CN111423591A - Amphiphilic graft copolymer based on hyaluronic acid and preparation method and application thereof - Google Patents
Amphiphilic graft copolymer based on hyaluronic acid and preparation method and application thereof Download PDFInfo
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- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
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- A61L2400/00—Materials characterised by their function or physical properties
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Abstract
the invention provides an amphiphilic graft copolymer based on hyaluronic acid, a preparation method and application thereof.
Description
Technical Field
The invention belongs to the technical field of high polymer materials and pharmaceutical preparations, and particularly relates to an amphiphilic graft copolymer based on hyaluronic acid, a preparation method thereof and application thereof in preparation of hemostatic sponges and anticancer drug release carriers.
Background
Cancer is a serious disease threatening human health, and its treatment and diagnosis have been the work focus and difficulty of many biologists, chemists and physicians. The existing cancer treatment means mainly comprise surgical treatment, radiotherapy and chemotherapy, wherein the chemotherapy is an effective measure for clinically treating the cancer at present, most of the used anti-cancer drugs are fat-soluble, and the problems of toxic and side effects, drug resistance and the like exist. Therefore, it is highly desirable to provide an anticancer drug delivery vehicle or a delivery composition comprising the same and an anticancer drug, which can solve the above problems.
the chitosan hemostatic material, although having non-toxic, non-antigenic, antibacterial and biocompatible properties and being degradable and absorbable in vivo, HAs great advantages in developing a rapid hemostatic material, however, the existing chitosan hemostatic material HAs problems of insufficient water absorption capacity, slow wound healing and insufficient adhesion to tissues, and the like, and the Hyaluronic Acid (HA) is a natural linear polysaccharide formed by repeated β - (1 → 4) -D-glucuronic acid and beta- (1 → 3) -N-acetyl-D-glucosamine units.
Disclosure of Invention
In order to solve the problems of the prior art, the present invention provides in a first aspect a hyaluronic acid-based amphiphilic graft copolymer comprising:
(1) Hyaluronic acid as a matrix scaffold;
(2) A deoxycholic acid group grafted onto a first primary alcohol group of hyaluronic acid;
(3) Methoxypolyethylene glycol units grafted onto the carboxyl groups of hyaluronic acid;
(4) an N-acetyl-L-cysteine group grafted onto the second primary alcohol group of hyaluronic acid.
in a second aspect, the present invention provides a process for preparing the amphiphilic graft copolymer of the first aspect of the present invention, which is prepared by reacting hyaluronic acid, deoxycholic acid, N-acetyl-L-cysteine, and methoxypolyethylene glycol as raw materials.
In a third aspect, the present invention provides a hemostatic sponge made from the amphiphilic graft copolymer of the first aspect of the present invention or made by the method of the second aspect of the present invention.
In a fourth aspect, the present invention provides an anticancer drug delivery vehicle prepared from the amphiphilic graft copolymer of the first aspect of the present invention or the amphiphilic graft copolymer prepared by the method of the second aspect of the present invention. Preferably, the anticancer drug is selected from the group consisting of docetaxel, paclitaxel, epirubicin, and camptothecin.
In a fifth aspect, the present invention provides the use of the amphiphilic graft copolymer of the first aspect of the present invention or the amphiphilic graft copolymer prepared by the method of the second aspect of the present invention in the preparation of a hemostatic sponge or an anticancer drug release carrier; preferably, the anticancer drug is selected from the group consisting of docetaxel, paclitaxel, epirubicin, and camptothecin.
Compared with the prior art, the invention has the following more prominent beneficial effects:
(1) The amphiphilic graft copolymer of the hyaluronic acid derivative is used as a drug carrier, has high drug loading rate, high entrapment rate, long and stable in-vivo circulation, increased drug utilization rate, good biocompatibility, small toxic and side effects and is degradable in vivo.
(2) The invention provides a tumor tissue microenvironment based on high-concentration biological reductive glutathione, selects the amphiphilic hyaluronic acid derivative containing sulfydryl, the material is easy to form disulfide bonds in an oxidation environment, and the disulfide bonds are opened by utilizing an oxidation-reduction mechanism in the tumor tissue microenvironment, so that the rapid targeted release of the anticancer drug in a living body can be realized.
(3) The invention takes polyethylene glycol and hyaluronic acid as main hydrophilic ends of an amphiphilic polymer drug carrier, takes hyaluronic acid as a target head, can actively target to the surface of a tumor cell, is combined with a CD44 receptor on the surface of the tumor cell and enters the tumor cell through the endocytosis of the cell, and overcomes the problem of low cell uptake capacity of a common carrier micelle carrier.
(4) The drug carrier disclosed by the invention is simple and convenient to prepare, has good biocompatibility and wide raw material sources, has multiple functional groups in a repeating unit, is easy to modify the structure, can quickly generate redox action in tumor cells to release the drug, thereby generating high-efficiency treatment effect, and has huge application potential in the controlled release of the drug.
(5) After the hyaluronic acid derivative disclosed by the invention is prepared into the hemostatic sponge, the water absorption capacity is large, and the water absorption speed is high.
Drawings
FIG. 1 is a scheme showing the synthesis scheme of mPEG-hyaluronic acid-N-acetyl-L-cysteine-deoxycholic acid in example 1.
FIG. 2 is an IR spectrum of the final product of example 1.
FIG. 3 is a NMR spectrum of the final product of example 1.
Detailed Description
The technical solution of the present invention is further defined below with reference to the specific embodiments, but the scope of the claims is not limited to the description.
As described above, the present invention provides in a first aspect a hyaluronic acid-based amphiphilic graft copolymer comprising:
(1) Hyaluronic acid as a matrix scaffold;
(2) A deoxycholic acid group grafted onto a first primary alcohol group of hyaluronic acid;
(3) Methoxy polyethylene glycol units grafted to the carboxyl groups of hyaluronic acid;
(4) an N-acetyl-L-cysteine group grafted onto the second primary alcohol group of hyaluronic acid.
in the present invention, the position of the first primary alcohol group grafted with a deoxycholic acid group, the carboxyl group grafted with a methoxypolyethylene glycol unit, and the second primary alcohol group grafted with an N-acetyl-L-cysteine group on the backbone is not particularly limited, and the first primary alcohol group and the second primary alcohol group are used only for distinguishing one from another, and there is no limitation on the order and importance thereof on the backbone.
In some preferred embodiments, the amphiphilic graft copolymer has a molecular structure as shown below:
Wherein n is 8 to 453 (e.g., 50, 65, 80), and m is 7 to 659 (e.g., 100, 150, 200).
In further preferred embodiments, the value of n is such that the average molecular weight of the methoxypolyethylene glycol units is from 350 to 20000Da, for example 500, 1000, 2000, 5000, 10000 or 15000 Da.
In further preferred embodiments, the value of m is such that the hyaluronic acid has an average molecular weight of 5000-500000Da, such as 10000, 15000, 20000 or 25000 Da.
the HA used for chemical modification includes carboxyl, hydroxyl and amino groups resulting from N-acetyl deacetylation, and can be used for chemical modification, for example, by esterification, crosslinking, grafting, and like modifying means.
in addition, the inventors have found that modification of HA improves the stability of HA and results in a derivative having superior properties, in which methoxy polyethylene glycol (mPEG) HAs good hydrophilicity, biocompatibility, nontoxicity and nonimmunogenicity, and that it is also a three-dimensional protective body of nanocarriers, can extend the circulation time of nanocarriers in vivo, HAs good compatibility with human tissues, HAs little toxic and side effects, HAs low irritation, and the like.
in a second aspect, the present invention provides a process for preparing the amphiphilic graft copolymer of the first aspect of the present invention, which is prepared by reacting hyaluronic acid, deoxycholic acid, N-acetyl-L-cysteine, and methoxypolyethylene glycol as raw materials.
in some preferred embodiments, the method comprises the steps of (1) synthesizing HA-mPEG using hyaluronic acid and methoxypolyethylene glycol, (2) synthesizing DCA-HA-mPEG using deoxycholic acid and the HA-mPEG, and (3) synthesizing NAC-HA-mPEG-DCA as the amphiphilic graft copolymer using N-acetyl-L-cysteine and the DCA-HA-mPEG, wherein HA represents hyaluronic acid as a parent backbone, DCA represents a cholic acid group, mPEG represents a methoxypolyethylene glycol unit, and NAC represents an N-acetyl-L-cysteine group.
In other preferred embodiments, in step (1), the HA-mPEG is isolated after dissolving hyaluronic acid in a first reaction solvent, adding a first catalyst, catalyzing at 0-60 ℃ (e.g., 10, 20, 30, 40, or 50 ℃) for 0.5-24 hours (e.g., 1, 3, 6, 9, 12, 15, 18, or 21 hours), then adding methoxypolyethylene glycol, reacting at 0-60 ℃ (e.g., 10, 20, 30, 40, or 50 ℃) for 2-96 hours (e.g., 2, 6, 12, 24, 48, 60, 72, or 84 hours) with stirring.
in other preferred embodiments, in step (2), the NAC-HA-mPEG is isolated after dissolving the N-acetyl-L-cysteine in the second reaction solvent, adding the second catalyst, catalyzing at 0-60 ℃ (e.g., 10, 20, 30, 40, or 50 ℃) for 0.5-24 hours (1, 3, 6, 9, 12, 15, 18, or 21 hours), adding the HA-mPEG, and reacting at 0-60 ℃ (e.g., 10, 20, 30, 40, or 50 ℃) for 2-96 hours (e.g., 2, 6, 12, 24, 48, 60, 72, or 84 hours) with stirring.
In other preferred embodiments, in step (3), deoxycholic acid is dissolved in a third reaction solvent, a third catalyst is added, the mixture is catalyzed at 0-60 ℃ (e.g., 10, 20, 30, 40 or 50 ℃) for 0.5-24 hours, NAC-HA-mPEG is added, and after stirring at 20-80 ℃ (e.g., 20, 30, 40, 50, 60 or 70 ℃) for 2-96 hours (e.g., 2, 6, 12, 24, 48, 60, 72 or 84 hours), NAC-HA-mPEG-DCA is isolated.
In further preferred embodiments, the value of n is such that the average molecular weight of the methoxypolyethylene glycol units is from 350 to 20000Da, for example 500, 1000, 2000, 5000, 10000 or 15000 Da.
In further preferred embodiments, the value of m is such that the hyaluronic acid has an average molecular weight of 5000-500000Da, such as 10000, 15000, 20000 or 25000 Da.
In other preferred embodiments, the first reaction solvent is selected from the group consisting of water, formamide, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, and N, N-dimethylacetamide, and preferably, the first reaction solvent is selected from the group consisting of formamide, N-dimethylformamide, tetrahydrofuran, and N, N-dimethylacetamide.
In other preferred embodiments, the second reaction solvent is selected from the group consisting of water, formamide, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, and N, N-dimethylacetamide, and preferably, the second reaction solvent is selected from the group consisting of formamide, N-dimethylformamide, tetrahydrofuran, and N, N-dimethylacetamide.
In other preferred embodiments, the third reaction solvent is selected from the group consisting of water, formamide, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, and N, N-dimethylacetamide, and preferably, the third reaction solvent is selected from the group consisting of formamide, N-dimethylformamide, tetrahydrofuran, and N, N-dimethylacetamide.
The first catalyst, the second catalyst, and the third catalyst are independently selected from the group consisting of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), NHS (N-hydroxysuccinimide), DMAP (4-dimethylaminopyridine), DCC (dicyclohexylcarbodiimide). The first catalyst, the second catalyst and the third catalyst may be the same or different. For example, the first catalyst may be selected from the group consisting of EDC, NHS, DCC, and DMAP; the second catalyst may be selected from the group consisting of EDC, NHS, DCC, DMAP; the third catalyst may be a group consisting of EDC, NHS and DCC.
In other preferred embodiments, in step (1), the molar ratio of the carboxyl groups of the hyaluronic acid to the hydroxyl groups of the methoxypolyethylene glycol is (1:10) to (100:1), for example 100:1, 50:1, 10:1, 1:5 or 1: 10. Additionally or alternatively, the molar ratio of the first catalyst to the carboxyl groups of the hyaluronic acid is (1:10) to (10:1), for example 1:0.1, 1:0.5, 1:1, 1:5 or 1: 10.
in other preferred embodiments, in step (2), the molar ratio of N-acetyl-L-cysteine to the hydroxyl groups of the HA-mPEG is (1:100) to (10:1), such as 1:1, 10:1, 1:50 or 1:100, additionally or further alternatively the molar ratio of the second catalyst to N-acetyl-L-cysteine is (1:10) to (10:1), such as 1:0.1, 1:0.5, 1:1, 1:5 or 1: 10.
In other preferred embodiments, in step (3), the molar ratio of deoxycholic acid to hydroxyl groups of the NAC-HA-mPEG is (1:100) to (10:1), for example 1:0.1, 1:0.5, 1:1, 1:5 or 1: 10. Additionally or alternatively, the molar ratio of the third catalyst to deoxycholic acid is (1:10) to (10:1), for example 1:0.1, 1:0.5, 1:1, 1:5 or 1: 10.
In some more specific embodiments, the method comprises the steps of:
(1) Synthesis of HA-mPEG: dissolving hyaluronic acid in a first reaction solvent, adding a first catalyst, and catalyzing at 0-60 ℃ for 0.5-24 hours. Then adding mPEG, stirring and reacting for 2-96 hours at the temperature of 0-60 ℃, dialyzing and drying to obtain the HA-mPEG.
(2) and (2) synthesizing NAC-HA-mPEG, namely dissolving N-acetyl-L-cysteine in a second reaction solvent, adding a second catalyst, catalyzing at 0-60 ℃ for 0.5-24 hours, adding the HA-mPEG derivative, stirring and reacting at 0-60 ℃ for 2-96 hours, dialyzing, and drying to obtain the NAC-HA-mPEG.
(3) Synthesis of NAC-HA-mPEG-DCA: and dissolving deoxycholic acid in a third reaction solvent, adding a third catalyst, catalyzing for 0.5-24 hours at 0-60 ℃, then adding the NAC-HA-mPEG, stirring for 12-96 hours at 20-80 ℃, dialyzing, purifying and freeze-drying a reaction product to obtain the NAC-HA-mPEG-DCA serving as the amphiphilic graft copolymer.
The amphiphilic graft copolymer based on hyaluronic acid (sometimes referred to as hyaluronic acid derivative) of the present invention can be used as a material for hemostatic sponges. Accordingly, in a third aspect, the present invention provides a haemostatic sponge made from an amphiphilic graft copolymer according to the first aspect of the invention or made by the process according to the second aspect of the invention. When the hemostatic sponge is prepared, the amphiphilic graft copolymer can be suspended in water to prepare an aqueous suspension, then calcium chloride is added for crosslinking, and finally the hemostatic sponge is obtained by freeze-drying. For example, the amphiphilic graft copolymer can be prepared into a 200mg/ml solution, and after being added with 30mg/ml calcium chloride for crosslinking for 2 hours, the solution is lyophilized to obtain the NAC-HA-mPEG-DCA hemostatic sponge.
In a fourth aspect, the present invention provides an anticancer drug delivery vehicle prepared from the amphiphilic graft copolymer of the first aspect of the present invention or the amphiphilic graft copolymer prepared by the method of the second aspect of the present invention. The amphiphilic graft copolymer can be used for encapsulating anticancer drugs, so that a multistage targeting polymer which releases the anticancer drugs in tumor cells under the triggering of redox is prepared. Accordingly, the present invention may also provide an anticancer drug releasing composition comprising: (a) an amphiphilic graft copolymer according to the first aspect of the present invention or obtainable according to the second aspect of the present invention; and (b) an anticancer drug entrapped in the amphiphilic graft copolymer. The anticancer drug can realize multi-stage targeted redox-triggered drug release. Therefore, the anti-cancer drug release carrier or the anti-cancer drug containing the carrier has the characteristics of multi-stage tumor targeting, enhancement of in vivo long circulation and redox-triggered drug release (sensitive to redox) in tumor cells.
In preparing the anticancer drug preparation, an anticancer drug such as paclitaxel may be dissolved in a solvent such as dichloromethane to prepare a paclitaxel solution. In addition, an aqueous solution of the amphiphilic graft copolymer was prepared. Then, the paclitaxel solution was added dropwise to the amphiphilic graft copolymer aqueous solution while stirring. After the dropwise addition, the stirring is continued so that the anticancer drug is sufficiently loaded in the amphiphilic graft copolymer. Then, the resultant is filtered to remove the aggregates of the free anticancer drug not being entrapped and the amphiphilic graft copolymer as a carrier, thereby preparing the anticancer drug releasing composition.
In a fifth aspect, the present invention provides the use of the amphiphilic graft copolymer of the first aspect of the present invention or the amphiphilic graft copolymer prepared by the method of the second aspect of the present invention in the preparation of a hemostatic sponge or an anticancer drug release carrier. It is preferable that the first and second liquid crystal layers are formed of,
In various embodiments of the present reference to the anticancer drug, the anticancer drug may be selected from the group consisting of docetaxel, paclitaxel, epirubicin, and camptothecin.
the invention provides a hyaluronic acid derivative and a preparation method and application thereof, wherein hyaluronic acid is used as a matrix skeleton, and deoxycholic acid is used for modifying the hyaluronic acid to prepare the amphiphilic hyaluronic acid derivative, on the basis, N-acetyl-L-cysteine and mPEG are used for modifying the hyaluronic acid to form a novel material which has good biocompatibility and can be used for carrying medicine and preparing hemostatic sponges.
Examples
The invention will be further illustrated by the following examples, to which, however, the scope of the invention as claimed is not limited.
Example 1
This example prepared a hyaluronic acid-based amphiphilic graft copolymer by a method comprising the steps of:
(1) Synthesis of hyaluronic acid-linked mPEG (abbreviated as HA-mPEG): dissolving hyaluronic acid in a first reaction solvent, adding EDC and NHS as first catalysts, catalyzing for 2 hours at 25 ℃, adding mPEG, stirring and reacting for 10 hours at 30 ℃, dialyzing, centrifuging, collecting products, and drying to obtain the mPEG connected with hyaluronic acid, namely HA-mPEG.
(2) the synthesis of NAC-DCA-mPEG comprises the steps of dissolving N-acetyl-L-cysteine in a second reaction solvent, using EDC and NHS as second catalysts, catalyzing at 10 ℃ for 2 hours, adding HA-mPEG, stirring at 35 ℃ for reacting for 15 hours, collecting a product, dialyzing the product, and freeze-drying to obtain NAC-HA-mPEG.
(3) Synthesis of NAC-HA-mPEG-DCA: and dissolving deoxycholic acid in a third reaction solvent, adding EDC and NHS as a third catalyst, catalyzing for 2 hours at 15 ℃, adding NAC-HA-mPEG, stirring for 96 hours at 80 ℃, dialyzing the reaction product for 13 hours, and freeze-drying to obtain NAC-HA-mPEG-DCA.
In this example, the average molecular weight of the HA is 9 kDa; the average molecular weight of the mPEG is 2000 Da. The first reaction solvent in the step (1) is water; the second reaction solvent in the step (2) is DMSO; the third reaction solvent in step (3) is formamide.
In step (1) of this example, the molar ratio of carboxyl groups of hyaluronic acid to hydroxyl groups of mPEG was 1: 10; the molar ratio of the total usage of EDC and NHS to the carboxyl groups of hyaluronic acid is 1: 10; the molar ratio of EDC to NHS was 1: 1.5.
in step (2) of this example, the molar ratio of N-acetyl-L-cysteine to the hydroxyl groups of HA-mPEG was 1:4, the molar ratio of N-acetyl-L-cysteine to the total amount of EDC and NHS was 3:5, and the molar ratio of EDC to NHS was 2: 1.
In step (3) of this example, the molar ratio of deoxycholic acid to hydroxyl groups of NAC-HA-mPEG was 3: 5; the molar ratio of deoxycholic acid to the total amount of EDC and NHS is 1: 5; the molar ratio of EDC to NHS was 4: 1.
The inventor finally carries out infrared detection and nuclear magnetic detection on the finally obtained product NAC-HA-mPEG-DCA, and the results are shown in figures 2 and 3.
In the infrared spectrum shown in FIG. 2, it is located at 3341cm -1The absorption peak at (A) is ascribed to the absorption peak of-OH on Hyaluronic Acid (HA), 2865cm -1Belongs to an absorption peak of-CH 3 on mPEG and is 1656cm -1The absorption peak is the absorption peak of C-O on NAC and is 2935cm -1The stretching vibration absorption peak at-CH 3 belongs to the characteristic absorption peak of DCA, thereby proving that NAC-HA-mPEG-DCA HAs been successfully synthesized.
In the NMR spectrum shown in FIG. 3, 2.13ppm was assigned to the characteristic absorption peak of-CH 3 on HA, 2.83 was assigned to the characteristic absorption peak of-CH 3 on mPEG, 2.66ppm was assigned to the characteristic absorption peak of-CH 2 on NAC, and 0.86ppm was assigned to the characteristic absorption peak of-CH 2 on DCA, thereby again demonstrating that NAC-HA-mPEG-DCA HAs been successfully synthesized.
Example 2
This example prepared a hyaluronic acid-based amphiphilic graft copolymer by a method comprising the steps of:
(1) Synthesis of HA-mPEG: dissolving hyaluronic acid in a first reaction solvent, catalyzing at 10 ℃ for 10 hours by using DCC as a first catalyst, adding mPEG, stirring and reacting at 60 ℃ for 3 hours, dialyzing for 1 hour, centrifuging, collecting a product, and drying to obtain the mPEG connected with the hyaluronic acid, namely HA-mPEG.
(2) the synthesis of the NAC-HA-mPEG comprises the steps of dissolving N-acetyl-L-cysteine in a second reaction solvent, catalyzing for 2 hours at 10 ℃ by using DCC as a second catalyst, adding the HA-mPEG, stirring and reacting for 24 hours at 15 ℃, collecting a product, dialyzing for 4 hours, and freeze-drying to obtain the NAC-HA-mPEG.
(3) Synthesis of NAC-HA-mPEG-DCA: and dissolving deoxycholic acid in a third reaction solvent, catalyzing for 1 hour at 5 ℃ by using DCC as a third catalyst, adding NAC-HA-mPEG, stirring for 60 hours at 60 ℃, dialyzing a reaction product for 48 hours, and performing freeze drying treatment to obtain NAC-HA-mPEG-DCA.
In this example, the average molecular weight of the HA is 50 kDa; the average molecular weight of mPEG is 20000 Da. The first reaction solvent in the step (1) is N, N-dimethylformamide; the second reaction solvent in the step (2) is N, N-dimethylacetamide; the third reaction solvent in the step (3) is tetrahydrofuran.
In step (1) of this example, the molar ratio of carboxyl groups of hyaluronic acid to hydroxyl groups of mPEG was 1: 10; the molar ratio of DCC to carboxyl groups of hyaluronic acid was 1: 10.
in step (2) of this example, the molar ratio of N-acetyl-L-cysteine to the hydroxyl groups of HA-mPEG was 1:4 and the molar ratio of N-acetyl-L-cysteine to DCC was 2: 1.
In step (3) of this example, the molar ratio of deoxycholic acid to hydroxyl groups of NAC-HA-mPEG was 1: 5; the molar ratio of deoxycholic acid to DCC was 1: 3.
Example 3
This example prepared a hyaluronic acid-based amphiphilic graft copolymer by a method comprising the steps of:
(1) Synthesis of HA-mPEG: dissolving hyaluronic acid in a first reaction solvent, adding DMAP (dimethyl formamide) serving as a first catalyst, catalyzing at 55 ℃ for 1 hour, adding mPEG, stirring at 45 ℃ for reacting for 10 hours, dialyzing, centrifuging, collecting a product, and drying to obtain HA-mPEG.
(2) the synthesis of the NAC-HA-mPEG comprises the steps of dissolving N-acetyl-L-cysteine in a second reaction solvent, catalyzing for 2 hours at 25 ℃ by taking DMAP as a second catalyst, adding the HA-mPEG, stirring and reacting for 15 hours at 35 ℃, collecting a product, dialyzing the product, and freeze-drying to obtain the NAC-HA-mPEG.
(3) Synthesis of NAC-HA-mPEG-DCA: and dissolving deoxycholic acid in a third reaction solvent, adding EDC and NHS as third catalysts, catalyzing for 2 hours at 35 ℃, adding NAC-HA-mPEG, stirring for 96 hours at 30 ℃, dialyzing a reaction product for 13 hours, and performing freeze drying treatment to obtain NAC-HA-mPEG-DCA.
In this example, the average molecular weight of the HA is 200000 Da; the average molecular weight of the mPEG is 4000 Da. The first reaction solvent in the step (1) is DMSO; the second reaction solvent in the step (2) is N, N-dimethylformamide; the third reaction solvent in the step (3) is a mixed solvent of DMSO and water (volume ratio is 1:1, v/v).
In step (1) of this example, the molar ratio of carboxyl groups of hyaluronic acid to hydroxyl groups of mPEG was 10: 1; the molar ratio of DMAP to mPEG hydroxyl was 1: 10.
in step (2) of this example, the molar ratio of N-acetyl-L-cysteine to the hydroxyl groups of HA-mPEG was 1:4 and the molar ratio of N-acetyl-L-cysteine to DMAP was 3: 5.
In step (3) of this example, the molar ratio of deoxycholic acid to hydroxyl groups of NAC-HA-mPEG was 1: 5; the mole ratio of deoxycholic acid to DMAP was 1: 5.
Comparative example 1
Proceeding to step (1) in the same manner as in example 1, HA-mPEG was obtained.
Comparative example 2
Proceeding to step (2) in the same manner as in example 1, NAC-HA-mPEG was prepared.
Preparation examples 1 to 3
In preparation examples 1 to 3, the amphiphilic graft copolymer prepared in examples 1 to 3 was suspended in water to prepare a 200mg/ml solution, and after adding 30mg/ml calcium chloride for crosslinking for 2 hours, NAC-HA-mPEG-DCA hemostatic sponge (i.e., hyaluronic acid derivative hemostatic sponge) was obtained by lyophilization.
Comparative preparation example 1
Suspending the same hyaluronic acid as used in example 1 in water to prepare a 200mg/ml solution, adding 30mg/ml calcium chloride for crosslinking for 2h, and freeze-drying to obtain the hyaluronic acid hemostatic sponge.
Comparative preparation example 2
The same procedure as in preparation example 1 was conducted, except that HA-mPEG prepared in comparative example 1 was used in place of NAC-HA-mPEG-DCA to prepare a hemostatic sponge.
Comparative preparation example 3
The same procedure as in preparation example 1 was conducted, except that NAC-HA-mPEG prepared in comparative example 1 was used in place of NAC-HA-mPEG-DCA to prepare a hemostatic sponge.
Testing the water absorption capacity of the hemostatic sponge: the hemostatic sponges prepared in preparations 1 to 3 and comparative preparations 1 to 3 were soaked in physiological saline for 10 minutes, and then water absorption rates thereof were measured. To test the rapid water absorption capacity of these hemostatic sponges, they were also tested for water absorption capacity within 5 seconds. The results are shown in table 1 below.
TABLE 1 Water absorption Properties of hemostatic sponges
| Examples of the invention | NAC-HA-mPEG-DCA | Multiple of water absorption (10min) | Multiple of water absorption (5s) |
| Preparation example 1 | Example 1 | 28 | 7 |
| Preparation example 2 | Example 2 | 30 | 6 |
| Preparation example 3 | Example 3 | 30 | 9 |
| Comparative preparation example 1 | Hyaluronic acid | 21 | 4 |
| Comparative preparation example 2 | Comparative example 1 | 27 | 13 |
| Comparative preparation example 3 | Comparative example 2 | 33 | 12 |
As can be seen from the data in the above table, the hemostatic sponges prepared using preparation examples 1 to 3 can absorb more than 25 times their own mass of water within 10 minutes. Within 5s, the hemostatic sponges prepared by the copolymers prepared in examples 1 to 3 can absorb more than 6 times of water of their own mass in 5s, which is far more than the water absorbed by the hyaluronic acid hemostatic sponges prepared in comparative examples 1 to 3 in the same time, and presumably because the surfaces of the prepared hemostatic sponges have PEG structures, the prepared hemostatic sponges are more hydrophilic and have higher water absorption speed. The above results show that the hemostatic sponges prepared from the materials of examples 1 to 3 of the present invention have faster water absorption effect.
Preparation examples 4 to 12
these preparation examples relate to the use of the hyaluronic acid-based amphiphilic graft copolymer of the present invention as an anticancer drug release carrier, in which an anticancer drug release composition comprising the amphiphilic graft copolymer and an anticancer drug entrapped by the amphiphilic graft copolymer is prepared, the anticancer drug release composition is nanoparticles comprising N-acetyl-L-cysteine-hyaluronic acid-mPEG-deoxycholic acid (i.e., NAC-HA-mPEG-DCA) entrapping Paclitaxel (PTX), first, PTX of various concentrations is dissolved in 0.5ml of dichloromethane to prepare a PTX solution, and second, NAC-HA-mPEG-DCA prepared in examples 1 to 3 (each 10mg) is dissolved in 10ml of distilled water, and under stirring conditions (stirring speed of 100rpm), a PTX solution is added dropwise, stirring is continued for 12 hours at 100rpm, so that PTX is sufficiently taken into the NAC-HA-mPEG-DCA, after which, rotary evaporation is performed at 35 ℃, dichloromethane is removed to obtain paclitaxel-loaded nanoparticles, and the anticancer drug release composition is prepared by filtering a microporous membrane to remove the weight percentage of the anticancer drug-loaded nanoparticles and the anticancer drug release composition is measured by using a filter membrane to obtain anticancer drug release composition.
Comparative preparation examples 4 and 5
An anticancer drug delivery composition was prepared in substantially the same manner as in preparation example 4, except that in comparative preparation examples 4 and 5, HA-mPEG and NAC-HA-mPEG prepared in comparative examples 1 and 2, respectively, were used instead of NAC-HA-mPEG-DCA.
Safety test
in order to evaluate whether the prepared anticancer drug release composition is safe to be used for intravenous injection administration, an in vitro hemolytic experiment is carried out on the prepared anticancer drug release composition, ear vein blood of New Zealand white rabbits is taken, fibrinogen is removed, normal saline is added for washing and centrifugation to prepare 2% (v/v) suspension, 2.5ml of erythrocyte suspension and 2.5ml of the anticancer drug release composition are uniformly mixed, the mixed solution is incubated for 4 hours at 37 ℃, then centrifuged for 10 minutes at the rotating speed of 3000r/min, supernate is collected, the absorbance of a sample is measured at 540nm, normal saline and distilled water are taken, the same method is carried out, the hemolysis percentage is calculated by respectively taking the normal saline and the distilled water as negative and positive controls, and the hemolysis percentage (the absorbance of the sample absorbance-negative control)/(the absorbance of the positive control-negative control) is × 100%, and the results are shown in the following table 2.
TABLE 2 encapsulation effect of anticancer drug and safety of anticancer drug delivery composition prepared therefrom
| Examples of the invention | Carrier | PTX/mg | Particle size/nm | Encapsulation efficiency/% | Loading capacity/% | Percent hemolysis/%) |
| Preparation example 4 | Example 1 | 3 | 161.9 | 86.9 | 16.2 | 3.5 |
| Preparation example 5 | Example 1 | 2 | 152.3 | 88.2 | 11.4 | 3.0 |
| Preparation example 6 | Example 1 | 4 | 170.6 | 81.3 | 20.5 | 4.0 |
| Preparation of Example 7 | Example 2 | 3 | 199.5 | 87.1 | 16.3 | 3.4 |
| Preparation example 8 | Example 2 | 2 | 191.9 | 89.7 | 11.6 | 2.9 |
| Preparation example 9 | Example 2 | 4 | 201.8 | 83.9 | 19.9 | 3.8 |
| Preparation example 10 | Example 3 | 3 | 221.8 | 92.3 | 15.6 | 3.4 |
| Preparation example 11 | Example 3 | 2 | 202.5 | 94.1 | 11.3 | 3.2 |
| Preparation example 12 | Example 3 | 4 | 231.2 | 90.1 | 20.7 | 4.0 |
| Comparative preparation example 4 | Comparative example 1 | 3 | 81.6 | 38.6 | 5.8 | 3.6 |
| Comparative preparation example 5 | Comparative example 2 | 3 | 103.8 | 42.2 | 7.5 | 3.5 |
The results show that all of the formulations of examples 4 to 12 have higher encapsulation and drug loading and particle sizes of less than 250nm, with the encapsulation decreasing and the particle size increasing with increasing initial drug loading.
In addition, when the paclitaxel concentration is in the range of 0-200. mu.g/ml, the hemolytic activity of the anticancer drug delivery composition is almost negligible, and the percentage of hemolysis thereof does not exceed 4.0%, indicating that the formulation has good hemolytic safety.
Test for antitumor Effect ：
a cervical cancer U14 tumor-bearing mouse model was constructed, tumor-bearing mice were randomly divided into 4 groups of 6 animals each, animals in each group were labeled and administered, and the administration was started, and the normal saline, the anticancer drug-releasing composition (dose 15mg/kg) prepared in preparation example 4 and comparative preparation examples 4 and 5 (treatment group) were administered, respectively, and the day was designated as administration day 1, the preparation was administered once every 3 days by tail vein injection, and 4 times of continuous administration were performed, and the animals were sacrificed, tumor masses were exfoliated, weighed, and the tumor-inhibition rate was calculated (normal saline group average tumor weight-treatment group average tumor weight)/normal saline group average tumor weight × 100%.
In addition, the present inventors performed experiments using H22 liver cancer mice. First, the mice were randomly divided into 4 groups of 6 animals each, and the animals of each group were individually numbered. Then, administration was started in which the anticancer drug releasing compositions prepared in physiological saline (control group), preparation example 4 and comparative preparation examples 4 and 5 (dose 15mg/kg) (treatment group) were administered, respectively, and the day was taken as the administration day 1. The medicine is administered by tail vein injection once every 3 days, and is administered for 4 times continuously. After 4 dosing cycles, animals were sacrificed, tumor masses were stripped, weighed, and tumor inhibition rates were calculated. As a result, it was found that the anticancer drug delivery composition prepared in preparation example 4 had an average tumor suppression rate of 64.2%, and thus had an obvious tumor growth suppression effect on liver cancer.
in addition, experiments were also conducted using L ewis lung cancer-bearing mice in which mice were randomly divided into 4 groups of 6 animals each, and animals of each group were individually numbered, at the time of administration, physiological saline, the anticancer drug-releasing compositions (dose 15mg/kg) prepared in preparation example 4 and comparative preparation examples 4 and 5 were administered (treatment groups), respectively, on the day of administration, day 1, once every 3 days of tail vein injection, 4 times of continuous administration, animals were sacrificed, tumor masses were peeled, weighed, and tumor-inhibiting rates were calculated, and as a result, it was found that the average tumor-inhibiting rate of the anticancer drug-releasing composition prepared in preparation example 4 was 71.4%, and thus, it had an obvious tumor growth-inhibiting effect on lung cancer.
TABLE 3 tumor inhibition Rate of anticancer drug Release compositions
| Mouse model | Preparation example 4 tumor inhibition Rate/%) | Comparative preparation example 4 tumor inhibition/%) | Comparative preparation example 5 tumor inhibition/%) |
| U14 tumor-bearing mouse | 69.8％ | 16.7％ | 23.1％ |
| H22 liver cancer mouse | 64.2％ | 14.5％ | 17.6％ |
| L ewis Lung cancer tumor | 71.4％ | 18.2％ | 19.9％ |
As can be seen from the data results shown in table 3 above, the anticancer drug release composition prepared by the present invention has significant inhibitory effect (tumor inhibition rate of 69.8%) on tumor cells of U14 mice, and also has significant inhibitory effect on other cancer cells such as liver cancer and lung cancer, and the tumor inhibition rates are 64.2% and 71.4%, respectively.
It should be noted that the above examples and test examples are only for further illustration and understanding of the technical solutions of the present invention, and are not to be construed as further limitations of the technical solutions of the present invention, and the invention which does not highlight essential features and significant advances made by those skilled in the art still belongs to the protection scope of the present invention.
Claims (10)
1. A hyaluronic acid-based amphiphilic graft copolymer, comprising:
(1) Hyaluronic acid as a matrix scaffold;
(2) A deoxycholic acid group grafted onto a first primary alcohol group of hyaluronic acid;
(3) Methoxypolyethylene glycol units grafted onto the carboxyl groups of hyaluronic acid;
(4) an N-acetyl-L-cysteine group grafted onto the second primary alcohol group of hyaluronic acid.
2. The amphiphilic graft copolymer of claim 1, wherein the amphiphilic graft copolymer has a molecular structure as shown below:
Wherein n is 8-453, and m is 7-659;
Preferably, the average molecular weight of the methoxypolyethylene glycol units is 350-20000 Da; and/or the average molecular weight of the hyaluronic acid is 5000-500000 Da.
3. a process for preparing the amphiphilic graft copolymer of claim 1 or 2, wherein the amphiphilic graft copolymer is prepared by reacting hyaluronic acid, deoxycholic acid, N-acetyl-L-cysteine and methoxypolyethylene glycol as raw materials.
4. A method according to claim 3, characterized in that the method comprises the steps of:
(1) Synthesizing HA-mPEG by using hyaluronic acid and methoxypolyethylene glycol;
(2) Synthesizing DCA-HA-mPEG using deoxycholic acid and the HA-mPEG;
(3) synthesizing NAC-HA-mPEG-DCA as the amphiphilic graft copolymer using N-acetyl-L-cysteine and the DCA-HA-mPEG;
wherein HA represents hyaluronic acid as a parent skeleton, DCA represents deoxycholic acid group, mPEG represents methoxypolyethylene glycol unit, and NAC represents N-acetyl-L-cysteine group;
preferably, in the step (1), hyaluronic acid is dissolved in a first reaction solvent, a first catalyst is added, catalysis is carried out for 0.5-24 hours at 0-60 ℃, then methoxypolyethylene glycol is added, the mixture is stirred and reacted for 2-96 hours at 0-60 ℃, and then HA-mPEG is obtained through separation, and/or in the step (2), N-acetyl-L-cysteine is dissolved in a second reaction solvent, a second catalyst is added, catalysis is carried out for 0.5-24 hours at 0-60 ℃, then HA-mPEG is added, the mixture is stirred and reacted for 2-96 hours at 0-60 ℃, and then NAC-HA-mPEG is obtained through separation, and/or in the step (3), cholic acid deoxidized is dissolved in a third reaction solvent, a third catalyst is added, catalysis is carried out for 0.5-24 hours at 0-60 ℃, then NAC-HA-mPEG is added, and NAC-DCA is obtained through separation after stirring for 2-96 hours at 20-80 ℃.
5. The method of claim 3 or 4, wherein:
The average molecular weight of the mPEG is 350-20000 Da; and/or
The average molecular weight of the hyaluronic acid is 5000-500000 Da.
6. The method according to any one of claims 3 to 5, wherein:
The first, second, and third reaction solvents are each independently selected from the group consisting of water, formamide, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, N-dimethylacetamide;
The first catalyst, the second catalyst, and the third catalyst are independently selected from the group consisting of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, 4-dimethylaminopyridine, and dicyclohexylcarbodiimide.
7. The method of any of claims 3 to 6, wherein:
In the step (1), the molar ratio of the carboxyl of the hyaluronic acid to the hydroxyl of the methoxypolyethylene glycol is (1:10) to (100: 1); and/or the molar ratio of the dosage of the first catalyst to the carboxyl of the hyaluronic acid is (1:10) - (10: 1);
in the step (2), the molar ratio of the N-acetyl-L-cysteine to the hydroxyl group of the HA-mPEG is (1:100) - (10:1), and/or the molar ratio of the second catalyst to the N-acetyl-L-cysteine is (1:10) - (10:1), and/or
In the step (3), the molar ratio of deoxycholic acid to hydroxyl groups of the NAC-HA-mPEG is (1:100) - (10: 1); and/or the molar ratio of the dosage of the third catalyst to the deoxycholic acid is (1:10) - (10: 1).
8. A hemostatic sponge made from the amphiphilic graft copolymer of claim 1 or 2 or the amphiphilic graft copolymer made by the method of any one of claims 3 to 7.
9. An anticancer drug delivery vehicle, wherein the anticancer drug delivery vehicle is prepared from the amphiphilic graft copolymer of claim 1 or 2 or the amphiphilic graft copolymer prepared by the method of any one of claims 3 to 7; preferably, the anticancer drug is selected from the group consisting of docetaxel, paclitaxel, epirubicin, and camptothecin.
10. Use of the amphiphilic graft copolymer of claim 1 or 2 or the amphiphilic graft copolymer prepared by the method of any one of claims 3 to 7 for the preparation of a hemostatic sponge or an anticancer drug release carrier; preferably, the anticancer drug is selected from the group consisting of docetaxel, paclitaxel, epirubicin, and camptothecin.
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