CN114344247A - Targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel and preparation method thereof - Google Patents
Targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel and a preparation method thereof, wherein the hydrogel is prepared by the following steps: and (3) adding HA-beta-CD and F127 into deionized water under the condition of keeping out of the sun, stirring for the first time, then adding alpha-CD, stirring for the second time, then adding DOX, stirring for the third time, then standing, and freeze-drying to obtain the target product. According to the invention, firstly, chain threading is carried out through the interaction between a subject and an object between F127 and HA-beta-CD, then adriamycin is dispersed in a hydrogel precursor solution, and then the targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel is prepared through the interaction between alpha-CD and F127. Compared with the prior art, the supermolecule hydrogel disclosed by the invention can improve the adriamycin loading capacity, reduce the toxic and side effects of adriamycin molecules, effectively prolong the release time of drug molecules, enhance the tissue permeability and drug effect, and improve the targeting performance, and has the advantages of easily available raw materials, stable drug-loading system, easily regulated and controlled properties and better biocompatibility.
Description
Technical Field
The invention belongs to the technical field of supramolecular hydrogel drug loading, and relates to targeted hyaluronic acid-cyclodextrin drug loading supramolecular hydrogel and a preparation method thereof.
Background
Adriamycin (DOX) is an anthracycline broad-spectrum antitumor antibiotic, and the action mechanism of the Adriamycin is mainly that Adriamycin molecules enter a cell nucleus to be combined with DNA, so that the synthesis and mitosis of nucleic acid are inhibited. Doxorubicin hydrochloride has a broad-spectrum anti-experimental tumor effect, also has an inhibitory effect on topoisomerase, and can be applied to acute leukemia, malignant lymphoma, multiple myeloma and the like. However, the drug has large toxic and side effects, and the acute side effects of the adriamycin include nausea, vomiting and arrhythmia. It can also cause neutropenia (neutropenia), as well as complete hair loss.
Hyaluronic acid is a linear macromolecular mucopolysaccharide consisting of two saccharide units of glucuronic acid and N-acetylglucosamine, which are alternately linked. It has excellent biocompatibility, biodegradability and high viscoelasticity, and can be combined with specific receptor on cell surface. The hyaluronic acid receptor CD44 has been found to be expressed at low levels on the surface of epithelial, hematopoietic and neuronal cells, but is overexpressed in many tumor cells. In addition, some hyaluronic acid groups such as hydroxyl, carboxyl and N-acetyl are suitable for chemical modification. Therefore, the hyaluronic acid and the derivatives thereof as drug carriers are beneficial to thickening, sustained release, transdermal absorption and improvement of drug targeting. The hyaluronic acid is modified into the supramolecular hydrogel based on cyclodextrin, so that the biocompatibility of the supramolecular hydrogel can be improved, and the adhesion of the hydrogel can be improved, and therefore, the hyaluronic acid has a wide expansion space in the application field of gel. Patent CN109620967A constructs a targeted adriamycin-loaded supramolecular hydrogel, wherein adriamycin molecules in the hydrogel are covalently modified on a cyclodextrin matrix and directly participate in the construction of the hydrogel, and folic acid molecules are taken as targeting groups. However, in the prior art, the adriamycin loading rate is low. The development of the supermolecule hydrogel with good biocompatibility and high drug loading rate has great significance.
Disclosure of Invention
The invention aims to provide a targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel and a preparation method thereof, and aims to overcome the defects of high toxic and side effects of adriamycin or low adriamycin loading rate and the like in the prior art.
The purpose of the invention can be realized by the following technical scheme:
one of the technical schemes of the invention provides a targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel, which comprises the following raw material components: hyaluronic acid modified cyclodextrin derivatives (HA-. beta. -CD), F127, alpha-cyclodextrin (alpha-CD) and Doxorubicin (DOX).
Further, the preparation process of the HA-beta-CD comprises the following steps:
HA-ADH and p-toluenesulfonyl cyclodextrin derivative (6-OTs-beta-CD) are dispersed in phosphate buffer solution with the pH value of 7.4, then N-methylpyrrolidone is added, and the target product is obtained through reaction, dialysis and freeze drying.
Furthermore, the addition ratio of the HA-ADH, the 6-OTs-beta-CD, the phosphate buffer solution and the N-methylpyrrolidone is (0.5-1.1) g: (0.5-3) g: 100 ml: (8-12) g.
Furthermore, the addition ratio of the HA-ADH, the 6-OTs-beta-CD, the phosphate buffer solution and the N-methylpyrrolidone is 0.5 g: 1 g: 100 ml: 10 g.
Furthermore, the reaction time is 24-30h, and the reaction temperature is 80 ℃.
Further, the preparation process of the HA-ADH comprises the following steps:
dispersing sodium hyaluronate and adipic dihydrazide in deionized water, adjusting pH, adding 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDC & HCl), reacting, dialyzing, and freeze-drying to obtain the target product.
Furthermore, the addition amount ratio of the sodium hyaluronate, the adipic acid dihydrazide, the deionized water and the EDC & HCl is 0.2 g: 1 g: 50 ml: 0.2 g.
Furthermore, EDC & HCl is added to react for 2-3h at 10-25 ℃.
Further, the pH was adjusted to 4.75, and EDC. HCl was added.
Further, the preparation process of the 6-OTs-beta-CD comprises the following steps:
s1, dispersing beta-cyclodextrin in deionized water, adding sodium hydroxide to activate hydroxyl, stirring, dropwise adding acetonitrile solution of paratoluensulfonyl chloride, reacting, and filtering to obtain filtrate;
and S2, adjusting the pH value of the obtained filtrate to 8, standing and filtering for the first time to obtain a solid, then re-dispersing the solid in deionized water, and standing, filtering and drying for the second time to obtain the target product.
Further, in step S1, the mass-to-volume ratio of p-toluenesulfonyl chloride to acetonitrile in the acetonitrile solution of p-toluenesulfonyl chloride is 30.2 g: 90ml, and the ratio of the addition amount of the beta-cyclodextrin, the deionized water, the sodium hydroxide and the acetonitrile solution of the p-toluenesulfonyl chloride is 210 g: (1050-: 34.4 g: 90 ml.
Further, in step S1, the acetonitrile solution of p-toluenesulfonyl chloride is added dropwise to carry out the reaction at the reaction temperature of 10-20 ℃ for 2-2.5 h.
Further, in step S1, the stirring time was 0.5 h.
Furthermore, in step S2, the temperature of the first standing is 4-8 ℃ and the time is 12 h.
Furthermore, in step S2, the temperature of the secondary standing is 4-8 ℃ and the time is 3-4 h.
The second technical scheme of the invention provides a preparation method of the supramolecular hydrogel, which comprises the following steps:
and (3) adding HA-beta-CD and F127 into deionized water under the condition of keeping out of the sun, stirring for the first time, then adding alpha-CD, stirring for the second time, then adding DOX, stirring for the third time, then standing, and freeze-drying to obtain the target product.
Furthermore, the addition ratio of the HA-beta-CD, the F127, the alpha-CD, the DOX and the deionized water is (0.2-0.4) g: 0.2 g: (0.4-0.8) g: 0.16 g: 3 mL.
Furthermore, the temperature in one stirring process is 60-70 ℃ and the time is 4-5 h.
Furthermore, the temperature in the secondary stirring process is 60-70 ℃ and the time is 4-5 h.
Further, the three-time stirring time was 2 hours.
Further, after three times of stirring, the standing time was 12 hours.
In order to reduce the toxic and side effects of the chemotherapy drug adriamycin and prevent the occurrence of drug resistance, the invention changes the dosage form of the adriamycin and delays the duration of the adriamycin in tumor tissues. Firstly, carrying out chemical modification on beta-cyclodextrin, and preparing a tosyl cyclodextrin derivative 6-OTS-beta-CD by utilizing nucleophilic substitution reaction of tosyl chloride on hydroxyl; then, putting hyaluronic acid derivatives HA-ADH and 6-OTS-beta-CD into N-methylpyrrolidone, and performing substitution reaction by using the N-methylpyrrolidone as a reaction catalyst to synthesize HA-beta-CD; and finally, constructing by taking alpha-CD, F127, HA-beta-CD and DOX as construction elements to obtain the hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel. Polyethylene glycol (PEO) segments in F127 form a poly-pseudo-rotaxane structure through the interaction with a host and a guest of cyclodextrin and the hydrogen bond interaction between cyclodextrin molecules. The cyclodextrin penetrates the PEO segment and is arranged according to the pipeline type crystal to form a physical cross-linking point in the gel structure.
Referring to fig. 1, firstly, a subject-object interaction between F127 and HA-beta-CD is used for threading, then an anticancer drug adriamycin molecule is dispersed in a hydrogel precursor solution, and then the interaction between alpha-CD and F127 is used for preparing the targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel. The adriamycin is embedded into the three-dimensional network structure of the hydrogel in a non-covalent bond mode. The hyaluronic acid can effectively thicken and improve the adriamycin loading rate, and the biocompatibility of the hyaluronic acid is particularly excellent.
According to the invention, the hyaluronic acid covalent modified beta-cyclodextrin, F127 and alpha-cyclodextrin are used for constructing the supermolecule hydrogel, and the adriamycin molecules are wrapped in the hydrogel network, so that the load of adriamycin is increased, the toxic and side effects of the adriamycin molecules are reduced, the release time of the drug molecules is effectively prolonged, and the tissue permeability is enhanced.
Compared with the prior art, the invention has the following advantages:
(1) the adriamycin in the supermolecule hydrogel is wrapped in the hydrogel three-dimensional network through the non-covalent effect, a more compact three-dimensional network structure is constructed by the interaction of the chain structure of hyaluronic acid molecules, F127 and alpha-cyclodextrin on the basis of not changing the molecular structure of the adriamycin, the adriamycin molecules can be better wrapped in the hydrogel, the load of the adriamycin is improved, the toxic and side effects of the adriamycin molecules are reduced, the release time of drug molecules can be effectively prolonged, the tissue permeability and the drug effect are enhanced, and a theoretical basis is provided for the follow-up research on the release performance of the adriamycin molecules;
(2) according to the invention, hyaluronic acid is introduced into hydrogel as a targeting group, so that the targeting performance is improved, and a direction is provided for the subsequent research on the targeting performance of drug molecules;
(3) the supermolecule hydrogel disclosed by the invention is easy to obtain raw materials, simple in preparation process, stable in drug-loaded system, easy to regulate and control in properties and better in biocompatibility.
Drawings
FIG. 1 is a diagram of the synthesis route of supramolecular hydrogels of the present invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum of the prodrug molecule HA- β -CD;
FIG. 3 is a nuclear magnetic hydrogen spectrum of an intermediate HA-ADH;
FIG. 4 is a scanning electron microscope image of the drug-loaded hydrogel system prepared in example 2;
FIG. 5 is a graph of the modulus versus frequency for the supramolecular hydrogels of examples 1-4;
FIG. 6 is an X-ray diffraction pattern of drug-loaded hydrogels prepared in examples 1-4;
fig. 7 is a graph showing the release of DOX from drug-loaded hydrogels prepared in examples 1, 3, and 4.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
In the following examples, unless otherwise specified, all the conventional commercially available raw materials or conventional processing techniques in the art are indicated.
Example 1:
a targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel is prepared from alpha-CD, F127, HA-beta-CD and adriamycin (DOX), wherein the adriamycin is embedded into a hydrogel network in a non-covalent manner.
The synthesis procedure of HA-beta-CD used was:
the intermediate HA-beta-CD is further synthesized by reacting a hyaluronic acid derivative HA-ADH with a tosyl modified cyclodextrin derivative 6-OTs-beta-CD, and the method comprises the following specific steps:
0.5g of the hyaluronic acid derivative HA-ADH and 1g of the cyclodextrin derivative 6-OTs-. beta. -CD were dissolved in 100mL of a phosphate buffer solution having a pH of 7.4, and after the dissolution, 10g N-methylpyrrolidone (NMP) was added and the mixture was allowed to react at 80 ℃ for 24 hours. Stopping the reaction, putting the mixture into a dialysis bag, dialyzing the mixture for 72 hours by using a large amount of deionized water, and freeze-drying the dialyzed mixture to obtain white powder HA-beta-CD, wherein the chemical structure of the white powder HA-beta-CD is characterized by 1H NMR (nuclear magnetic resonance), and D2O is used as a solvent. Characterization by nuclear magnetic resonance techniques, as shown in FIG. 2, revealed that HA-. beta. -CD HAs been successfully synthesized. Chemical shifts were used to shift the-CH peak (e) at the 6 position of beta-CD at 4.99ppm and the-CH of hyaluronic acid at 1.93ppm3The peak area ratio of the peak (6') is calculated to obtain the average number of modified beta-CD molecules of 36 per 100 hyaluronic acid units.
Wherein the synthesis steps of the HA-ADH are as follows:
the method comprises the following steps of chemically modifying sodium hyaluronate by adipic acid dihydrazide to prepare the hyaluronic acid derivative HA-ADH, and specifically comprises the following steps:
0.2g of sodium hyaluronate HA (Mw 90000-100000) and 1g of adipic dihydrazide ADH were dissolved in 50mL of distilled water, and after the solutions were dissolved, the pH of the reaction mixture was adjusted to 4.75 by adding 0.1mol/L hydrochloric acid solution. Next, 0.2g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl) was added, and the pH of the reaction mixture was maintained at 4.75 by adding 0.1mol/L hydrochloric acid solution, and checking was performed every 10 minutes. And the reaction was allowed to proceed at 25 ℃ for 2 hours. The reaction was then quenched by adjusting the pH of the reaction mixture to 7 with sodium hydroxide solution. The reacted solution was dialyzed against pure water for two days, and water was changed once for 12 hours. And (4) freeze-drying the liquid obtained by dialysis to obtain a white solid product HA-ADH. Its chemical structure is characterized by 1H NMR, D2O is used as a solvent. Characterization by nuclear magnetic techniques, as shown in FIG. 3, can lead to the conclusion that HA-ADH HAs been successfully synthesized. By chemical shift-CH on ADH at 2.1-2.4ppm2Peak (a, d) and-CH of hyaluronic acid at 1.93ppm3The ratio of the peak areas of the peaks (6') was calculated, and an average of 50 ADH molecules was successfully modified per 100 hyaluronic acid units.
The synthesis procedure of the 6-OTs-beta-CD used was:
210g of beta-CD is added into 1500mL of deionized water, 34.4g of sodium hydroxide is added, stirring is carried out for 0.5h to obtain an activated cyclodextrin solution, 30.2g of paratoluensulfonyl chloride is dissolved into 90mL of acetonitrile and slowly dropped into the cyclodextrin solution, and stirring is carried out for 2h at 15 ℃. Standing, filtering to obtain filtrate, adjusting pH to 8 to generate a large amount of white precipitate, standing in a refrigerator at 4 deg.C for 12h, filtering to obtain white solid, re-dispersing the white solid in water, standing in a refrigerator at 4 deg.C for 3h, filtering, and drying to obtain 6-OTs-beta-CD.
The preparation method of the targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel comprises the following steps:
0.2g HA-. beta. -CD, 0.2g F127 g was placed in a reactor, 3mL deionized water was added, and the mixture was stirred at 60 ℃ for 4 hours. Then 0.4g of alpha-CD is added into the reaction system, stirring is continued for 4h under the condition of 60 ℃, the whole process is carried out under the condition of keeping out of the light, then 0.16g of DOX is added into the hydrogel, and stirring is continued for 2 h. After stirring, slowly cooling the system to room temperature, standing for 12h, and freeze-drying for 12h to obtain the dry targeting hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel.
Example 2:
HA-. beta. -CD used in this example was the HA-. beta. -CD prepared in example 1.
A targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel is prepared from alpha-CD, F127, HA-beta-CD and DOX, and adriamycin is embedded into a hydrogel network in a non-covalent manner. The preparation method of the targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel comprises the following steps:
0.4g HA-. beta. -CD, 0.2g F127 g was placed in a reactor, 3mL deionized water was added, and the mixture was stirred at 60 ℃ for 4 hours. Then 0.4g of alpha-CD was added to the system and stirring was continued for 4h at 60 ℃ with the whole process being carried out in the dark, then 0.16g of DOX was added to the hydrogel and stirring was continued for 2 h. After stirring, slowly cooling the system to room temperature, standing for 12h, and freeze-drying for 12h to obtain the dry targeting hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel.
Example 3:
HA-. beta. -CD used in this example was the HA-. beta. -CD prepared in example 1.
A targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel is prepared from alpha-CD, F127, HA-beta-CD and DOX, and adriamycin is embedded into a hydrogel network in a non-covalent manner. The preparation method of the targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel comprises the following steps:
0.2g HA-. beta. -CD, 0.2g F127 g was placed in a reactor, 3mL deionized water was added, and the mixture was stirred at 60 ℃ for 4 hours. Then 0.6g of α -CD was added to the system and stirring was continued for 4h at 60 ℃ with the whole process being carried out in the dark, then 0.16g of DOX was added to the hydrogel and stirring was continued for 2 h. After stirring, slowly cooling the system to room temperature, standing for 12h, and freeze-drying for 12h to obtain the dry targeting hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel.
Example 4:
HA-. beta. -CD used in this example was the HA-. beta. -CD prepared in example 1.
A targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel is prepared from alpha-CD, F127, HA-beta-CD and DOX, and adriamycin is embedded into a hydrogel network in a non-covalent manner. The preparation method of the targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel comprises the following steps:
0.2g HA-. beta. -CD, 0.2g F127 g was placed in a reactor, 3mL deionized water was added, and the mixture was stirred at 60 ℃ for 4 hours. Then 0.8g of alpha-CD was added to the system and stirring was continued for 4h at 60 ℃ with the whole process being carried out in the dark, then 0.16g of DOX was added to the hydrogel and stirring was continued for 2 h. After stirring, slowly cooling the system to room temperature, standing for 12h, and freeze-drying for 12h to obtain the dry targeting hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel.
As shown in fig. 4, is a scanning electron microscope image of the drug-loaded hydrogel system prepared in example 2. The appearance of the targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel in example 2 is characterized by a field emission Scanning Electron Microscope (SEM), and it can be seen from fig. 4 that the supramolecular hydrogel is a disordered flocculent appearance, which illustrates the successful preparation of the supramolecular hydrogel in terms of substance morphology.
As shown in fig. 5, a plot of modulus versus frequency for the four supramolecular hydrogels prepared in examples 1-4. By analyzing the dynamic scanning curve of the hydrogel, the influence rule of the concentration of the constructed elements on the gel strength can be summarized and concluded. With the continuous change of the frequency, the elastic modulus of the supermolecular hydrogel is basically kept unchanged, and the supermolecular hydrogel shows the unique property of 'solid-like'. As can be seen by comparing the G 'and G' of the hydrogels of the respective groups, the elastic modulus (G ') and the viscous modulus (G') are of the order of magnitude of from the first 10 with increasing concentration of alpha-CD3Pa is gradually increased to 105Pa, and thus can be modulated by modulating the concentration of alpha-CDStrength of supramolecular hydrogels.
As shown in fig. 6, which is an X-ray diffraction pattern of the drug-loaded hydrogels obtained in examples 1 to 4, the four drug-loaded hydrogels were all poly-pseudorotaxane structure, and therefore they are collectively called Hydrogel in the figure. Uniformly mixing HA-beta-CD and F127 by using deionized water, adding alpha-CD and DOX at the temperature of 60 ℃, stirring to uniformly mix the alpha-CD and the DOX, standing and cooling the system to room temperature, and forming the hyaluronic acid-cyclodextrin supramolecular hydrogel with bioactivity after a period of time. This is because the polyethylene glycol (PEO) segment in F127 forms the structure of poly-pseudorotaxane through the interaction with the host and guest of cyclodextrin and the hydrogen bond interaction between cyclodextrin molecules. The cyclodextrin penetrates the PEO segment and is arranged according to the pipeline type crystal to form a physical cross-linking point in the gel structure. The XRD pattern shown in fig. 6 confirms the formation of this polymeric pseudorotaxane structure, and the gel samples showed characteristic diffraction peaks at 2 θ ═ 19.5 ° and 22.7 ° different from HA- β -CD and α -CD, corresponding to planes 210 and 300 of the hexagonal unit cell, respectively, indicating that the cyclodextrin was arranged according to the tunnel type crystal.
As shown in fig. 7, which is a graph of in vitro release of the supramolecular hydrogel with different α -CD contents to the drug doxorubicin in examples 1, 3 and 4, it can be seen from the graph that the supramolecular hydrogels with three different ratios all have good controlled release effect to the anticancer drug doxorubicin, no burst release phenomenon occurs, and the release time can last for more than 60 hours. By comparing the release ratios of the three different ratios of supramolecular hydrogels, the release ratio becomes smaller as the alpha-CD loading of the hydrogel increases. This is because the α -CD and β -CD utilizing cavities present in the hydrogel can still bond DOX molecules through host-guest interactions, thereby slowing the release rate of the drug from the hydrogel, and this interaction is related to the concentration of α -CD in the hydrogel, with higher α -CD concentrations resulting in stronger DOX-cyclodextrin bonding, which in turn results in slower release rates of the drug molecules from the high-loaded hydrogel. Therefore, the release rate of the drug can be controlled by adjusting the content of alpha-CD in the supramolecular hydrogel system, so as to achieve the aim of reasonably controlling the release of the drug.
Example 5:
most of them were the same as in example 1, except that in this example, the ratio of the amounts of HA-ADH, 6-OTs-. beta. -CD, phosphate buffer solution and N-methylpyrrolidone added was adjusted to 1.1 g: 0.5 g: 100 ml: 8 g.
Example 6:
most of them were the same as in example 1, except that in this example, the ratio of the amounts of HA-ADH, 6-OTs-. beta. -CD, phosphate buffer solution and N-methylpyrrolidone added was adjusted to 0.8 g: 3 g: 100 ml: 12 g.
Example 7:
compared with example 1, most of them are the same except that in this example, the reaction time at 80 ℃ for 24 hours is changed to 80 ℃ for 30 hours.
Example 8:
compared with example 1, most of them are the same except that in this example, the reaction time at 80 ℃ for 24 hours is changed to 80 ℃ for 28 hours.
Example 9:
compared to example 1, most of them are the same except that in this example, the 2 hours at 25 ℃ is changed to 3 hours at 10 ℃.
Example 10:
compared to example 1, the majority are the same except that in this example, the 2 hour at 25 ℃ was changed to 2.5 hours at 15 ℃.
Example 11:
compared with example 1, most of the same except that in this example, "take 0.2g HA-beta-CD, 0.2g F127 in the reactor, add 3mL deionized water, stir at 60 ℃ for 4 h. Then 0.4g of alpha-CD is added into the system, and the stirring is continued for 4h under the condition of 60 ℃, and then 0.2g of HA-beta-CD and 0.2g F127 are taken into the reactor, 3mL of deionized water is added, and the stirring is carried out for 5h at the temperature of 70 ℃. Then 0.4g of alpha-CD was added to the system and stirring was continued at 70 ℃ for 5h ".
Example 12:
compared with example 1, most of the same except that in this example, "take 0.2g HA-beta-CD, 0.2g F127 in the reactor, add 3mL deionized water, stir at 60 ℃ for 4 h. Then 0.4g of alpha-CD is added into the system, and the stirring is continued for 4h under the condition of 60 ℃, and then 0.2g of HA-beta-CD and 0.2g F127 are taken into the reactor, 3mL of deionized water is added, and the stirring is carried out for 4.5h at the temperature of 65 ℃. Then 0.4g of alpha-CD was added to the system and stirring was continued at 65 ℃ for 4.5 h'.
Example 13:
compared with example 1, the ratio of the addition amounts of HA-beta-CD, F127, alpha-CD, DOX and deionized water is adjusted to 0.3 g: 0.2 g: 0.4 g: 0.16 g: 3 mL.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. A targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel is characterized by comprising the following raw material components: HA-. beta. -CD, F127,. alpha. -CD, and DOX.
2. The targeted supramolecular hydrogel for carrying hyaluronic acid-cyclodextrin drugs according to claim 1, wherein the preparation process of HA-beta-CD comprises the following steps:
dispersing HA-ADH and 6-OTs-beta-CD in phosphate buffer solution with pH of 7.4, adding N-methylpyrrolidone, reacting, dialyzing, and freeze-drying to obtain the target product.
3. The targeted supramolecular hydrogel carrying hyaluronic acid-cyclodextrin of claim 2, wherein the addition amount ratio of HA-ADH, 6-OTs-beta-CD, phosphate buffer solution and N-methylpyrrolidone is (0.5-1.1) g: (0.5-3) g: 100 ml: (8-12) g;
the addition ratio of the HA-ADH, the 6-OTs-beta-CD, the phosphate buffer solution and the N-methylpyrrolidone is 0.5 g: 1 g: 100 ml: 10g of a mixture;
the reaction time is 24-30h, and the reaction temperature is 80 ℃.
4. The targeted supramolecular hydrogel carrying hyaluronic acid-cyclodextrin of claim 2, wherein the HA-ADH is prepared by the following steps:
and (3) dispersing sodium hyaluronate and adipic dihydrazide in deionized water, adjusting the pH, adding EDC & HCl, reacting, dialyzing, and freeze-drying to obtain the target product.
5. The targeted supramolecular hydrogel carrying hyaluronic acid-cyclodextrin of claim 4, wherein the ratio of the addition amounts of sodium hyaluronate, adipic acid dihydrazide, deionized water and EDC-HCl is 0.2 g: 1 g: 50 ml: 0.2 g;
adding EDC & HCl, reacting at 10-25 deg.C for 2-3 h;
the pH was adjusted to 4.75 and EDC. HCl was added.
6. The targeted supramolecular hydrogel for carrying hyaluronic acid-cyclodextrin drugs according to claim 2, wherein the preparation process of 6-OTs-beta-CD comprises the following steps:
s1, dispersing beta-cyclodextrin in deionized water, adding sodium hydroxide, stirring, dropwise adding acetonitrile solution of paratoluensulfonyl chloride, reacting, and filtering to obtain filtrate;
and S2, adjusting the pH value of the obtained filtrate to 8, standing and filtering for the first time to obtain a solid, then re-dispersing the solid in deionized water, and standing, filtering and drying for the second time to obtain the target product.
7. The targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel of claim 6, wherein in the step S1, the mass-to-volume ratio of p-toluenesulfonyl chloride to acetonitrile in the acetonitrile solution of p-toluenesulfonyl chloride is 30.2 g: 90ml, and the ratio of the addition amount of the beta-cyclodextrin, the deionized water, the sodium hydroxide and the acetonitrile solution of the p-toluenesulfonyl chloride is 210 g: (1050-: 34.4 g: 90 ml;
in the step S1, dropwise adding acetonitrile solution of p-toluenesulfonyl chloride, and reacting at the temperature of 10-20 ℃ for 2-2.5 h;
in step S1, the stirring time was 0.5 h.
8. The method for preparing the targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel according to any one of claims 1 to 7, which comprises the following steps:
and (3) adding HA-beta-CD and F127 into deionized water under the condition of keeping out of the sun, stirring for the first time, then adding alpha-CD, stirring for the second time, then adding DOX, stirring for the third time, then standing, and freeze-drying to obtain the target product.
9. The preparation method of the targeted supramolecular hydrogel for carrying hyaluronic acid and cyclodextrin as claimed in claim 8, wherein the addition amount ratio of HA- β -CD, F127, α -CD, DOX and deionized water is (0.2-0.4) g: 0.2 g: (0.4-0.8) g: 0.16 g: 3 mL.
10. The preparation method of the targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel as claimed in claim 8, wherein the temperature is 60-70 ℃ in one stirring process, and the time is 4-5 hours;
the temperature is 60-70 ℃ in the secondary stirring process, and the time is 4-5 h;
the third stirring time is 2 hours;
after three times of stirring, the standing time is 12 hours.
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