a major difficulty in actual production. At the same time, as a drug delivery carrier, the drug delivery and drug release capabilities of PNIPAM hydrogels also pose challenges to the manufacturing process of PNIPAM hydrogel carriers. How to prepare PNIPAM hydrogel carriers with excellent mechanical properties and drug delivery and release capabilities has become a difficulty in actual production. Traditional preparation methods can only be improved through continuous experimental attempts, but this is not only time-consuming, but also has high R&D costs, which is not conducive to applications in biomedicine and clinical applications.

[0005] At present, there are literatures and patents reporting on the construction of cross-linking models, but there are no reports on molecular simulation of thermosensitive PNIPAM hydrogels for drug delivery. Patent [1] proposes a method for preparing a polyvinyl alcohol cartilage scaffold with controllable mechanical properties by molecular dynamics, but the method adopted in the patent is physical cross-linking, and its ability to regulate mechanical properties is lower than the dynamic cross-linking algorithm of the present invention. The present invention can implement more precise regulation of the mechanical properties of hydrogels by adjusting the two factors of cross-linking degree and water content. Patent [2] also proposes a method and system for simulating and generating a spatial network structure of a cross-linked polymer. There are also certain differences between this method and the present invention, mainly in that the present invention proposes a dynamic cross-linking algorithm model that can simulate the actual process of the cross-linking reaction; at the same time, the present invention emphasizes that it is a method for designing a thermosensitive PNIPAM hydrogel carrier for drug delivery, rather than just modeling the cross-linked polymer network structure. Patent [3] experimentally proposes a method for preparing and applying a dynamically cross-linked degradable hydrogel. The research focuses on exploring the characteristics and potential uses of the hydrogel through actual synthesis and testing. In contrast, the present invention goes deeper into the theoretical simulation level, aiming to accurately quantify the effects of crosslinking degree and water content on the mechanical properties of PNIPAM (poly(N-isopropylacrylamide)) hydrogels through computer simulation methods. The present invention not only focuses on how to adjust these two key parameters to design hydrogel carriers with better performance, but also aims to reveal the intrinsic connection between the microstructure of the hydrogel and its macroscopic properties. This method allows the properties of hydrogels under different conditions to be predicted before actual preparation, thus providing an efficient and economical way to develop new smart materials.

[0006] References

[0007] [1] Wang Yanen, Wei Qinghua, Li Xinpei, et al. Preparation method of polyvinyl alcohol cartilage scaffold with controllable mechanical properties: CN201610031634.2[P]. CN105664241A[2025-01-02].

[0008] [2] Huang Ming, Jiang Lijun. Method and system for simulating and generating spatial network structure of cross-linked polymer: CN202210564784.5[P]. CN114664390A[2025-01-02].

[0009] [3] You Mingliang, Liu Song, Feng Zongmiao. Dynamic cross-linked degradable hydrogel, preparation method and application: CN202211036465.3[P]. CN202211036465.3[2025-01-02]. Summary of the invention

[0010] The purpose of the present invention is to propose a design method for a thermosensitive PNIPAM hydrogel carrier with temperature response, excellent mechanical properties, and can be used for drug delivery. A 3D cross-linking model of PNIPAM hydrogel is constructed by a dynamic cross-linking algorithm, and then the mechanical properties of the constructed PNIPAM hydrogel are simulated by a molecular dynamics method, and a PNIPAM hydrogel model with excellent mechanical properties is screened out, and then the process of drug release of the hydrogel carrier at different temperatures is simulated. This design method can greatly reduce the R&D time and R&D cost, and provide patients with a thermosensitive PNIPAM hydrogel carrier with temperature response, drug delivery and excellent mechanical properties.

[0011] To achieve the above object, the technical solution of the present invention is:

[0012] A method for designing a thermosensitive PNIPAM hydrogel carrier for drug delivery, characterized in that the method adopts a molecular dynamics method to design a thermosensitive PNIPAM hydrogel carrier. The method comprises the following steps:

[0013] S1. The PNIPAM molecular chain model, the cross-linker BIS model and the water molecule model were constructed respectively by molecular dynamics software, and the constructed models were assigned force fields and optimized to obtain stable structures.

[0014] S2. The constructed PNIPAM molecular chain and the cross-linker BIS are mixed in a certain ratio to construct an amorphous unit cell model of the PNIPAM hydrogel system, and the geometry is optimized.

[0015] S3. The amorphous unit cell model of S2 was used to construct a cross-linked structure using a dynamic cross-linking algorithm to obtain PNIPAM cross-linked structures with different cross-linking degrees, and then the structure was optimized.

[0016] S4. Using the density filling method, water molecules of different proportions are filled into the PNIPAM cross-linked structures with different cross-linking degrees obtained in S3 to form PNIPAM hydrogel structures with different water contents, and the structures are optimized.

[0017] S5. The mechanical properties of PNIPAM hydrogels with different crosslinking degrees and water contents obtained in S3 and S4 were simulated using molecular dynamics software.

[0018] S6. Using the α-shape method, the volume of the PNIPAM hydrogel cavity was calculated.

[0019] S7. During the heating process, the PNIPAM hydrogel carrier undergoes structural changes above and below the LCST (lower critical solution temperature, approximately 305K), and the process of expelling water molecules from the cavity simulates the release process of drug molecules from the hydrogel carrier.

[0020] The molecular dynamics software described in the design method of the thermosensitive PNIPAM hydrogel carrier according to the present invention includes: LAMMPS, Gromacs, Materials Studio, etc.

[0021] The method for designing a thermosensitive PNIPAM hydrogel carrier according to the present invention is characterized in that the dynamic cross-linking algorithm in S3 comprises the following steps:

[0022] Step 1: Pre-set parameters for the structure obtained by S2, including: setting the cross-linking degree threshold, that is, stopping the operation when the cross-linking degree reaches this threshold; setting the reaction atom (i.e., reaction site) of the PNIPAM molecular chain to R1, and the reaction atom of the cross-linker BIS to R2; setting the minimum threshold of the reaction distance between R1 and R2 to That is, the reaction atoms at this distance form a bond; the maximum threshold of the reaction distance between R1 and R2 is set to That is, the reaction atoms cannot form bonds if the distance is greater than this value. Set the distance increment for each judgment to

[0023] Step 2: Determine the cross-linking degree of the structure obtained in S2. If the cross-linking degree does not reach the cross-linking degree threshold, execute step 3; if the cross-linking degree reaches the cross-linking degree threshold, execute step 13.

[0024] Step 3: Calculate the distance between reaction sites R1 and R2.

[0025] Step 4: Determine whether the distance between R1 and R2 meets the bonding requirement. Start judging from the minimum bonding threshold. If it meets the bonding requirement, go to step 5; if it does not meet the bonding requirement, go to step 9.

[0026] Step 5: Bonding between reactive atoms R1 and R2. The double bond connected to R1 in the original PNIPAM becomes a single bond, and the double bond connected to R2 in the crosslinker BIS becomes a single bond, and hydrogen atoms are added to saturate the bonds.

[0027] Step 6: Update the force field information of the structure obtained in step 5.

[0028] Step 7: Perform molecular dynamics equilibrium on the structure obtained in step 6.

[0029] Step 8: Execute step 2 and re-judge the cross-linking degree threshold.

[0030] Step 9: If there are no atoms that can form bonds under the current threshold, the bonding distance is judged to increase

[0031] Step 10: Determine whether the reaction distance in step 9 is greater than the maximum reaction distance threshold. If not, execute step 11; if the maximum reaction distance threshold is reached, execute step 13.

[0032] Step 11: Perform molecular dynamics equilibrium on the structure obtained in step 9.

[0033] Step 12: Perform step 3 on the structure obtained in step 11. Recalculate the distances between the reaction atoms and perform step 4.

[0034] Step 13: End the cross-linking process and output the cross-linking results.

[0035] Step 14: Perform molecular dynamics equilibrium on the structure obtained in step 13.

[0036] According to S4 described in the present invention, the density filling method in S4 refers to calculating the initial density of the model based on the relative molecular mass and volume of the model, and then calculating the final density of the model after adding a certain proportion of water molecules, and using the packing function of the Amorphous Cell Calculation module of the Materials Studio software, inputting the final density and filling molecules as water molecules, PNIPAM hydrogels with different water contents can be obtained.

[0037] According to S5 of the present invention, the cross-linking degree refers to the ratio of the PNIPAM reaction atomic sites participating in the dynamic cross-linking reaction to the total PNIPAM reaction sites;

[0038] According to S5 of the present invention, the water content refers to the ratio of the content of water molecules to the dry weight of the hydrogel.

[0039] According to S5 described in the present invention, the molecular dynamics software includes molecular dynamics software such as LAMMPS, Gromacs, MaterialsStudio, etc.

[0040] Preferably, the molecular dynamics software is LAMMPS.

[0041] According to S5 of the present invention, the mechanical property simulation includes tensile property simulation, Young's modulus calculation, structural change simulation and the like.

[0042] Preferably, the mechanical property simulation is to simulate the uniaxial stretching of the PNIPAM hydrogel model in the X, Y, and Z axes to obtain the stress-strain curve of the PNIPAM hydrogel. The Young's modulus is calculated based on the stress-strain curve. The structural change refers to the structural change of the PNIPAM hydrogel at different temperatures.

[0043] According to S6 described in the present invention, the α shape method refers to an algorithm for constructing a polymer surface. The principle is to assume that the particles themselves are point-shaped, and introduce the concept of a virtual detection ball to define which areas of the space are accessible and which are inaccessible. The accessible areas are connected to form the structure of the polymer surface. A smooth surface can be obtained by using a smoothing algorithm, and the volume of the cavity is calculated by calling the Construct surface mesh module of the ovito software.

[0044] According to S7 of the present invention, the structural change of the PNIPAM hydrogel carrier above and below the LCST temperature means that when the temperature of the PNIPAM hydrogel is lower than the LCST, its polymer network relaxes and is in a liquid state. When the temperature rises above the LCST, its polymer network shrinks inward to exclude water molecules and becomes a gel state. Through this property, it can be used as a carrier for drug delivery to release water molecules together with the drug.

[0045] According to the present invention, the drug molecules described in S7 include but are not limited to mRNA, growth factors, small molecule drugs, ions and the like that are soluble in water and the drug molecules are not larger than the volume of the cavity.

[0046] The beneficial effects of the present invention are:

[0047] (1) The present invention proposes a design method for a thermosensitive PNIPAM hydrogel carrier for drug delivery, and constructs an initial PNIPAM model with different cross-linking degrees through a dynamic cross-linking algorithm.

[0048] (2) The present invention proposes a design method for a thermosensitive PNIPAM hydrogel carrier for drug delivery, by initially filling PNIPAM with different cross-linking degrees with water molecules in different proportions, thereby forming a PNIPAM hydrogel model with different cross-linking degrees and water contents. By adjusting the cross-linking degree and water content of the PNIPAM hydrogel, the mechanical properties of the hydrogel can be adjusted, so as to design a PNIPAM hydrogel carrier suitable for use under different conditions.

[0049] (3) The PNIPAM hydrogel carrier of the present invention has the function of delivering drugs. When the PNIPAM hydrogel is used as a carrier to carry drug molecules, it can be discharged near the human body temperature (ie, LCST), achieving the function of drug release. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 Flowchart designed for thermoresponsive PNIPAM hydrogel carriers.

[0051] Figure 2 Schematic diagram for the construction of thermosensitive PNIPAM hydrogel carrier.

[0052] Figure 3 Flowchart of the dynamic cross-linking algorithm designed for thermoresponsive PNIPAM hydrogel carriers.

[0053] Figure 4 The stress-strain curves of the thermosensitive PNIPAM hydrogel carrier in three main directions.

[0054] Figure 5 Diagram of the drug release process of thermosensitive PNIPAM hydrogel carrier. DETAILED DESCRIPTION

[0055] In order to make the technical solution and advantages of the present application clearer, the technical solution of the present invention will be further described in detail below in conjunction with the accompanying drawings. It will be understood that the specific embodiments described herein are only partial embodiments of the present invention, which are only used to explain the present application, rather than to limit the present application. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be considered isolated, and they can be combined with each other to achieve better technical effects. The same reference numerals appearing in the drawings of the following embodiments represent the same features or components, which can be applied to different embodiments.

[0056] In addition, unless otherwise defined, the technical terms or scientific terms used in the description of the present invention should have the common meanings understood by those skilled in the art in the art to which the present invention belongs.

[0057] The present invention is further described in detail below in conjunction with the accompanying drawings:

[0058] Reference Figure 1 , a flow chart of the design of thermosensitive PNIPAM hydrogel carrier, comprising the following steps:

[0059] S100. The PNIPAM molecular chain model, crosslinker BIS model and water molecule model were constructed respectively by molecular dynamics software, and the constructed models were assigned force fields and optimized to obtain stable structures.

[0060] Step S101, constructing the constituent molecules of the PNIPAM hydrogel carrier by molecular dynamics software, including:

[0061] Step S101 - 1 PNIPAM molecular chain. Here, we select a PNIPAM molecular chain with a degree of polymerization of 10, and perform structural optimization on the PNIPAM molecular chain with a degree of polymerization of 10 to obtain a structure with the lowest energy.

[0062] The PNIPAM molecular chain with a polymerization degree of 10 described in step S101 - 1 is only used for demonstration in this example. In actual use, different polymerization degrees can be adjusted according to specific circumstances.

[0063] Step S101-2, crosslinking agent BIS. Here, BIS is selected as a crosslinking agent to connect different PNIPAM molecular chains to form a 3D network of PNIPAM hydrogel. The crosslinking agent BIS is structurally optimized to obtain the structure with the lowest energy.

[0064] Step S101-3, water molecule: construct a water molecule model and perform structural optimization.

[0065] The molecular dynamics software described in step S101 can be any software that can be used to construct PNIPAM molecular chains, cross-linking agent BIS, and water molecules.

[0066] Preferably, Materials Studio software.

[0067] Reference Figure 2 , Schematic diagram of the construction of thermosensitive PNIPAM hydrogel carrier. a, b, c are the structural diagrams of PNIPAM monomer, crosslinker BIS and water molecules respectively, d is the chemical principle of crosslinking between PNIPAM molecular chain and crosslinker BIS, e is the structure before crosslinking reaction, and f is the structure after crosslinking reaction. In e and f, gray represents the uncrosslinked structure, red represents the crosslinked structure, and green represents the water molecules.

[0068] S200. The constructed PNIPAM molecular chain is mixed with the cross-linking agent BIS in a certain proportion to construct an amorphous unit cell model of the PNIPAM hydrogel system and perform geometric optimization.

[0069] The PNIPAM molecular chain described in step S200 is mixed with the crosslinker BIS in a certain ratio to construct an amorphous unit cell model of the PNIPAM hydrogel system. Since one PNIPAM molecular chain has two reaction sites and one crosslinker BIS has four reaction sites, the ratio can be 2:1. It can also be adjusted according to actual use by appropriately increasing the amount of the crosslinker BIS.

[0070] Step S200-1, selecting 40 PNIPAM molecular chains described in step S101-1 and 20 crosslinking agents BIS described in step S101-2 to construct an amorphous unit cell model, and performing geometry optimization.

[0071] S300. The amorphous unit cell model of S2 was used to construct the cross-linked structure, and PNIPAM cross-linked structures with different cross-linking degrees were obtained and then structurally optimized.

[0072] Reference Figure 3 , a flow chart of the dynamic cross-linking algorithm for the design of thermosensitive PNIPAM hydrogel carriers, comprising the following steps:

[0073] Step S300-1: pre-setting parameters for the structure described in S200-1, including: setting a cross-linking degree threshold, that is, stopping the operation when the cross-linking degree reaches this threshold; setting the reaction atom (i.e., reaction site) of the PNIPAM molecular chain to R1, and the reaction atom of the cross-linking agent BIS to R2; setting the minimum threshold of the reaction distance between R1 and R2 to That is, the reaction atoms at this distance form a bond; the maximum threshold of the reaction distance between R1 and R2 is set to That is, the reaction atoms cannot form bonds if the distance is greater than this value. Set the distance increment for each judgment to

[0074] In this example, the cross-linking degree threshold of step S300-1 is set to 80%, that is, when this cross-linking degree threshold is reached, the script stops running. The above settings can be adjusted according to actual conditions.

[0075] Step S300-2: Determine the degree of crosslinking of the structure obtained in S200-1. If the degree of crosslinking does not reach the threshold value, execute step 300-3; if the degree of crosslinking reaches the threshold value, execute step S300-13.

[0076] Step S300 - 3 : Calculate the distance between the reaction sites R1 and R2.

[0077] Step S300-4: Determine whether the distance between R1 and R2 meets the bonding requirement. Determine from the minimum bonding threshold, if it meets the bonding requirement, execute step 5; if it does not meet the bonding requirement, execute step S300-9.

[0078] Step S300-5: Reaction atoms R1 and R2 form a bond. The double bond connected to R1 in the original PNIPAM becomes a single bond, and the double bond connected to R2 in the crosslinker BIS becomes a single bond, and hydrogen atoms are added to saturate the bond.

[0079] Step S300-6: Update the force field information of the structure obtained in step S300-5.

[0080] Step S300-7: Perform molecular dynamics equilibrium on the structure obtained in step S300-6.

[0081] Step S300 - 8 : Execute step S300 - 2 and re-determine the cross-linking degree threshold.

[0082] Step S300-9: If there is no atom that can form a bond under the current threshold, then the bonding distance is determined to increase.

[0083] Step S300-10: Determine whether the reaction distance of step S300-9 is greater than the maximum reaction distance threshold. If not, execute step S300-11. If the maximum reaction distance threshold is reached, execute step S300-13.

[0084] Step S300-11: Perform molecular dynamics equilibrium on the structure obtained in step S300-9.

[0085] Step S300-12: Execute step S300-3 on the structure obtained in step S300-11, recalculate the distance between the reaction atoms, and execute step S300-4.

[0086] Step S300-13: End the cross-linking process and output the cross-linking result.

[0087] Step S300 - 14: Perform molecular dynamics equilibrium on the structure obtained in step S300 - 13 .

[0088] Preferably, the step S300-2 determines whether the degree of crosslinking reaches the threshold value of the degree of crosslinking. The initial degree of crosslinking is 0, the judgment result is no, and the crosslinking process is started. The entire crosslinking reaction process is carried out under the NVT ensemble, and the reaction temperature is 500k. The temperature is raised to 500k by the stepwise heating method, and the distance of the reaction atoms at this time is calculated. If the distance of the reaction atoms is within the minimum threshold range, a crosslinking bond is generated, and the original double bond becomes a single bond, and the charge is balanced by the hydrogenation method. After each new bond is generated, the force field update operation is performed, the purpose is to assign a force field to the new bond and update the change of the force field after the reaction atom breaks the bond. If no atom that can react is found within this threshold range, the reaction distance is increased by 1, and the above judgment process is repeated. Until the maximum threshold is reached, this round of crosslinking reaction is completed.

[0089] Furthermore, one round of cross-linking reaction often does not reach the desired cross-linking degree, so multiple rounds of cross-linking are required. The final structure of the first round of cross-linking is used as the input structure of the second round of cross-linking, and the cross-linking process of S300 is re-executed to calculate the new cross-linking results.

[0090] Furthermore, as the number of cross-linking rounds increases, the number of atoms that can undergo cross-linking continues to decrease until no more atoms can be found. If the degree of cross-linking does not meet the requirements at this time, the initial structure needs to be readjusted or a longer balancing process needs to be carried out.

[0091] Furthermore, in the process of geometry optimization and heating, cooling, and molecular dynamics equilibrium calculation, the fastest gradient method is used for energy minimization, Nose-Hoove is used for isothermal control, and Anderson is used for isobaric control. The ensembles used are NPT and NVT, and the appropriate ensemble is selected according to actual use.

[0092] S400. Using the density filling method, different proportions of water molecules are filled into the PNIPAM cross-linked structure with different cross-linking degrees obtained in S300 to form PNIPAM hydrogel structures with different water contents, and the structure is optimized.

[0093] In this example, the initial density of the model is 0.5 g / cm3. After adding a certain amount of water molecules, when the water content reaches 20%, the density of the model is calculated to be 0.62 g / cm3 by using the density equal to the relative molecular mass divided by the volume. By using the packing function of the Amorphous Cell Calculation module of the Materials Studio software, the model density and the filling molecules are input as water molecules, and a PNIPAM hydrogel with a water content of 20% can be obtained. Hydrogels with other water contents are also constructed using the same method.

[0094] Further, in step S400, the result file after the first round of cross-linking is used as the input file of the second round of cross-linking, which can improve the cross-linking degree of the model. After multiple rounds of cross-linking, we select cross-linking structures with the required cross-linking degrees of 30%, 60%, and 80%. After obtaining the PNIPAM cross-linking structure with the required cross-linking degree, the process of adding water molecules is performed. Here, water molecules are added to reach a water content of 20% and 50%.

[0095] S500. The mechanical properties of the PNIPAM hydrogels with different crosslinking degrees and water contents obtained in steps S300 and S400 are simulated by molecular dynamics software.

[0096] The molecular dynamics software in step S500 includes LAMMPS, Gromacs, Materials Studio and other molecular dynamics software.

[0097] Preferably, the molecular dynamics software is LAMMPS.

[0098] The mechanical property simulation includes tensile property simulation, Young's modulus calculation, structural change simulation and the like.

[0099] The mechanical property simulation is to simulate the uniaxial stretching of the PNIPAM hydrogel model in the X, Y, and Z axes to obtain the stress-strain curve of the PNIPAM hydrogel. The Young's modulus is calculated based on the stress-strain curve. The structural change refers to the structural change of the PNIPAM hydrogel at different temperatures.

[0100] Preferably, the simulation of the structural change of PNIPAM hydrogel refers to simulating the structural change of PNIPAM hydrogel at temperatures below LCST and above LCST, respectively, and simulating the process of PNIPAM hydrogel transitioning from a stretched state to a curled state through the structural change of PNIPAM hydrogel above and below LCST.

[0101] Reference Figure 4 As shown in the figure, the stress-strain curves in three main directions of the thermosensitive PNIPAM hydrogel carrier with a crosslinking degree of 80% and a water content of 50% in the embodiment are shown. It can be seen that the constructed PNIPAM hydrogel is an anisotropic material and has good tensile properties.

[0102] Referring to Table 1, there is a table of Young's modulus of PNIPAM hydrogels with different crosslinking degrees (0, 30%, 60%, 80%) and water contents (0, 20%, 50%) constructed in the examples. As can be seen from the table, with the increase of the degree of crosslinking, the Young's modulus of the PNIPAM hydrogel gradually increases; with the increase of the water content, the Young's modulus of the PNIPAM hydrogel gradually decreases. The Young's modulus of the PNIPAM hydrogel can be adjusted by adjusting the degree of crosslinking and the water content, which provides support for the construction of PNIPAM hydrogels adapted to different mechanical properties. In Table 1, wt represents the water content, DOC represents the degree of crosslinking, and the same below. Table 1 Young's modulus of thermosensitive PNIPAM hydrogel carrier at different crosslinking degrees and water contents

[0103] S600. Using the α shape method, the volume of the PNIPAM hydrogel cavity was calculated.

[0104] Preferably, the Construct Surface Mesh module of the Ovito software is called by a code written in a Python program to calculate the PNIPAM hydrogel cavity volume, and the change in the cavity volume at different temperatures indicates that as the temperature increases, the PNIPAM hydrogel structure gradually changes from a relaxed state to a curled state. Refer to Table 2, which is a table of the cavity volumes of PNIPAM hydrogels with different crosslinking degrees and water contents at different temperatures in the embodiment. Table 2 Cavity volume of thermosensitive PNIPAM hydrogel carrier at different temperatures

[0105] S700. During the heating process, the PNIPAM hydrogel carrier undergoes structural changes above and below the LCST (lower critical solution temperature, about 305K), and the water molecules in the cavity are expelled to simulate the release process of drug molecules from the hydrogel carrier.

[0106] Reference Figure 5 As shown, for the PNIPAM hydrogel with a cross-linking degree of 60% and a water content of 20% constructed in the embodiment, when the temperature is below LCST, the water molecules and the delivered drugs are located in the central cavity. As the temperature increases and exceeds the LCST, the water molecules and the delivered drugs in the central cavity are expelled from the PNIPAM hydrogel carrier.

Claims

1. A method for designing a thermosensitive PNIPAM hydrogel carrier for drug delivery, characterized in that: The molecular dynamics method was used to design the thermosensitive PNIPAM hydrogel carrier.

2. The method for designing a thermosensitive PNIPAM hydrogel carrier for drug delivery according to claim 1, characterized in that: The design method of the thermosensitive PNIPAM hydrogel carrier is designed by a molecular dynamics method, which includes the following steps: S1. Use molecular dynamics software to build PNIPAM molecular chain model, crosslinker BIS model and water molecule model respectively. And the constructed model is given a force field and optimized to obtain a stable structure; S2. Mix the constructed PNIPAM molecular chain with the cross-linking agent BIS in a certain ratio to construct an amorphous unit cell model of the PNIPAM hydrogel system and perform geometric optimization; S3. Use a dynamic cross-linking algorithm to construct a cross-linked structure of the amorphous unit cell model of S2, obtain PNIPAM cross-linked structures with different cross-linking degrees, and perform structural optimization; S4. Using a density filling method, water molecules of different proportions are filled into the PNIPAM cross-linked structures with different cross-linking degrees obtained in S3 to form PNIPAM hydrogel structures with different water contents, and the structures are optimized; S5. The mechanical properties of PNIPAM hydrogels with different crosslinking degrees and water contents obtained in S3 and S4 were simulated by molecular dynamics software; S6. Using the α shape method, calculate the volume of the PNIPAM hydrogel cavity; S7. During the heating process, the PNIPAM hydrogel carrier undergoes structural changes above and below the LCST (lower critical solution temperature, approximately 305K), and the process of expelling water molecules from the cavity simulates the release process of drug molecules from the hydrogel carrier.

3. The design method of the thermosensitive PNIPAM hydrogel carrier according to claim 2, characterized in that: The molecular dynamics software includes: LAMMPS, Gromacs, Materials Studio, etc.

4. The design method of the thermosensitive PNIPAM hydrogel carrier according to claim 2, characterized in that: In S3, a dynamic cross-linking algorithm is used to construct a cross-linked structure for the amorphous unit cell model, and the dynamic cross-linking algorithm includes the following steps: Step 1: Pre-set parameters for the structure obtained by S2, including: setting the cross-linking degree threshold, that is, stopping the operation when the cross-linking degree reaches this threshold; setting the reaction atom (i.e., reaction site) of the PNIPAM molecular chain to R1, and the reaction atom of the cross-linker BIS to R2; setting the minimum threshold of the reaction distance between R1 and R2 to That is, the reaction atoms at this distance form a bond; the maximum threshold of the reaction distance between R1 and R2 is set to That is, the reaction atoms cannot form bonds if the distance is greater than this value. Set the distance increment for each judgment to Step 2: Determine the cross-linking degree of the structure obtained in S2. If the cross-linking degree does not reach the cross-linking degree threshold, execute step 3; if the cross-linking degree reaches the cross-linking degree threshold, execute step 13; Step 3: Calculate the distance between reaction sites R1 and R2; Step 4: Determine whether the distance between R1 and R2 meets the bonding requirement. Start judging from the minimum bonding threshold. If it meets the bonding requirement, go to step 5; if it does not meet the bonding requirement, go to step 9; Step 5: Bonding between the reactive atoms R1 and R2. The double bond connected to R1 in the original PNIPAM becomes a single bond, and the double bond connected to R2 in the crosslinker BIS becomes a single bond, and hydrogen atoms are added to saturate the bond; Step 6: Update the force field information of the structure obtained in step 5; Step 7: Perform molecular dynamics equilibrium on the structure obtained in step 6; Step 8: Execute step 2 and re-judge the cross-linking degree threshold; Step 9: If there are no atoms that can form bonds under the current threshold, the bonding distance is judged to increase Step 10: Determine whether the reaction distance in step 9 is greater than the maximum reaction distance threshold. If not, execute step 11. If the maximum reaction distance threshold is reached, execute step 13. Step 11: Perform molecular dynamics equilibrium on the structure obtained in step 9; Step 12: Perform step 3 on the structure obtained in step 11, recalculate the distance between the reaction atoms, and perform step 4; Step 13: End the cross-linking process and output the cross-linking result; Step 14: Perform molecular dynamics equilibrium on the structure obtained in step 13.

5. The design method of the thermosensitive PNIPAM hydrogel carrier according to claim 2, characterized in that: The density filling method in S4 refers to calculating the initial density of the model based on the relative molecular mass and volume of the model, and then calculating the final density of the model after adding a certain proportion of water molecules. By using the packing function of the Amorphous Cell Calculation module of the Materials Studio software, the final density and the filling molecules are input as water molecules, and PNIPAM hydrogels with different water contents can be obtained.

6. The method for designing a thermosensitive PNIPAM hydrogel carrier according to claim 2, characterized in that: The α shape method in S6 refers to an algorithm for constructing polymer surfaces. The principle is to assume that the particles themselves are point-shaped and introduce the concept of a virtual detection ball to define which areas of the space are accessible and which are inaccessible. The accessible areas are connected to form the structure of the polymer surface. A smooth surface can be obtained by using a smoothing algorithm, and the volume of the cavity can be calculated by calling the Construct surface mesh module of the ovito software.

7. The method for designing a thermosensitive PNIPAM hydrogel carrier for drug delivery according to claim 2, characterized in that: The structural change of the PNIPAM hydrogel carrier above and below the LCST temperature means that when the temperature of the PNIPAM hydrogel is lower than the LCST, its polymer network relaxes and is in a liquid state. When the temperature rises above the LCST, its polymer network shrinks inward to exclude water molecules and becomes a gel state. Through this property, it can be used as a carrier for drug delivery to release water molecules together with the drug.

8. The method for designing a thermosensitive PNIPAM hydrogel carrier for drug delivery according to claim 2, characterized in that: The drug molecules include but are not limited to mRNA, growth factors, small molecule drugs, ions and the like which are soluble in water and whose drug molecules are not larger than the volume of the cavity.

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