CN116617449A - Nano composite hydrogel of controlled release gene carrier and preparation method thereof - Google Patents
Nano composite hydrogel of controlled release gene carrier and preparation method thereof Download PDFInfo
- Publication number
- CN116617449A CN116617449A CN202310656165.3A CN202310656165A CN116617449A CN 116617449 A CN116617449 A CN 116617449A CN 202310656165 A CN202310656165 A CN 202310656165A CN 116617449 A CN116617449 A CN 116617449A
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- pdrn
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- hydrogel
- chitosan
- caco
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract
The invention belongs to the technical field of biomedical materials, and in particular relates to a nano composite hydrogel of a controlled release gene carrier and a preparation method thereof. The preparation method of the invention comprises the following steps: (1) Preparation of polydeoxynucleotide-loaded calcium carbonate nanoparticles PDRN@CaCO 3 The method comprises the steps of carrying out a first treatment on the surface of the (2) Preparing double bond/quaternized modified chitosan modified by 2, 3-epoxypropyl trimethyl ammonium chloride and glycidyl methacrylate; (3) Preparing double bond/quaternized modified chitosan obtained in the step (2) and N-isopropyl acrylamide and molybdenum disulfide slices into premix; pdrn@caco 3 And adding the potassium persulfate solution into the premix solution, uniformly mixing, and standing to obtain the hydrogel. All reactions are carried out at normal temperature, so that the control is easy, raw materials are easy to obtain, and the cost is low; the prepared hydrogel has uniform structure and good strength, can slowly release the gene carrier, has the effects of resisting bacteria and promoting repair, and can realize effective nursing of wounds.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and in particular relates to a nano composite hydrogel of a controlled release gene carrier and a preparation method thereof.
Background
Both acute wounds, such as surgical incisions, superficial skin wounds, II degree burn and scald wounds, and the like, and chronic wounds, such as venous ulcers, arterial ulcers, diabetic (foot) ulcers, traumatic ulcers, pressure ulcers, can cause pain and burden to the patient. The wound care is effective in time, and has great significance for accelerating wound healing, reducing pain of patients and relieving economic burden of the patients. The wound dressing can provide favorable microenvironment for wound healing, and has the effects of stopping bleeding, preventing wound infection, promoting wound healing and the like. The hydrogel is a gel-like substance which has a three-dimensional network structure, smooth surface and is insoluble in water, and has good biocompatibility and strong water absorption capacity. The hydrogel dressing not only can effectively absorb wound exudates and prevent dehydration on the surface of a wound, but also can cling to uneven wound surfaces, reduce the chance of bacterial growth, prevent wound infection, accelerate the formation of new blood vessels and promote the growth of epithelial cells. In addition, other functional factors can be added into the hydrogel, so that the antibacterial property and the like of the hydrogel dressing are endowed.
Chitosan is an amino derivative with good biocompatibility and biodegradability, and the rich amino groups on the chitosan skeleton enable the chitosan to have antibacterial/antiviral properties. After the wound dressing made of chitosan is contacted with blood, red blood cells are gathered under the mutual attraction of positive and negative charges, so that the blood coagulation is promoted. However, the antibacterial performance of the common chitosan is often limited and not durable, so that the further functional modification of the chitosan is very important. The Chinese patent No. 113876996A uses glycidyl methacrylate modified chitosan quaternary ammonium salt and nano-sheet composite material as raw materials to prepare the medical composite hemostatic material, but the composite hemostatic material has single function and does not have the function of promoting healing.
PDRN has effects of improving angiogenesis, increasing collagen synthesis, promoting fibroblast activity, and resisting inflammation. However, PDRN is currently the technology of medical products, such as chinese patent nos. CN113456571a and CN112656701a, which are usually directly incorporated into emulsions, so that free DNA molecules are easily hydrolyzed or degraded by dnase in vivo; meanwhile, since both cell membranes and DNA molecules exhibit electronegativity, the DNA molecules are difficult to be taken up by cells. Chinese patent No. CN112089886A prepared CaCO with DNA-loaded nano calcium carbonate particle 3 Topical delivery of DNA was achieved by @ DNA, but on-demand release of therapeutic factors could not be achieved according to wound healing laws.
Disclosure of Invention
The invention aims to solve the technical problems that the nano composite hydrogel of the controlled release gene carrier and the preparation method thereof are provided, all reactions are carried out at normal temperature, the control is easy, the raw materials are easy to obtain, and the cost is low; the prepared hydrogel has uniform structure and good strength, can slowly release the gene carrier, has the effects of resisting bacteria and promoting repair, and can realize effective nursing of wounds.
The invention is realized by the following technical scheme:
the nano composite hydrogel of the controlled release gene carrier is of a three-dimensional porous structure, comprises a crosslinked network formed by chitosan and poly N-isopropyl acrylamide (PNIPAAm), and can release and load calcium carbonate nano particles PDRN@CaCO of PDRN in a controlled manner 3 。
The preparation method of the nanocomposite hydrogel of the controlled release gene vector comprises the following steps:
(1) Preparation of polydeoxynucleotide-loaded calcium carbonate nanoparticles PDRN@CaCO 3 ；
(2) Preparing 2, 3-epoxypropyl trimethyl ammonium chloride (GTMAC) and Glycidyl Methacrylate (GMA) modified double bond/quaternized modified chitosan;
(3) Double bond/quaternized modified chitosan obtained in the step (2) and N-isopropyl acrylamide, molybdenum disulfide flake (MoS) 2 NS) preparing a premix; pdrn@caco 3 And adding the potassium persulfate solution into the premix solution, uniformly mixing, and standing to obtain the hydrogel.
The step (1) specifically comprises the following steps:
11 CaCl) is added 2 Adding cyclohexane into the solution, uniformly mixing, and dropwise adding Igepal CO-520 to form microemulsion; adding PDRN water solution into the microemulsion, stirring, and adding Na 2 CO 3 Slowly dripping the solution into the reaction solution, and continuously stirring to obtain a reaction mixture;
12 Adding absolute ethyl alcohol into the reaction mixture to demulsify, centrifuging, and collecting precipitate; freeze drying the precipitate to obtain PDRN@CaCO 3 。
Preferably, the PDRN has a molecular weight of 25-700bp; the concentration of the PDRN aqueous solution is 1-5mg/mL;
CaCl 2 the concentration of the solution is 0.1-0.5mol/L; na (Na) 2 CO 3 The concentration of the solution is 0.1-0.5mol/L;
CaCl 2 with Na and Na 2 CO 3 The molar ratio of (1) to (5); PDRN and CaCl 2 The mass ratio of (3) to (6) is 1;
CaCl 2 solutions, cyclohexane, igepal CO-520The volume ratio is 1 (20-50) to 10-30;
the stirring time for the two times is 0.2-2h;
PDRN@CaCO 3 the particle size of the particles is 100-400nm; PDRN@CaCO 3 The loading of PDRN in the particles was 18-35%.
The step (2) specifically comprises the following steps:
21 Dropwise adding the 2, 3-epoxypropyl trimethyl ammonium chloride solution into the water-soluble chitosan solution, and stirring at room temperature to obtain a crude quaternized chitosan solution;
22 Dropwise adding glycidyl methacrylate into the crude quaternized chitosan solution, and stirring at room temperature to obtain a reaction mixture;
23 Centrifuging the reaction mixture to obtain a supernatant, dialyzing the supernatant with deionized water and freeze-drying to obtain the 2, 3-epoxypropyl trimethyl ammonium chloride and glycidyl methacrylate modified double bond/quaternized modified chitosan.
Preferably, the concentration of the chitosan solution is 20-100mg/mL;
the concentration of the 2, 3-epoxypropyl trimethyl ammonium chloride solution is 10-50mg/mL;
the molar ratio of the 2, 3-epoxypropyl trimethyl ammonium chloride monomer to the glycidyl methacrylate monomer to the amino group on the chitosan is (5-1): 1;
the stirring time for the two times is 10-30h.
The step (3) specifically comprises the following steps:
31 Adding double bond/quaternized modified chitosan into N-isopropyl acrylamide aqueous solution and uniformly stirring;
32 Adding MoS to the mixture obtained in step 31) 2 NS, performing ultrasonic treatment in a water bath to obtain a premix;
33 Pdrn@caco) 3 Adding the mixture into the premix, degassing with nitrogen, adding potassium persulfate solution, and standing to obtain the hydrogel.
Preferably, the mass ratio of the N-isopropyl acrylamide to the double bond/quaternized modified chitosan is 1 (1-5);
MoS 2 the mass ratio of NS to double bond/quaternized modified chitosan is 1 (20-100);
PDRN@CaCO 3 the mass ratio of the chitosan to the double bond/quaternized modified chitosan is 1 (20-100);
the mass ratio of the potassium persulfate to the double bond/quaternized modified chitosan is 1 (50-500);
the ultrasonic treatment time is 10-60min; the degassing treatment time is 10-60min.
In the patent of the invention, the gene vector for loading the PDRN is innovatively prepared and combined with the hydrogel, so that the gene therapy concept is introduced into the field of regenerative medicine, and the intelligent wound dressing is designed while the endocytosis efficiency of the PDRN is improved. The simultaneous presence of hydrophilic amide groups and hydrophobic isopropyl groups on the poly (N-isopropylacrylamide, PNIPAAm) molecular segments results in a polymer having a critical solution temperature (LCST) in water. The polymer PNIPAAm is selected as the main component of hydrogel, and is prepared by using photothermal agent MoS under NIR 2 The photo-thermal effect of NS increases the system temperature to be above the LCST of PNIPAAm, triggers the volume shrinkage of hydrogel through the hydrophilic/hydrophobic structure transformation of PNIPAAm, and realizes the NIR-mediated gene vector PDRN@CaCO 3 Release is controlled as needed. Since the radical polymerization initiation site is located at MoS 2 The NS surface, therefore, in addition to the reported antimicrobial enhancement function (CN 113559262B), moS2 NS also acts as a nano-crosslinking site in the present invention. The nano composite hydrogel of the controlled release gene carrier can be applied to the treatment of various acute and chronic wounds, has the effects of resisting bacteria and promoting repair, and can realize the effective nursing of the wounds.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention provides a preparation method of a nano composite hydrogel of a controlled release gene vector, which comprises the steps of firstly preparing calcium carbonate nano particles PDRN@CaCO loaded with PDRN 3 Then PDRN@CaCO 3 Double bond/quaternized modified chitosan, poly-N-isopropylacrylamide and MoS 2 NS is used as a raw material to prepare hydrogel. Specifically, moS 2 Redox system composed of NS and potassium persulfatePolymerization of N-isopropyl acrylamide and double bond/quaternized modified chitosan is initiated by free radical, and the initiation site of free radical polymerization is located in MoS 2 The NS surface, therefore, the molybdenum disulfide nanosheets also act as nano cross-linking sites. Therefore, in the preparation method of the hydrogel provided by the embodiment of the invention, all reactions are carried out at normal temperature, so that the control is easy, the raw materials are easy to obtain, and the cost is low; in addition, the prepared hydrogel not only can slowly release the gene carrier, but also has uniform structure and good strength;
2. the preparation method of the nano composite hydrogel of the controlled release gene carrier provided by the invention adopts a coprecipitation method to prepare the calcium carbonate nano particles loaded with PDRN, and the loading capacity of the nano composite hydrogel can reach 35%. PDRN has effects of improving angiogenesis, increasing collagen synthesis, promoting osteoblast activity, and exerting antiinflammatory effect;
3. the invention also provides a nano composite hydrogel of the controlled release gene carrier, which is prepared by the preparation method of the hydrogel; therefore, the hydrogel has uniform structure and good strength. When the hydrogel is applied to a wound surface, the hydrogel can absorb seepage, block bacteria and maintain a wet environment; moS (MoS) 2 The NS has a photo-thermal conversion function, can convert NIR into heat energy, so that the temperature of the hydrogel is increased, when the temperature is increased to be higher than the LCST of poly-N-isopropyl acrylamide, the molecular chain of the poly-N-isopropyl acrylamide is contracted, so that the volume of the hydrogel is contracted, the internal nano-carrier is extruded, and the NIR triggering controllable release of the gene carrier is realized. The calcium carbonate nanoparticles can more efficiently transfer the PDRN into cells and promote proliferation of the cells. In addition, moS 2 Both the photothermal properties of NS and the quaternized chitosan have antibacterial and bactericidal effects. The hydrogel can be used in the field of acute and chronic wound repair, and also can be used in the medical field to recover the regeneration capability of aged and atrophic skin and improve the skin function.
Drawings
FIG. 1 is a PDRN@CaCO prepared in example 1 3 Characterization of the morphology of the gene vector: (a) SEM photographs, (b) AFM images, (c) particle size analysis, and (d) TEM photographs;
FIG. 2 is a synthetic route for double bond/quaternized modified chitosan prepared in example 1;
FIG. 3 is a structural representation of double bond/quaternized modified chitosan prepared in example 1: (a) nuclear magnetic resonance hydrogen spectroscopy and (b) infrared spectroscopy;
FIG. 4 is a characterization of morphology of MoS2 NS prepared in example 1: (a) a TEM photograph, (b) an AFM image, and (c) particle size analysis;
FIG. 5 is a schematic representation of the synthesis of hydrogels prepared in example 1;
FIG. 6 is a photograph showing the gelling process of the hydrogel prepared in example 1;
FIG. 7 is a schematic representation of the morphology of the hydrogels prepared in example 1;
fig. 8 is the rheological properties of the hydrogels prepared in example 1: (a) Changes in storage modulus (G ') and loss modulus (G') of NIR-gel over time at constant temperature; (b) Changes in storage modulus (G ') and loss modulus (G') of NIR-gel over time at varying temperatures;
FIG. 9 is a photo-thermal conversion property test of the hydrogel prepared in example 1;
fig. 10 is an evaluation of cell compatibility of the hydrogel prepared in example 1: (a) And (b) cell viability assays for NIH 3T3 cells and L929 cells, respectively;
FIG. 11 is a blood compatibility evaluation of the hydrogel prepared in example 1;
FIG. 12 is an evaluation of antibacterial properties of the hydrogel prepared in example 1;
FIG. 13 shows the wound healing promoting effect of the hydrogel prepared in example 1;
FIG. 14 is a section analysis of wound site tissue in example 1.
Detailed Description
To further illustrate the method and effect of the present invention, the present invention is further illustrated below with reference to examples. If specific conditions are not indicated in the examples, they are generally conventional conditions, or recommended by the reagent company; the reagents, consumables, etc. used in the following examples are commercially available unless otherwise specified.
Example 1
The preparation method of the nanocomposite hydrogel of the controlled release gene vector comprises the following steps:
step (1): 1mL of CaCl with concentration of 0.5mol/L 2 The aqueous solution was added to 20mL of cyclohexane. Igepal CO-520 (10 mL) was added dropwise to form a microemulsion. To the microemulsion was added 3.5mL of an aqueous solution of PDRN (5 mg/mL). After stirring for 15 minutes, 1mL of Na was added at a concentration of 0.5mol/L 2 CO 3 The aqueous solution was slowly dropped into the reactor and stirring was continued for 15 minutes. Absolute ethanol is then added to the reaction mixture to break the emulsion. After the reaction was completed, the sample was transferred to a centrifuge (11000 rpm) for 25 minutes to collect a precipitate. Repeatedly washing with absolute ethanol, freeze drying to obtain pure PDRN@CaCO 3 A gene vector.
Step (2): 30mL of 2, 3-epoxypropyl trimethyl ammonium chloride (50 mg/mL) was added dropwise to 50mL of a water-soluble chitosan solution (20 mg/mL), and stirred at room temperature for 10 hours to obtain crude quaternized chitosan. 1mL of glycidyl methacrylate was added dropwise to the above quaternized chitosan solution, and stirred at room temperature for 10 hours to obtain a mixture including a reaction product. And (3) performing centrifugal separation on the mixture, dialyzing the supernatant by using deionized water, and freeze-drying to obtain the 2, 3-epoxypropyl trimethyl ammonium chloride and glycidyl methacrylate modified double bond/quaternized modified chitosan.
Step (3): 5g of double bond/quaternized modified chitosan was added to 5mL of N-isopropylacrylamide aqueous solution (1 mg/mL) and stirred well, 0.25g of MoS was added 2 And NS, performing ultrasonic treatment in a water bath for 10min to obtain a premix. 0.25g of PDRN@CaCO 3 To the above premix, the reactor was degassed with nitrogen for 30 minutes, and then 1mL of an aqueous potassium persulfate solution (0.05 g/mL) was added. Pouring the mixed solution into a mould, and standing for 5min to obtain the hydrogel.
Wherein, PDRN@CaCO prepared in step (1) of example 1 3 Scanning electron microscope pictures, atomic force microscope images and projection electron microscope images of the nanoparticles are shown in fig. 1; as can be seen from fig. 1: PDRN@CaCO 3 The particle size of (2) is about 120nm.
The synthetic route of the double bond/quaternized modified chitosan prepared in the step (2) of example 1 is shown in fig. 2, and successful preparation of the double bond/quaternized modified chitosan is confirmed by nuclear magnetic resonance hydrogen spectrum and infrared spectrum, as shown in fig. 3.
MoS used in step (3) of example 1 2 The transmission electron microscope image, atomic force microscope image and particle size distribution of NS are shown in fig. 4. FIG. 5 is a schematic representation of the preparation of hydrogels of example 1. In the gelling process shown in fig. 6, the mixed solution can be rapidly gelled at room temperature. FIG. 7 is a scanning electron micrograph showing the fracture surface of the lyophilized hydrogel; it can be observed that the hydrogel interior assumes a porous structure. By testing the rheological properties of hydrogels, as shown in fig. 8, the storage modulus (G') was greater than the loss modulus (G ") over the angular frequency range studied, indicating that the hydrogels have elastomeric behavior. The photo-thermal conversion properties of the hydrogels were recorded by an infrared thermal camera. As shown in fig. 9, under NIR irradiation, due to MoS 2 The photothermal conversion function of NS causes the hydrogel temperature to rise.
Using Quant-iTMCalculating PDRN@CaCO by using dsDNA quantitative detection kit 3 Loading of PDRN in the particles. First, a standard curve of the concentration (x) of double-stranded DNA versus the fluorescence value (y) was drawn according to the kit instructions to be y=138.373068x+1.311 (R 2 =0.999). 1mg of PDRN@CaCO was weighed out 3 Added to 1mL of 10% hydrochloric acid solution, and cleaved for 20min. 100. Mu.L of lysate was taken and 100. Mu.L of Quant-iTM +.>Is incubated for 5min. The excitation light of the fluorescence enzyme labeling instrument is 480nm, the emission light is 520nm, and the fluorescence intensity of the sample at 520nm is measured. And calculating the content of the DNA in the sample according to a standard curve of the DNA concentration and the fluorescence value. Calculated, PDRN@CaCO in this example 3 The loading of DNA in the particles was 35%.
The hydrogel prepared in step (3) of example 1 was tested for biocompatibility analysis using the MTT method. Specifically, L929 cells and NIH 3T3 were refinedCells were inoculated in 96-well plates (10 per well) 4 Individual cells) in DMEM containing 10% Fetal Bovine Serum (FBS) and 1% penicillin streptomycin at 5% CO 2 Culturing under atmosphere until the wall-attached growth is achieved. During this time, the synthetic hydrogel was immersed in DMEM overnight. Then, the original culture medium is replaced by the hydrogel culture medium extracts with different concentrations, and the culture is continued for 24 hours. After the above medium was discarded, 100. Mu.L of MTT solution (0.5 mg/mL) was added to each well and incubation was continued for 4 hours at 37 ℃. Subsequently, the medium was replaced with 100 μl DMSO to completely dissolve formazan crystals. Cell viability was expressed by measuring absorbance at 492nm wavelength relative to control. The calculation formula is as follows: cell viability (%) = [ a] t -[A] 0 /[A]-[A] 0 X 100%. Wherein [ A ]] t 、[A] 0 [ A ]]-[A] 0 The optical density values in the corresponding wells of the experimental group (cells incubated with hydrogel), the negative control group (cells dispersed in PBS) and the positive control group (blood cells dispersed in Triton X-100) are shown, respectively. The final absorbance is the average absorbance value under parallel experimental conditions. The final absorbance is the average measurement of 6 parallel wells. Cytotoxicity of the hydrogels shown in fig. 10. As can be seen from fig. 10: the prepared hydrogel has good cell compatibility in the test concentration range.
The hydrogel was tested for hemocompatibility, in particular, fresh blood from the tail vein of the mice was collected, centrifuged and washed multiple times with sterilized normal saline to obtain pure Red Blood Cells (RBCs), which were resuspended in 5% by volume PBS. mu.L of RBCs suspension was mixed with 500. Mu.L of a series of concentration gradients (0.75 wt% to 50 wt%) of hydrogel physiological saline system (experimental group), triton X-100 (positive control group), PBS (negative control group) respectively and incubated on a shaker at 37℃for 1h. After centrifugation at 3000 rpm for 10min, the supernatant (50. Mu.L per well) was placed in a 96-well plate and absorbance at 570nm was measured using a Varison Flash reader. The rate of hemolysis was determined according to the formula hemolysis (%) = [ (a) t -A n )/(A p -A n )]X 100% calculation. Wherein A is t Represents the absorbance of the sample, A p And A n Absorbance values are shown for the positive and negative groups, respectively. Each of whichThree groups of parallel experiments are set for all the group samples, and the final absorbance is the average absorbance value. Cytotoxicity of the hydrogels shown in fig. 11. As can be seen from fig. 11: the prepared hydrogel has good blood compatibility in the test concentration range.
Staphylococcus aureus (s.aureus), escherichia coli (e.coli) and pseudomonas aeruginosa (p.aeromonas) were used to evaluate the antimicrobial properties of the preformed hydrogels. Hydrogels with a diameter of 8mm and a thickness of 5mm were placed in corresponding wells on a 24-well plate and rinsed three times with sterilized PBS buffer. After ultraviolet sterilization, 10. Mu.L (10 8 CFU/mL) of three bacterial suspensions were added uniformly to the hydrogel surface. Subsequently, the 24-well plate was placed in a humidified incubator and incubated at 37℃for 5 hours. During this time, three bacteria were selected for hydrogel co-incubation, near infrared light (806 nm,1.5W/cm 2 ) Irradiation for 10min>50 ℃). Then, 1.5mL of sterile PBS solution was added to each well to resuspend the surviving bacteria and to take it as the final bacterial suspension. For the blank group, 10. Mu.L of bacterial liquid (10 8 CFU/mL) was added directly to 1.5mL of sterilized PBS solution. mu.L of the final suspension was spread evenly on agar-broth medium and incubated at 37℃for 12h. Bacterial growth and colony count on LB agar plates were recorded by separate photographs. FIG. 12 is an evaluation of antibacterial properties of the prepared hydrogels. As can be seen from fig. 12: the prepared hydrogel has good antibacterial effect on three bacteria, and particularly has higher antibacterial efficiency under NIR (near infrared) irradiation.
FIG. 13 is a photograph showing the use of the hydrogel prepared in example 1 for repairing a wound on the back of a mouse. A wound model was built on the back of mice, and the experimental group was treated with the hydrogel prepared in example 1, and the control group was bandaged. The dressing is changed every two days. It can be observed that the hydrogel-treated group showed significantly greater wound healing rate and quality than the control group. Of these, the hydrogel group had a wound closure of 97.7%, the NIR-irradiated hydrogel wound closure of 100%, and the control group had only 76.5%. This illustrates PDRN@CaCO 3 The carried PDRN has wound promoting effect, and MoS is under NIR effect 2 NS enhances antibacterial properties so that the near infrared irradiated hydrogel group exhibits optimal therapeutic effects.
Example 2
The preparation method of the nanocomposite hydrogel of the controlled release gene vector comprises the following steps:
step (1): 1mL of CaCl with concentration of 0.5mol/L 2 The aqueous solution was added to 20mL of cyclohexane. Igepal CO-520 (10 mL) was added dropwise to form a microemulsion. To the microemulsion was added 2mL of an aqueous solution of PDRN (5 mg/mL). After stirring for 15 minutes, 1mL of Na was added at a concentration of 0.5mol/L 2 CO 3 The aqueous solution was slowly dropped into the reactor and stirring was continued for 15 minutes. Absolute ethanol is then added to the reaction mixture to break the emulsion. After the reaction was completed, the sample was transferred to a centrifuge (11000 rpm) for 25 minutes to collect a precipitate. Repeatedly washing with absolute ethanol, freeze drying to obtain pure PDRN@CaCO 3 A gene vector.
Step (2): 30mL of 2, 3-epoxypropyl trimethyl ammonium chloride (50 mg/mL) was added dropwise to 50mL of a water-soluble chitosan solution (20 mg/mL), and stirred at room temperature for 10 hours to obtain crude quaternized chitosan. 1mL of glycidyl methacrylate was added dropwise to the above quaternized chitosan solution, and stirred at room temperature for 10 hours to obtain a mixture including a reaction product. And (3) performing centrifugal separation on the mixture, dialyzing the supernatant by using deionized water, and freeze-drying to obtain the 2, 3-epoxypropyl trimethyl ammonium chloride and glycidyl methacrylate modified double bond/quaternized modified chitosan.
Step (3): 5g of double bond/quaternized modified chitosan was added to 5mL of N-isopropylacrylamide aqueous solution (1 mg/mL) and stirred well, 0.25g of MoS was added 2 And NS, performing ultrasonic treatment in a water bath for 10min to obtain a premix. 0.25g of PDRN@CaCO 3 To the above premix, the reactor was degassed with nitrogen for 30 minutes, and then 1mL of an aqueous potassium persulfate solution (0.05 g/mL) was added. Pouring the mixed solution into a mould, and standing for 5min to obtain the hydrogel.
The PDRN@CaCO prepared in step (1) of example 2 was observed by a scanning electron microscope 3 The particle size of the nanoparticles was about 250nm. In addition, PDRN@CaCO was measured by the method described in example 1 3 The loading of the intermediate PDRN was 26.4%. The above description: lifting handleThe high PDRN usage will result in PDRN@CaCO 3 The particle size of the nanoparticle increases while the loading of DNA decreases.
The double bond/quaternized modified chitosan prepared in example 2 was subjected to structural analysis using the test method in example 1, confirming its successful synthesis.
The morphology, rheological properties and photo-thermal conversion properties of the hydrogels prepared in example 2 were characterized using the test method in example 1. The characterization structure is as follows: the hydrogel interior exhibits a porous structure. The hydrogel has a storage modulus (G ') greater than the loss modulus (G') and has elastomeric behavior. Has good photo-thermal conversion performance, and can rapidly heat up the hydrogel under the action of NIR.
The biocompatibility of the hydrogels prepared in example 2 was tested using the MTT method and blood compatibility experiments (see in particular the method described in example 1), and the test results showed that: the prepared hydrogel has good cell compatibility in the test concentration range.
The antibacterial properties of the hydrogels prepared in example 2 and wound repair in animal models were characterized using the test method in example 1. The prepared hydrogel has good antibacterial effect on three bacteria, and particularly has higher antibacterial efficiency under NIR (near infrared) irradiation. In the animal model wound repair procedure, the hydrogel group had a wound closure of 84.1% and the NIR-irradiated hydrogel group had a wound closure of 87.4% on day 14, both of which were higher than 75.2% of the control group. The hydrogel dressing prepared using example 2 had a faster wound healing rate than the control group, but was slower than the experimental group in example 1. This is probably due to pdrn@caco at larger particle sizes 3 Nanoparticles are not favorable for uptake by cells, while pdrn@caco 3 The decreased loading of PDRN results in a decreased amount of DNA absorbed by the cells, which in turn results in a decreased rate of wound healing.
Example 3
The preparation method of the nanocomposite hydrogel of the controlled release gene vector comprises the following steps:
step (1): concentration of 1mLCaCl of 0.5mol/L 2 The aqueous solution was added to 20mL of cyclohexane. Igepal CO-520 (10 mL) was added dropwise to form a microemulsion. To the microemulsion was added 3.5mL of an aqueous solution of PDRN (5 mg/mL). After stirring for 15 minutes, 1mL of Na was added at a concentration of 0.5mol/L 2 CO 3 The aqueous solution was slowly dropped into the reactor and stirring was continued for 15 minutes. Absolute ethanol is then added to the reaction mixture to break the emulsion. After the reaction was completed, the sample was transferred to a centrifuge (11000 rpm) for 25 minutes to collect a precipitate. Repeatedly washing with absolute ethanol, freeze drying to obtain pure PDRN@CaCO 3 A gene vector.
Step (2): 20mL of 2, 3-epoxypropyl trimethyl ammonium chloride (50 mg/mL) is added dropwise to 50mL of water-soluble chitosan solution (20 mg/mL), and the mixture is stirred at room temperature for 10h, so as to obtain crude quaternized chitosan. 1mL of glycidyl methacrylate was added dropwise to the above quaternized chitosan solution, and stirred at room temperature for 10 hours to obtain a mixture including a reaction product. And (3) performing centrifugal separation on the mixture, dialyzing the supernatant by using deionized water, and freeze-drying to obtain the 2, 3-epoxypropyl trimethyl ammonium chloride and glycidyl methacrylate modified double bond/quaternized modified chitosan.
Step (3): 5g of double bond/quaternized modified chitosan was added to 5mL of N-isopropylacrylamide aqueous solution (1 mg/mL) and stirred well, 0.25g of MoS was added 2 And NS, performing ultrasonic treatment in a water bath for 10min to obtain a premix. 0.25g of PDRN@CaCO 3 To the above premix, the reactor was degassed with nitrogen for 30 minutes, and then 1mL of an aqueous potassium persulfate solution (0.05 g/mL) was added. Pouring the mixed solution into a mould, and standing for 5min to obtain the hydrogel.
The PDRN@CaCO prepared in step (1) of example 3 was observed by a scanning electron microscope 3 The particle size of the nanoparticles was about 120nm. PDRN@CaCO was measured by the method described in example 1 3 The loading of PDRN was 35%.
Structural analysis was performed on the double bond/quaternized modified chitosan prepared in example 3 using the test method in example 1, confirming successful synthesis.
The morphology, rheological properties and photo-thermal conversion properties of the hydrogels prepared in example 3 were characterized using the test method in example 1. The characterization structure is as follows: the hydrogel interior exhibits a porous structure. The hydrogel has a storage modulus (G ') greater than the loss modulus (G') and has elastomeric behavior. Has good photo-thermal conversion performance, and can rapidly heat up the hydrogel under the action of NIR.
The biocompatibility of the hydrogels prepared in example 3 (see in particular the method described in example 1) was tested using the MTT method and blood compatibility experiments, and the test results showed that: the prepared hydrogel has good cell compatibility in the test concentration range.
The antibacterial properties of the hydrogels prepared in example 3 and wound repair in animal models were characterized using the test method in example 1. The prepared hydrogel showed a certain antibacterial effect on all three bacteria, but the number of colonies on the medium was increased compared to examples 1 and 2. As described above, decreasing the quaternization degree of chitosan may decrease the antibacterial property of the hydrogel. In the animal model wound repair procedure, the hydrogel group was wound closed by 87.5% and the NIR-irradiated hydrogel group was wound closed by 93.5% in the group treated with the hydrogel prepared in example 3 on day 14, which were both higher than 75.2% of the control group. The hydrogel dressing prepared using example 3 had a faster wound healing rate than the control group, but was slower than the experimental group in example 1. This may be due to the reduced antimicrobial properties of the hydrogel, increasing the risk of infection of the wound, and thus reducing the quality of wound healing.
Comparative example 1
Comparative example 1 is an unloaded PDRN@CaCO 3 The preparation method of the hydrogel of the gene vector comprises the following specific steps:
30mL of 2, 3-epoxypropyl trimethyl ammonium chloride (50 mg/mL) was added dropwise to 50mL of a water-soluble chitosan solution (20 mg/mL), and stirred at room temperature for 10 hours to obtain crude quaternized chitosan. 1mL of glycidyl methacrylate was added dropwise to the above quaternized chitosan solution, and stirred at room temperature for 10 hours to obtain a mixture including a reaction product. And (3) performing centrifugal separation on the mixture, dialyzing the supernatant by using deionized water, and freeze-drying to obtain the 2, 3-epoxypropyl trimethyl ammonium chloride and glycidyl methacrylate modified double bond/quaternized modified chitosan.
5g of double bond/quaternized modified chitosan was added to 5mL of N-isopropylacrylamide aqueous solution (1 mg/mL) and stirred well, 0.25g of MoS was added 2 And NS, performing ultrasonic treatment in a water bath for 10min to obtain a premix. After the reactor was degassed with nitrogen for 30min, 1mL of an aqueous potassium persulfate solution (0.05 g/mL) was added. Pouring the mixed solution into a mould, and standing for 5min to obtain the hydrogel.
Structural analysis was performed on the double bond/quaternized modified chitosan prepared in comparative example 1 using the test method in example 1, confirming successful synthesis.
The morphology, rheological properties and photo-thermal conversion properties of the hydrogels prepared in comparative example 1 were characterized using the test method in example 1. The characterization structure is as follows: the hydrogel interior exhibits a porous structure. The hydrogel has a storage modulus (G ') greater than the loss modulus (G') and has elastomeric behavior. Has good photo-thermal conversion performance, and can rapidly heat up the hydrogel under the action of NIR.
The biocompatibility of the hydrogels prepared in comparative example 1 (see in particular the method described in example 1) was tested using the MTT method and the haemocompatibility test, and the test results showed that: the prepared hydrogel has good cell compatibility in the test concentration range.
The antibacterial properties of the hydrogels prepared in comparative example 1 and wound repair in animal models were characterized using the test method in example 1. The prepared hydrogels showed a certain antibacterial effect against all three bacteria, and the antibacterial properties were similar to those of the hydrogels prepared in example 1 and example 2. In the animal model wound repair procedure, the hydrogel group had a wound closure of 80.1% and the NIR-irradiated hydrogel group had a wound closure of 84.8% in the group treated with the hydrogel prepared in comparative example 1 on day 14, both higher than 75.2% of the control group. As described above, decreasing the quaternization degree of chitosan may decrease the antibacterial property of the hydrogel. No load of PDRN@CaCO 3 The hydrogel of the gene vector has reduced wound repair function.
In conclusion, the nano composite hydrogel of the controlled release gene vector and the preparation method thereof of the invention firstly prepare double bond/quaternized modified chitosan and PDRN@CaCO 3 A gene vector. The calcium carbonate nano-particles loaded with PDRN are prepared by adopting a coprecipitation method. PDRN has effects of improving angiogenesis, increasing collagen synthesis, promoting osteoblast activity, and exerting antiinflammatory effect. Then PDRN@CaCO 3 Double bond/quaternized modified chitosan, poly-N-isopropylacrylamide and MoS 2 NS is used as a raw material to prepare hydrogel. When the hydrogel is applied to a wound surface, the hydrogel can absorb seepage, block bacteria and maintain a wet environment; moS (MoS) 2 The NS has a photo-thermal conversion function, can convert NIR into heat energy, so that the temperature of the hydrogel is increased, when the temperature is increased to be higher than the LCST of poly-N-isopropyl acrylamide, the molecular chain of the poly-N-isopropyl acrylamide is contracted, so that the volume of the hydrogel is contracted, the internal nano-carrier is extruded, and the NIR triggering controllable release of the gene carrier is realized. The calcium carbonate nanoparticles can more efficiently transfer the PDRN into cells and promote proliferation of the cells. In addition, moS 2 Both the photothermal properties of NS and the quaternized chitosan have antibacterial and bactericidal effects. The hydrogel can be used in the field of acute and chronic wound repair, and also can be used in the medical field to recover the regeneration capability of aged and atrophic skin and improve the skin function.
The above description is only of the preferred embodiments of the present invention, and is not intended to limit the present invention in any way, but any simple modification, equivalent variation and modification made to the above embodiments according to the technical substance of the present invention still fall within the scope of the technical solution of the present invention.
Claims (10)
1. The nano composite hydrogel of the controlled release gene carrier is characterized by being of a three-dimensional porous structure and comprising a crosslinked network formed by chitosan and poly-N-isopropyl acrylamide, and can be used for controlling release of calcium carbonate nano particles PDRN@CaCO loaded with PDRN 3 。
2. A method for preparing the nanocomposite hydrogel of the controlled release gene vector according to claim 1, comprising the steps of:
(1) Preparation of polydeoxynucleotide-loaded calcium carbonate nanoparticles PDRN@CaCO 3 ；
(2) Preparing double bond/quaternized modified chitosan modified by 2, 3-epoxypropyl trimethyl ammonium chloride and glycidyl methacrylate;
(3) Preparing double bond/quaternized modified chitosan obtained in the step (2) and N-isopropyl acrylamide and molybdenum disulfide slices into premix; pdrn@caco 3 And adding the potassium persulfate solution into the premix solution, uniformly mixing, and standing to obtain the hydrogel.
3. The preparation method according to claim 2, wherein the step (1) specifically comprises the steps of:
11 CaCl) is added 2 Adding cyclohexane into the solution, uniformly mixing, and dropwise adding Igepal CO-520 to form microemulsion; adding PDRN water solution into the microemulsion, stirring, and adding Na 2 CO 3 Slowly dripping the solution into the reaction solution, and continuously stirring to obtain a reaction mixture;
12 Adding absolute ethyl alcohol into the reaction mixture to demulsify, centrifuging, and collecting precipitate; freeze drying the precipitate to obtain PDRN@CaCO 3 。
4. A method of preparation according to claim 3, wherein the PDRN has a molecular weight of 25-700bp and the aqueous PDRN solution has a concentration of 1-5mg/mL; caCl (CaCl) 2 The concentration of the solution is 0.1-0.5mol/L; na (Na) 2 CO 3 The concentration of the solution is 0.1-0.5mol/L; caCl (CaCl) 2 With Na and Na 2 CO 3 The molar ratio of (1) to (5); PDRN and CaCl 2 The mass ratio of (3) to (6) is 1; caCl (CaCl) 2 The volume ratio of the solution to the cyclohexane to the Igepal CO-520 is 1 (20-50): 10-30; the stirring time for the two times is 0.2-2h.
5. The method according to claim 4, wherein PDRN@CaCO 3 The particle size of the particles is 100-400nm, PDRN@CaCO 3 PDR in particlesThe loading of N is 18-35%.
6. The preparation method according to claim 2, wherein the step (2) specifically comprises the steps of:
21 Dropwise adding the 2, 3-epoxypropyl trimethyl ammonium chloride solution into the water-soluble chitosan solution, and stirring at room temperature to obtain a crude quaternized chitosan solution;
22 Dropwise adding glycidyl methacrylate into the crude quaternized chitosan solution, and stirring at room temperature to obtain a reaction mixture;
23 Centrifuging the reaction mixture to obtain a supernatant, dialyzing the supernatant with deionized water and freeze-drying to obtain the 2, 3-epoxypropyl trimethyl ammonium chloride and glycidyl methacrylate modified double bond/quaternized modified chitosan.
7. The method according to claim 6, wherein the concentration of the chitosan solution is 20-100mg/mL; the concentration of the 2, 3-epoxypropyl trimethyl ammonium chloride solution is 10-50mg/mL; the molar ratio of the 2, 3-epoxypropyl trimethyl ammonium chloride monomer to the glycidyl methacrylate monomer to the amino group on the chitosan is (5-1): 1; the stirring time for the two times is 10-30h.
8. The preparation method according to claim 2, wherein the step (3) specifically comprises the steps of:
31 Adding double bond/quaternized modified chitosan into N-isopropyl acrylamide aqueous solution and uniformly stirring;
32 Adding a molybdenum disulfide sheet into the mixture obtained in the step 31), and performing ultrasonic treatment in a water bath to obtain a premix;
33 Pdrn@caco) 3 Adding the mixture into the premix, degassing with nitrogen, adding potassium persulfate solution, and standing to obtain the hydrogel.
9. The method according to claim 8, wherein the N-isopropylacrylamide is mixed withThe mass ratio of the double bond to the quaternized modified chitosan is 1 (1-5); the mass ratio of the molybdenum disulfide flake to the double bond/quaternized modified chitosan is 1 (20-100); PDRN@CaCO 3 The mass ratio of the chitosan to the double bond/quaternized modified chitosan is 1 (20-100); the mass ratio of the potassium persulfate to the double bond/quaternized modified chitosan is 1 (50-500).
10. The method according to claim 8, wherein the ultrasonic treatment time is 10 to 60 minutes; the degassing treatment time is 10-60min.
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