A design method for a temperature-sensitive pnipam hydrogel carrier for drug delivery

Abstract

The present application relates to the field of hydrogel carrier, in particular to a design method of a temperature-sensitive PNIPAM (poly-N-isopropyl acrylamide) hydrogel carrier for drug delivery. The method comprises: constructing a PNIPAM molecular chain model, a crosslinking agent BIS model and a water molecule model respectively by a molecular dynamics software and performing structure optimization; constructing an amorphous cell model of the PNIPAM hydrogel system according to a certain proportion of the constructed PNIPAM molecular chain and the crosslinking agent BIS (N, N-methylene bisacrylamide) and performing geometric optimization; constructing PNIPAM crosslinking structures with different crosslinking degrees by using a dynamic crosslinking algorithm; filling the PNIPAM crosslinking structures with different crosslinking degrees with different proportions of water molecules by using a density filling method, so as to form PNIPAM hydrogel structures with different crosslinking degrees and water contents; calculating the mechanical properties of the PNIPAM hydrogel by using a molecular dynamics simulation method; calculating the size of the cavity volume of the PNIPAM hydrogel by using an alpha shape method; and simulating a drug release process by simulating a water molecule discharge process in the cavity of the PNIPAM hydrogel in a temperature rising process.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for designing a temperature-sensitive PNIPAM hydrogel carrier for drug delivery, in particular to a method for designing a temperature-sensitive PNIPAM hydrogel carrier for drug delivery by using molecular dynamics simulation. The carrier has the characteristics of temperature response and adjustable mechanical properties, and can deliver drugs such as mRNA, growth factors, small molecule drugs, ions, etc. BACKGROUND

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

[0003] In biomedicine, temperature-sensitive PNIPAM hydrogel carriers need to have certain mechanical properties, because the carrier needs to act as a scaffold and play a certain supporting role in the human body; at the same time, it also needs to act as a carrier and can have a cavity to carry certain small molecule drugs to the designated position to play a therapeutic role. PNIPAM hydrogel has unique temperature-sensitive properties, and when the temperature is below LCST, it behaves as a liquid, and when the temperature is above LCST, it behaves as a gel, which can well play the role of a scaffold and a drug-carrying carrier in the body.

[0004] Traditional PNIPAM hydrogel has poor mechanical properties and cannot well play the role of a scaffold. Therefore, it is a big difficulty in actual production to prepare PNIPAM hydrogel with excellent mechanical properties. At the same time, as a drug delivery carrier, the drug delivery and release capacity of PNIPAM hydrogel also poses a challenge to the manufacturing process of PNIPAM hydrogel carrier. How to prepare a PNIPAM hydrogel carrier with excellent mechanical properties and drug delivery and release capacity has become a difficulty in actual production. Traditional preparation methods can only be improved by continuous experimental attempts, but this not only consumes time, but also has high research and development costs, which is not conducive to application in biomedicine and clinical application.

[0005] There are some literatures and patents reported the construction of crosslinking model, but the molecular simulation of constructing temperature-sensitive PNIPAM hydrogel for drug delivery has not been reported. There is a patent [1] that proposes a method of preparing a polyvinyl alcohol cartilage scaffold with controllable mechanical properties by molecular dynamics, but the method used in this patent is physical crosslinking, which has lower adjustment ability of mechanical properties than the dynamic crosslinking algorithm of the present invention. By adjusting the crosslinking degree and water content, the present invention can more finely control the mechanical properties of the hydrogel. There is also a patent [2] that proposes a method and system for simulating the generation of a spatial network structure of crosslinked polymers, which has some differences with the present invention. The main difference is that the present invention proposes a dynamic crosslinking algorithm model that can simulate the actual process of crosslinking reaction. At the same time, the present invention emphasizes a design method for temperature-sensitive PNIPAM hydrogel carriers for drug delivery, not just modeling the network structure of crosslinked polymers. Patent [3] is a method for preparing and applying a dynamic crosslinking degradable hydrogel from experiments, which focuses on exploring the characteristics and potential uses of hydrogels through actual synthesis and testing. In contrast, the present invention goes deeper into the theoretical simulation level, aiming to accurately quantify the influence of crosslinking degree and water content on the mechanical properties of PNIPAM (poly(N-isopropylacrylamide)) hydrogel through computer simulation. The present invention not only focuses on how to adjust these two key parameters to design a hydrogel carrier with better performance, but also aims to reveal the internal relationship between the microstructure of the hydrogel and its macroscopic properties. This method allows the properties of the hydrogel under different conditions to be predicted before actual preparation, providing an efficient and economical way to develop new intelligent materials.

[0006] REFERENCES

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

[0008] [2] Huang, M., Jiang, L. Method and system for simulating the generation of a spatial network structure of crosslinked polymers: CN202210564784.5[P]. CN114664390A [2025-01-02].

[0009] [3] You, M., Liu, S., Feng, Z. A dynamic crosslinking degradable hydrogel, preparation method and application: CN202211036465.3[P]. CN202211036465.3 [2025-01-02]. SUMMARY

[0010] The application aims at providing a design method of a temperature-sensitive PNIPAM hydrogel carrier with excellent temperature response and mechanical properties, which can be used for drug delivery. A 3D cross-linking model of the 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 to screen out a PNIPAM hydrogel model with excellent mechanical properties, and then the drug release process of the hydrogel carrier at different temperatures is simulated. The design method can greatly reduce the research and development time and cost, and provide a temperature-sensitive PNIPAM hydrogel carrier with excellent temperature response, drug delivery and mechanical properties for patients.

[0011] To achieve the above-mentioned purpose, the technical scheme of the application is:

[0012] A design method of a temperature-sensitive PNIPAM hydrogel carrier for drug delivery, characterized by using a molecular dynamics method to design the temperature-sensitive PNIPAM hydrogel carrier. The method comprises the following steps:

[0013] S1. Construct a PNIPAM molecular chain model, a cross-linking agent BIS model and a water molecule model by a molecular dynamics software, and give a force field to the constructed model and optimize to obtain a stable structure.

[0014] S2. Construct an amorphous cell model of the PNIPAM hydrogel system according to a certain proportion of the constructed PNIPAM molecular chain and the cross-linking agent BIS, and perform geometric optimization.

[0015] S3. Use a dynamic cross-linking algorithm to construct a cross-linking structure for the amorphous cell model of S2 to obtain PNIPAM cross-linking structures with different cross-linking degrees, and perform structure optimization.

[0016] S4. Fill different proportions of water molecules in the PNIPAM cross-linking structures with different cross-linking degrees obtained in S3 to form PNIPAM hydrogel structures with different water contents by a density filling method, and perform structure optimization.

[0017] S5. Simulate the mechanical properties of the PNIPAM hydrogels with different cross-linking degrees and water contents obtained in S3 and S4 by a molecular dynamics software.

[0018] S6. Calculate the size of the cavity volume of the PNIPAM hydrogel by an alpha shape method.

[0019] S7. Simulate the drug release process from the hydrogel carrier by simulating the process of expelling water molecules in the cavity of the PNIPAM hydrogel carrier when the structure of the PNIPAM hydrogel carrier changes above and below the LCST (low critical solution temperature, about 305k) in the heating process.

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

[0021] The design method for the thermosensitive PNIPAM hydrogel carrier according to the present invention is characterized in that: the dynamic crosslinking algorithm in S3 includes the following steps:

[0022] Step 1: Pre-set parameters for the structure obtained in S2, including: setting a crosslinking degree threshold, i.e., stopping the process when the crosslinking degree reaches this threshold; setting the reaction atoms (i.e., reaction sites) of the PNIPAM molecular chain as R1, and the reaction atoms of the crosslinking agent BIS as R2; setting the minimum threshold for the reaction distance between R1 and R2. That is, the reacting atoms form bonds at this distance; the maximum threshold for the reaction distance between R1 and R2 is set to... That is, reacting atoms beyond this distance cannot form bonds; the distance increment is set to be [value missing] for each judgment.

[0023] Step 2: Determine the degree of crosslinking of the structure obtained in S2. If the degree of crosslinking does not reach the crosslinking threshold, proceed to step 3; if the degree of crosslinking reaches the crosslinking threshold, proceed to step 13.

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

[0025] Step 4: Determine if the distance between R1 and R2 meets the bonding requirements. Start judging from the minimum bonding threshold. If the bonding requirements are met, proceed to Step 5; otherwise, proceed to Step 9.

[0026] Step 5: Bonding occurs between reactant 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 crosslinking agent BIS becomes a single bond. 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-determine the crosslinking degree threshold.

[0030] Step 9: If there are no atoms capable of bonding at the current threshold, then the bonding distance is increased.

[0031] Step 10: Determine whether the reaction distance in step 9 is greater than the maximum reaction distance threshold. If it is not, proceed to step 11. If it reaches the maximum reaction distance threshold, proceed to 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 reacting atoms and perform step 4.

[0034] Step 13: End the crosslinking process. Output the crosslinking results.

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

[0036] According to S4 of 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. By using the packing function of the Amorphous Cell Calculation module of Materials Studio software, and inputting the final density and the filling molecules as water molecules, PNIPAM hydrogels with different water contents can be obtained.

[0037] In S5 according to the present invention, the degree of crosslinking refers to the ratio of the PNIPAM reaction atomic sites participating in the reaction to the total PNIPAM reaction sites in dynamic crosslinking;

[0038] In S5 according to the present invention, the water content refers to the proportion of water molecules to the dry weight of the hydrogel.

[0039] In S5 of the present invention, the molecular dynamics software includes molecular dynamics software such as LAMMPS, Gromacs, and MaterialsStudio.

[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, etc.

[0042] Preferably, the mechanical property simulation involves performing uniaxial tensile simulations along the X, Y, and Z axes on a PNIPAM hydrogel model to obtain the stress-strain curves of the PNIPAM hydrogel. Young's modulus is calculated based on the stress-strain curves. Structural change refers to simulating the structural changes of the PNIPAM hydrogel at different temperatures.

[0043] In S6 of the present invention, the α-shape method refers to a polymer surface construction algorithm. Its principle is to assume that the particles themselves are point-like, introduce the concept of virtual probe spheres to define which regions of space are accessible and which are inaccessible. The accessible regions are connected to form the structure of the polymer surface. A smooth surface can be obtained by using a smoothing algorithm. The volume of the cavity is calculated by calling the Construct surface mesh module of the Ovito software.

[0044] According to the present invention S7, the structural change of the PNIPAM hydrogel carrier at and around the LCST temperature means that when the temperature is below the LCST, the polymer network of the PNIPAM hydrogel expands and becomes liquid, and when the temperature rises above the LCST, the polymer network contracts inward to expel water molecules and becomes gel. Through this characteristic, it can be used as a carrier for drug delivery, releasing water molecules along with the drug.

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

[0046] The beneficial effects of this invention are:

[0047] (1) This invention proposes a design method for a thermosensitive PNIPAM hydrogel carrier for drug delivery, and constructs an initial PNIPAM model with different degrees of crosslinking through a dynamic crosslinking algorithm.

[0048] (2) This invention proposes a design method for a thermosensitive PNIPAM hydrogel carrier for drug delivery. By initially filling PNIPAM with different degrees of crosslinking with different proportions of water molecules, PNIPAM hydrogel models with different degrees of crosslinking and water content are constructed. By adjusting the degree of crosslinking and water content of the PNIPAM hydrogel, the mechanical properties of the hydrogel can be adjusted, thereby designing 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 carries drug molecules as a carrier, it can be discharged near the human body temperature (i.e., LCST) to achieve the function of drug release. Attached Figure Description

[0050] Figure 1 A flowchart for the design of a temperature-sensitive PNIPAM hydrogel carrier.

[0051] Figure 2 A schematic diagram illustrating the construction principle of a temperature-sensitive PNIPAM hydrogel carrier.

[0052] Figure 3 Flowchart of the dynamic crosslinking algorithm designed for the thermosensitive PNIPAM hydrogel carrier.

[0053] Figure 4 The stress-strain curves of the temperature-sensitive PNIPAM hydrogel support are shown in the three principal directions.

[0054] Figure 5 This diagram illustrates the drug release process of a thermosensitive PNIPAM hydrogel carrier. Detailed Implementation

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

[0056] Furthermore, unless otherwise defined, the technical or scientific terms used in this invention description shall have the ordinary meaning understood by one of ordinary skill in the art to which this invention pertains.

[0057] The present invention will now be described in further detail with reference to the accompanying drawings:

[0058] Reference Figure 1 The flowchart for the design of a temperature-sensitive PNIPAM hydrogel carrier includes the following steps:

[0059] S100. A PNIPAM molecular chain model, a crosslinking agent BIS model, and a water molecule model were constructed using molecular dynamics software. Force fields were then applied to the constructed models, and the models were optimized to obtain stable structures.

[0060] Step S101: Construct the constituent molecules of the PNIPAM hydrogel carrier using 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 the structure with the lowest energy.

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

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

[0064] Step S101-3, Water Molecule. Construct a water molecule model and optimize its structure.

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

[0066] Preferably, Materials Studio software.

[0067] Reference Figure 2 This diagram illustrates the construction principle of a thermosensitive PNIPAM hydrogel carrier. Figures a, b, and c show the structures of PNIPAM monomers, cross-linking agent BIS, and water molecules, respectively. Figure d illustrates the chemical principle of cross-linking between PNIPAM molecular chains and BIS. Figure e shows the structure before the cross-linking reaction, and figure f shows the structure after the cross-linking reaction. In figures e and f, gray represents the uncross-linked structure, red represents the cross-linked structure, and green represents water molecules.

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

[0069] In step S200, the PNIPAM molecular chains and crosslinking agent BIS are mixed 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 crosslinking agent BIS has four reaction sites, the ratio can be 2:1, or it can be adjusted according to actual use by appropriately increasing the amount of crosslinking agent BIS.

[0070] In step S200-1, 40 PNIPAM molecular chains described in step S101-1 and 20 crosslinking agents BIS described in step S101-2 are selected to form an amorphous unit cell model, and geometric optimization is performed.

[0071] S300. The dynamic cross-linking algorithm is used to construct the cross-linking structure of the amorphous unit cell model of S2, obtain PNIPAM cross-linking structures with different degrees of cross-linking, and optimize the structure.

[0072] Reference Figure 3 The flowchart of the dynamic crosslinking algorithm for designing temperature-sensitive PNIPAM hydrogel carriers includes the following steps:

[0073] Step S300-1: Pre-setting parameters for the structure described in S200-1, including: setting a crosslinking degree threshold, i.e., stopping operation when the crosslinking degree reaches this threshold; setting the reaction atoms (i.e., reaction sites) of the PNIPAM molecular chain as R1, and the reaction atoms of the crosslinking agent BIS as R2; setting the minimum threshold for the reaction distance between R1 and R2. That is, the reacting atoms form bonds at this distance; the maximum threshold for the reaction distance between R1 and R2 is set to... That is, reacting atoms beyond this distance cannot form bonds; the distance increment is set to be [value missing] for each judgment.

[0074] In this example, the crosslinking degree threshold mentioned in step S300-1 is set to 80%, meaning the script stops running when this threshold is reached. All of the above settings can be adjusted according to actual circumstances.

[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 crosslinking threshold, proceed to step S300-3; if the degree of crosslinking reaches the crosslinking threshold, proceed to step S300-13.

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

[0077] Step S300-4: Determine whether the distance between R1 and R2 meets the bonding requirements. Start judging from the minimum bonding threshold. If the bonding requirements are met, proceed to step 5; if the bonding requirements are not met, proceed to step S300-9.

[0078] Step S300-5: Bonding occurs between reactant 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 crosslinking agent BIS becomes a single bond. Hydrogen atoms are added to saturate the bonds.

[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 to re-determine the crosslinking degree threshold.

[0082] Step S300-9: If there are no atoms capable of bonding at the current threshold, then the bonding distance is increased.

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

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

[0085] Step S300-12: Perform step S300-3 on the structure obtained in step S300-11. Recalculate the distances between the reacting atoms and perform step S300-4.

[0086] Step S300-13: End the crosslinking process. Output the crosslinking results.

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

[0088] Preferably, in step S300-2, it is determined whether the degree of crosslinking has reached the crosslinking threshold. The initial degree of crosslinking is 0. If the determination result is negative, the crosslinking process begins. The entire crosslinking reaction process is carried out under the NVT ensemble at a reaction temperature of 500 K. The temperature is gradually increased to 500 K, and the distance between the reacting atoms is calculated. If the distance between the reacting atoms is within the minimum threshold range, a crosslinking bond is formed, and the original double bond becomes a single bond. The charge is balanced by adding hydrogen. After each new bond is formed, a force field update operation is performed to assign a force field to the new bond and update the force field changes after the reacting atom breaks the bond. If no reacting atom is found within this threshold range, the reaction distance is incremented by 1, and the above determination process is repeated. This process continues until the maximum threshold is reached, completing this round of crosslinking reaction.

[0089] Furthermore, a single round of crosslinking reaction often fails to achieve the desired degree of crosslinking, thus requiring multiple rounds of crosslinking. The final structure from the first round of crosslinking is used as the input structure for the second round of crosslinking, and the S300 crosslinking process is repeated, with the new crosslinking results analyzed.

[0090] Furthermore, as the number of cross-linking rounds increases, the number of atoms capable of cross-linking decreases until eventually no atoms are found that can undergo cross-linking. If the degree of cross-linking is insufficient at this point, the initial structure needs to be readjusted, or a longer equilibration process needs to be performed.

[0091] Furthermore, in the geometric optimization and heating / cooling, molecular dynamics equilibrium calculations, the steepest gradient method was used for energy minimization, Nose-Hoove was used for isothermal control, and Anderson was used for isobaric control. The ensembles used were NPT and NVT, with the appropriate ensemble selected based on the specific application.

[0092] S400. Using the density-filling method, different proportions of water molecules were filled into the PNIPAM cross-linked structures with different degrees of cross-linking obtained from S300 to form PNIPAM hydrogel structures with different water contents, and the structures were 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 dividing the relative molecular mass by the volume. Using the packing function of the Amorphous Cell Calculation module in Materials Studio software, by inputting the model density and the filling molecules as water molecules, a PNIPAM hydrogel with a water content of 20% can be obtained. Hydrogels with other water contents are constructed in the same way.

[0094] Further, in step S400, using the result file from the first round of crosslinking as the input file for the second round of crosslinking can improve the crosslinking degree of the model. After multiple rounds of crosslinking, we select crosslinking structures with desired crosslinking degrees of 30%, 60%, and 80%. After obtaining the PNIPAM crosslinking structures with the desired crosslinking degrees, a process of adding water molecules is performed. Here, water molecules are added to achieve water contents of 20% and 50%.

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

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

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

[0098] The mechanical property simulation includes simulations of tensile properties, calculation of Young's modulus, and simulations of structural changes.

[0099] The mechanical property simulation involved performing uniaxial tensile simulations along the X, Y, and Z axes on a PNIPAM hydrogel model to obtain the stress-strain curves of the PNIPAM hydrogel. Young's modulus was calculated based on the stress-strain curves. Structural changes refer to simulating the structural changes of the PNIPAM hydrogel at different temperatures.

[0100] Preferably, the simulation of structural changes in PNIPAM hydrogel refers to simulating the structural changes of PNIPAM hydrogel at temperatures below and above LCST, respectively. By simulating the structural changes of PNIPAM hydrogel above and below LCST, the process of PNIPAM hydrogel transitioning from an extended state to a coiled state is simulated.

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

[0102] Table 1 shows the Young's modulus of PNIPAM hydrogels constructed in the examples with different degrees of crosslinking (0, 30%, 60%, 80%) and water contents (0, 20%, 50%). As can be seen from the table, the Young's modulus of the PNIPAM hydrogel gradually increases with increasing crosslinking degree; conversely, the Young's modulus gradually decreases with increasing water content. Adjusting the crosslinking degree and water content allows for the adjustment of the Young's modulus of the PNIPAM hydrogel, providing support for constructing PNIPAM hydrogels with different mechanical properties. In Table 1, wt represents water content, and DOC represents the degree of crosslinking; the same applies below.

[0103] Table 1 Young's modulus of thermosensitive PNIPAM hydrogel carriers at different degrees of crosslinking and water content.

[0104]

[0105] S600. The α-shape method was used to calculate the cavity volume of the PNIPAM hydrogel.

[0106] Preferably, the cavity volume of the PNIPAM hydrogel is calculated by calling the Construct surface mesh module of the Ovito software using code written in Python. The change in cavity volume at different temperatures represents the gradual transformation of the PNIPAM hydrogel structure from a relaxed state to a contracted state as the temperature increases. Refer to Table 2, which shows the cavity volume of PNIPAM hydrogels with different degrees of crosslinking and water content at different temperatures in the examples.

[0107] Table 2. Cavity volume of temperature-sensitive PNIPAM hydrogel carrier at different temperatures.

[0108]

[0109]

[0110] S700 simulates the release of drug molecules from the hydrogel carrier by simulating the structural changes of the PNIPAM hydrogel carrier around LCST (low critical solution temperature, approximately 305 K) during the heating process, which causes water molecules to be expelled from the cavity.

[0111] Reference Figure 5 As shown, the PNIPAM hydrogel constructed for the example has a crosslinking degree of 60% and a water content of 20%. When the temperature is below the LCST, water molecules and delivered drugs are located in the central cavity. As the temperature rises and exceeds the LCST, water molecules and delivered drugs in the central cavity are expelled from the PNIPAM hydrogel carrier.

Claims

1. A method for designing a temperature-sensitive PNIPAM hydrogel carrier for drug delivery, characterized in that, The method of molecular dynamics is adopted to design the temperature-sensitive PNIPAM hydrogel carrier, including the following steps: S1. Construct a PNIPAM molecular chain model, a crosslinking agent BIS model and a water molecule model respectively by a molecular dynamics software, and give a force field to the constructed model and optimize it to obtain a stable structure; S2. Mix the constructed PNIPAM molecular chain and the crosslinking agent BIS according to a certain proportion to construct an amorphous unit cell model of the PNIPAM hydrogel system, and perform geometric optimization; S3. The amorphous unit cell model of S2 is used to construct a crosslinking structure using a dynamic crosslinking algorithm to obtain a PNIPAM crosslinking structure with different crosslinking degrees, and the structure is optimized; The dynamic crosslinking algorithm includes the following steps: Step 1: Perform pre-parameter setting on the structure obtained in S2, including: setting a crosslinking degree threshold, i.e. stopping running when the crosslinking degree reaches this threshold; marking the atoms in the PNIPAM molecular chain used for crosslinking reaction as R1, and the reaction atoms of the crosslinking agent BIS as R2; setting the minimum threshold of the reaction distance between R1 and R2 as 4 angstrom, i.e. the reaction atoms within this distance form a bond; setting the maximum threshold of the reaction distance between R1 and R2 as 11 angstrom, i.e. the reaction atoms beyond this distance cannot form a bond; setting the distance increase amplitude as 1 angstrom for each distance judgment; Step 2: Perform crosslinking degree judgment on the structure obtained in S2, if the crosslinking degree does not reach the crosslinking degree threshold, then execute step 3; if the crosslinking degree reaches the crosslinking degree threshold, then execute step 13; Step 3: Calculate the distance between the reaction sites R1 and R2; Step 4: Judge whether the distance between R1 and R2 meets the bonding requirement, starting from the minimum bonding threshold, if it meets the bonding requirement, then execute step 5; if it does not meet the bonding requirement, then execute step 9; Step 5: The reaction atoms R1 and R2 form a bond, the double bond in the original PNIPAM connected with R1 becomes a single bond, the double bond in the crosslinking agent BIS connected with R2 becomes a single bond, and a hydrogen atom is added to make the bond saturated; 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 to re-judge the crosslinking degree threshold; Step 9: For the atoms that cannot form a bond under the current threshold, increase the reaction distance by 1 angstrom; Step 10: Judge whether the reaction distance of step 9 is greater than the maximum reaction distance threshold, if not, execute step 11, if it reaches the maximum reaction distance threshold, execute step 13; Step 11: Perform molecular dynamics equilibrium on the structure obtained in step 9; Step 12: Execute step 3 on the structure obtained in step 11 to recalculate the distance between the reaction atoms, and execute step 4; Step 13: End the crosslinking process and output the crosslinking result; Step 14: Perform molecular dynamics equilibrium on the structure obtained in step 13; S4. Using the density filling method, fill the PNIPAM crosslinked structure of different crosslinking degrees obtained in S3 with different proportions of water molecules to form PNIPAM hydrogel structures with different water contents, and perform structure optimization; The density filling method refers to calculating the initial density of the model according to the relative molecular mass and volume of the model, then calculating the final density of the model after adding a certain proportion of water molecules, 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, and then obtaining PNIPAM hydrogels with different water contents; S5. The PNIPAM hydrogels with different crosslinking degrees and water contents obtained in S3 and S4 are subjected to mechanical property simulation by molecular dynamics software; S6. The size of the cavity volume of the PNIPAM hydrogel is calculated by the alpha shape method; The alpha shape method refers to a construction algorithm for polymer surfaces, the principle of which is to assume that the particle itself is point-shaped, introduce the concept of a virtual probe ball to define which regions of space are accessible and which are inaccessible, and the accessible regions are connected to form the structure of the polymer surface. The smooth algorithm can obtain a smooth surface, and the volume of the cavity is calculated by calling the Construct surface mesh module of the ovito software; S7. The water molecules in the cavity are discharged by the structural change of the PNIPAM hydrogel carrier above and below the LCST, and the process of releasing the drug molecules from the hydrogel carrier is simulated.

2. The method of designing a temperature-sensitive PNIPAM hydrogel carrier according to claim 1, characterized in that, The molecular dynamics software includes: LAMMPS, Gromacs, Materials Studio.

3. A method of designing a thermosensitive PNIPAM hydrogel carrier for drug delivery as claimed in claim 1, wherein, The structural change of the PNIPAM hydrogel carrier above and below the LCST temperature refers to the fact that when the temperature of the PNIPAM hydrogel is lower than the LCST, the polymer network relaxes and is in a liquid state, and when the temperature rises above the LCST, the polymer network shrinks inward to expel water molecules and is in a gel state. Through this characteristic, it can be used as a drug delivery carrier to release water molecules together with drugs.

4. A method of designing a thermosensitive PNIPAM hydrogel carrier for drug delivery as claimed in claim 1, wherein, The drug molecules are selected from mRNA, growth factors and small molecule drugs, which are soluble in water, and the drug molecules are not larger than the small molecules in the cavity volume.

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