CN114984244A - Hyperbranched polylysine-containing hydrogel carrier material and preparation method thereof - Google Patents
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Abstract
The invention discloses a hyperbranched polylysine-containing hydrogel carrier material and a preparation method thereof. One component of the hydrogel material is hyperbranched polylysine (HBPL) and a modifier thereof, the other component is at least one of aldehyde hyaluronic acid and hyaluronic acid grafted with adamantane, and the two components can form hydrogel through Schiff base or supermolecule action. The hyperbranched polylysine hydrogel can entrap different drugs for treating brain injury, deliver the drugs to a lesion area, realize controllable release, achieve the effect of treating the brain injury, and simultaneously prevent bacterial infection brought in the operation process. The hydrogel has the characteristics of uniform structure, no toxicity, good biocompatibility, proper biodegradation speed, injectability, proper viscosity, mild gelling condition, soft gel, sterilization by a conventional method and the like.
Description
Technical Field
The invention relates to a hydrogel carrier material containing hyperbranched polylysine, a preparation method and application thereof, and belongs to the field of biological medicines.
Background
Traumatic Brain Injury (TBI) has been one of the leading causes of disability and death. Over 5000 million people per year suffer from TBI worldwide. By 2005, about 317 million TBI survivors experienced complications from post-injury neuropsychological problems and the like to disability, with the number of new cases in our country being 55.4-64.1/10 thousands of people per year. The high treatment costs for TBI patients place a heavy burden on healthcare systems and society. There are two mechanisms in the TBI process: primary and secondary injury. Primary injury is caused directly by mechanical force, which can lead to blood brain barrier destruction, blood vessel destruction, etc.; secondary injury refers to further tissue and cell damage following extrinsic injury. Primary injury is usually irreversible acute physical injury and cellular necrosis, while secondary injury gradually increases with time, and secondary injury is the leading cause of death and disability.
The main mechanisms of secondary injury are: excitotoxicity, mitochondrial dysfunction, oxidative stress, lipid peroxidation, neuroinflammation, axonal degeneration and apoptosis. Reduction of secondary injury is beneficial to central nervous system recovery by targeting these mechanisms with different drugs as shown in table 1 below.
Table 1: TBI post-pathophysiology, therapeutic target and corresponding medicine
Hydrogels are polymeric materials with a cross-linked structure that are hydrophilic and insoluble in water, and that are capable of absorbing large amounts of water (typically greater than 50% of the total mass) with water as the dispersing medium. Because of physical and chemical crosslinking between polymer chains, it is not dissolved in water, but swells and maintains a certain shape. Meanwhile, the hydrogel also has good water permeability and biocompatibility, and can reduce adverse reactions when used as a human implant, so that the hydrogel is widely applied to biomedical materials.
At present, the main categories of medical hydrogel carriers are hyaluronic acid, chitosan and the like, gel is mainly formed through chemical crosslinking, and the main defects are as follows: the gel lacks shear thinning properties, which leads to poor injectability; the gel has no antibacterial performance, so that the problem of postoperative infection can occur; the gelling requirement is high, the gelling is usually completed before production, and the performance can not be adjusted according to actual requirements; gels have difficulty maintaining the activity of the drug protein, resulting in rapid inactivation of both.
Disclosure of Invention
The invention aims to provide a hydrogel carrier material containing hyperbranched polylysine (HBPL) and a preparation method thereof, aiming at the defects of the prior art. One component of the hydrogel material is hyperbranched polylysine (HBPL) or HBPL grafted with cyclodextrin, and the other component can be aldehyde hyaluronic acid or hyaluronic acid grafted with adamantane; the two components can be simply physically mixed to form a hydrogel, which serves to maintain pharmaceutical activity, drug delivery, and resistance to bacterial infection. The hydrogel has the characteristics of uniform structure, no toxicity, good biocompatibility, proper biodegradation speed, injectability, proper viscosity, mild gelling condition, soft gel, sterilization by a conventional method and the like.
The invention relates to a preparation method of a hydrogel carrier material containing hyperbranched polylysine, which comprises the following steps:
the first step is as follows: dissolving beta-cyclodextrin and sodium hydroxide in water, and adding chloroacetic acid solution to react to obtain carboxyl cyclodextrin.
The second step is that: dissolving HBPL, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide and carboxyl cyclodextrin in Phosphate Buffer Solution (PBS) to react to obtain hyperbranched polylysine connected with cyclodextrin.
The third step: preparing hyperbranched polylysine (or hyperbranched polylysine) connected with cyclodextrin into a solution, and preparing aldehyde group hyaluronic acid or hyaluronic acid connected with adamantane into a solution (gel forming component);
the fourth step: and mixing the two solutions obtained in the third step to obtain the hydrogel carrier material containing the hyperbranched polylysine.
Furthermore, the molecular weight of the hyperbranched polylysine is 5000-6000 g/mol.
Further, the method comprises the following steps: in the first step, the mass ratio of chloroacetic acid to beta-cyclodextrin is 1: 1 to 1: 5.
further: in the second step, the mass ratio of HBPL to carboxyl cyclodextrin is 1: 1 to 1: 5.
further: in the third step, the concentration of the solution containing hyperbranched polylysine is 5-10%, and the concentration of the aldehyde group hyaluronic acid or the hyaluronic acid solution connected with adamantane is 5-10%.
The HBPL hydrogel carrier material can be used for loading drugs for treating brain injury such as dexanabinol, dezocyclopine, dihydroxyquinone, s-emepamil, ziconotide, nimodipine, nicardipine, cyclosporine A, methylprednisolone, minocycline and rapamycin, and one or more of proteins and polypeptides such as neurotrophic factors (brain-derived neurotrophic factors, nerve growth factors, basic fibroblast growth factors and epidermal growth factors) and chondroitin sulfate lyase.
The method for loading the drug by the HBPL hydrogel carrier material is to dissolve the drug, protein and the like in the HBPL solution by ultrasound, and then mix the HBPL solution containing the drug or protein with the cross-linking component solution to obtain the drug-loaded HBPL hydrogel.
The invention has the beneficial effects that: the HBPL hydrogel disclosed by the invention has better biocompatibility and injectability, and has no biotoxicity. The hydrogel is formed by the host-guest action of cyclodextrin and adamantane grafted on the components or the action of aldehyde group of oxidized hyaluronic acid and amino group of HBPL through Schiff base, the hydrogel can be simply and physically mixed into gel, compared with medical hydrogel, the gel forming condition is lower, and the operation is simpler; meanwhile, the hydrogel has proper degradation performance, and degradation products are nontoxic and have certain nutritional value; it can form electrostatic or hydrophilic and hydrophobic effect with drug protein to facilitate the slow release of drug protein and maintain the activity of drug protein. When injected into the injured part, the hydrogel can inhibit the growth of bacteria, thereby reducing the problem of bacterial infection caused by operation, promoting the survival of neuron cells, reducing the infiltration of astrocytes and microglia, reducing nerve injury caused by excitotoxicity, and promoting the generation of nerve vessels at the injured part.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of aldehyde hyaluronic acid prepared in example 1 of the present invention.
FIG. 2 shows the NMR spectra of carboxycyclodextrins prepared in example 1 of the present invention.
FIG. 3 shows the NMR spectrum of grafted cyclodextrin HBPL prepared in example 1 of the present invention.
FIG. 4 shows a HBPL hydrogel carrier material prepared in example 1 of the present invention.
FIG. 5 is the drug release rate of minocycline-loaded HBPL hydrogel prepared in example 3 of the present invention.
Detailed Description
The invention is further illustrated by the following description in conjunction with the figures and the specific examples.
Example 1
Mixing hyaluronic acid and sodium periodate in distilled water under dark conditions, reacting for 24 hours, adding 1mL of ethylene glycol to terminate the reaction, pouring the reaction solution into a dialysis bag, dialyzing for 3 days, and freeze-drying the solution to obtain aldehyde hyaluronic acid (HA-ALH), wherein the composition of the aldehyde hyaluronic acid is characterized by NMR, and the result is shown in figure 1. 10g of beta-cyclodextrin and 9.3g of sodium hydroxide were dissolved in 37mL of distilled water, and 27mL of a 16.3% chloroacetic acid solution was added to the solution to react at 50 ℃ for 5 hours. The reaction solution was precipitated 3-5 times with a large amount of methanol to obtain carboxycyclodextrin whose composition was characterized by NMR, and the results are shown in FIG. 2. 0.25g of the resulting carboxycyclodextrin and 100mg of HBPL were dissolved in PBS solution, pH was adjusted to 5, 1.146g of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) and 0.345g of NHS (N-hydroxysuccinimide) were sequentially added thereto, the mixture was reacted at 37 ℃ and pH 6 for 4 hours overnight, and the resulting reaction solution was dialyzed and lyophilized to obtain cyclodextrin-linked HBPL (HBPL-CD), and the composition thereof was characterized by NMR, as shown in FIG. 3. Respectively dissolving the prepared HA-ALH and HBPL-CD in water according to the mass volume fraction of 10%, then dissolving brain-derived neurotrophic factor (BDNF) in an HBPL-CD solution according to the concentration of 2%, and after the BDNF-containing HBPL-CD solution and the HA-ALH solution are fully dissolved, mixing the HBPL-CD solution containing the BDNF with the HA-ALH solution according to the volume ratio of 2: and (3) carrying out ultrasonic blending on the ratio of 1 for 20s to obtain a hyperbranched polylysine hydrogel material containing BDNF. Hydrogel display figure 4 shows that the hydrogel, after being placed in a syringe, can be extruded through a needle, showing good injectability.
Example 2
Mixing hyaluronic acid and sodium periodate in distilled water under the condition of keeping out of the sun, reacting for 24 hours, adding 1mL of ethylene glycol to terminate the reaction, pouring the reaction solution into a dialysis bag, dialyzing for 3 days, and freeze-drying the solution to obtain aldehyde hyaluronic acid (HA-ALH). Respectively dissolving the prepared HA-ALH and HBPL in water according to the mass volume fraction of 10%, then respectively dissolving dexanabinol and nimodipine in HBPL solution according to the concentration of 1%, and after the solution is fully dissolved, mixing the solution with the HA-ALH solution according to the volume ratio of 2: 1 for 20s by ultrasonic blending to obtain the hyperbranched polylysine hydrogel material containing dexanabinol and nimodipine.
Example 3
Mixing hyaluronic acid and sodium periodate in distilled water under the condition of keeping out of the sun, reacting for 24 hours, adding 1mL of ethylene glycol to terminate the reaction, pouring the reaction solution into a dialysis bag, dialyzing for 3 days, and freeze-drying the solution to obtain aldehyde hyaluronic acid (HA-ALH). 10g of beta-cyclodextrin and 9.3g of sodium hydroxide were dissolved in 37mL of distilled water, and 27mL of 16.3% chloroacetic acid solution was added to the solution, followed by reaction at 50 ℃ for 5 hours. Precipitating the reaction solution with a large amount of methanol for 3-5 times to obtain the carboxyl cyclodextrin. 0.25g of the resulting carboxycyclodextrin and 100mg of HBPL were dissolved in a PBS solution, the pH was adjusted to 5, 1.146g of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) and 0.345g of NHS (N-hydroxysuccinimide) were sequentially added thereto, the mixture was reacted at 37 ℃ and pH 6 for 4 hours and then overnight, and the resulting reaction solution was dialyzed and lyophilized to obtain cyclodextrin-ligated HBPL (HBPL-CD). Respectively dissolving the HA-ALH and the HBPL-CD prepared in the above way in water according to the mass volume fraction of 10%, then dissolving minocycline hydrochloride in the HBPL-CD solution according to the concentration of 2%, and after the minocycline hydrochloride in the HBPL-CD solution is fully dissolved, mixing the minocycline hydrochloride in the HBPL-CD solution and the HA-ALH solution according to the volume ratio of 2: and (3) ultrasonically blending the mixture for 20s to obtain the minocycline-containing hyperbranched polylysine hydrogel material. Putting 100 mul of minocycline-loaded hyperbranched polylysine hydrogel material into a 5mL centrifuge tube, adding 2mL PBS, taking 0.4mL of solution in each of 1h, 3h, 6h, 19h and 24h, adding 0.4mL PBS, diluting the obtained solution by 5 times, measuring the ultraviolet absorption value of the solution at 345nm, and obtaining a minocycline release curve as shown in FIG. 5.
Example 4
Dissolving 3.0 g of hyaluronic acid in 150mL of deionized water, adding 9.0g of Dowex 50 Wx8 ion exchange resin into the solution, stirring for 30min at room temperature, performing suction filtration to obtain a hyaluronic acid solution, adjusting the pH of the hyaluronic acid solution to 7.02-7.05 by using tetrabutylammonium hydroxide solution (TBA), and performing freeze-drying to obtain HA-TBA. The flask was charged with 2.5g of HA-TBA, 2.04g of 1-adamantane acetic acid, 0.32g of 4-dimethylaminopyridine and 125mL of anhydrous dimethyl sulfoxide, after the solid was completely dissolved, 0.35mL of di-tert-butyl dicarbonate was added, the reaction was carried out at 45 ℃ for 20 hours under a nitrogen atmosphere, then dialysis was carried out for 14 days, solid impurities were removed by suction filtration, and the filtrate was lyophilized to obtain adamantane-grafted hyaluronic acid (HA-Ad). 10g of beta-cyclodextrin and 9.3g of sodium hydroxide were dissolved in 37mL of distilled water, and 27mL of a 16.3% chloroacetic acid solution was added to the solution to react at 50 ℃ for 5 hours. Precipitating the reaction solution with a large amount of methanol for 3-5 times to obtain the carboxyl cyclodextrin. 0.25g of the resulting carboxycyclodextrin and 100mg of HBPL were dissolved in PBS solution, pH was adjusted to 5, 1.146g of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) and 0.345g of NHS (N-hydroxysuccinimide) were sequentially added thereto, the mixture was reacted at 37 ℃ and pH 6 for 4 hours overnight, and the resulting reaction solution was dialyzed and lyophilized to obtain cyclodextrin-conjugated HBPL (HBPL-CD). Dissolving the prepared HA-Ad and HBPL-CD in water according to the mass volume fraction of 10%, then dissolving minocycline in the HBPL-CD solution according to the concentration of 1%, and after the minocycline is fully dissolved, mixing the HBPL-CD solution containing the minocycline and the HA-Ad solution according to the volume ratio of 1: 1, and performing ultrasonic blending for 20s to obtain the minocycline-containing hyperbranched polylysine hydrogel material.
Claims (10)
1. The hydrogel carrier material containing hyperbranched polylysine is formed by the interaction of functional groups on a gel-forming component and amino groups on the hyperbranched polylysine or grafted cyclodextrin molecules through Schiff bases or supramolecules.
2. The hydrogel carrier material containing hyperbranched polylysine as claimed in claim 1, wherein the gel-forming component is aldehyde group hyaluronic acid and hyaluronic acid grafted with adamantane, and the molecular weight of the hyperbranched polylysine is 6000g/mol and 5000-.
3. The method for preparing the hyperbranched polylysine-containing hydrogel carrier material according to claim 1, comprising the following steps:
(1) dissolving beta-cyclodextrin and sodium hydroxide in water, and adding chloroacetic acid solution to react to obtain carboxyl cyclodextrin;
(2) dissolving hyperbranched polylysine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide and carboxyl cyclodextrin in phosphate buffer solution to react to obtain hyperbranched polylysine connected with cyclodextrin;
(3) preparing hyperbranched polylysine connected with cyclodextrin or hyperbranched polylysine into a solution A, and preparing aldehyde hyaluronic acid or hyaluronic acid connected with adamantane into a gel-forming component into a solution B;
(4) and (4) mixing the solution A and the solution B in the step (3) to obtain the hydrogel carrier material containing the hyperbranched polylysine.
4. The method for preparing the hydrogel carrier containing hyperbranched polylysine according to claim 3, wherein in the step (1), the mass ratio of the chloroacetic acid to the beta-cyclodextrin is 1: 1 to 1: 5.
5. the method for preparing the hydrogel carrier containing hyperbranched polylysine according to claim 3, wherein in the step (2), the mass ratio of the hyperbranched polylysine to the carboxyl cyclodextrin is 1: 1 to 1: 5.
6. the method for preparing the hydrogel carrier containing hyperbranched polylysine according to claim 3, wherein in the step (3), the concentration of the solution A is 5-10%, and the concentration of the solution B is 5-10%.
7. The hyperbranched polylysine-containing hydrogel carrier material of claim 1, wherein the material is used to carry at least one of a drug, a protein, and a polypeptide for the treatment of brain injury.
8. The hyperbranched polylysine-containing hydrogel carrier material of claim 7, wherein the drug is one or more of dexanabinol, dezocyclopine, dihydroxyquinone, s-ememopamide, ziconotide, nimodipine, nicardipine, cyclosporine a, methylprednisolone, minocycline, and rapamycin, and the protein and polypeptide are neurotrophic factors such as: one or more of brain-derived neurotrophic factor, nerve growth factor, basic fibroblast growth factor, epidermal growth factor, or chondroitin sulfate lyase.
9. The hyperbranched polylysine-containing hydrogel carrier material according to claim 7, wherein the loading method comprises dissolving a substance to be loaded in a hyperbranched polylysine solution containing hyperbranched polylysine or grafted with cyclodextrin by ultrasound, and mixing the obtained solution with aldehyde hyaluronic acid or a hyaluronic acid solution grafted with adamantane to obtain a drug-loaded hydrogel, wherein the hydrogel can be used for loading drugs and realizing the controlled release of the loaded substance.
10. Use of a hydrogel carrier material according to any of claims 7 to 9 as a carrier material for loading a drug for the treatment of brain injury.
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