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CN115105606B - Hyaluronic acid-mangiferin-methotrexate anti-tumor conjugate drug and preparation method thereof - Google Patents

Hyaluronic acid-mangiferin-methotrexate anti-tumor conjugate drug and preparation method thereof Download PDF

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CN115105606B
CN115105606B CN202210809819.7A CN202210809819A CN115105606B CN 115105606 B CN115105606 B CN 115105606B CN 202210809819 A CN202210809819 A CN 202210809819A CN 115105606 B CN115105606 B CN 115105606B
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mangiferin
mtx
hyaluronic acid
methotrexate
conjugate
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CN115105606A (en
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朱沛志
邵万飞
樊露
梅宇程
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Yangzhou University
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Abstract

The invention discloses a hyaluronic acid-mangiferin-methotrexate anti-tumor coupling drug and a preparation method thereof. The method comprises the steps of firstly carrying out carboxylic acid activation on hyaluronic acid, then adding mangiferin, reacting to obtain a hyaluronic acid-mangiferin conjugate, and then reacting carboxylic acid activated methotrexate with the hyaluronic acid-mangiferin conjugate to obtain the hyaluronic acid-mangiferin-methotrexate antitumor conjugated drug. The preparation method is simple, and by introducing mangiferin, the combination of hyaluronic acid and mangiferin can improve the targeted anti-tumor effect of the medicine while the three medicines respectively play roles, further reduce the toxic and side effects of methotrexate and improve the biocompatibility, bioavailability and degradability of the medicine.

Description

Hyaluronic acid-mangiferin-methotrexate antitumor coupling medicine and preparation method thereof
Technical Field
The invention belongs to the technical field of medicine preparation, and relates to a hyaluronic acid-mangiferin-methotrexate anti-tumor coupling medicine and a preparation method thereof.
Background
Chemotherapy is a major means of treating cancer, and although pain can be relieved and certain therapeutic effects can be achieved, with inevitable side effects, not all cancer patients can survive from malignant tumors and side effects of chemotherapy. The polymer-drug conjugate can overcome the defects of the chemical anticancer drugs, the polymer is used as a carrier and is connected with the chemical anticancer drugs, and the polymer macromolecules can stay in tumor cells and enhance the permeation of the tumor cells, so that the targeted treatment of tumors is realized.
Methotrexate (MTX) is an antimetabolite tumor drug, which has a structure similar to Folic Acid (FA) and is an inhibitor of dihydrofolate reductase (DHFR). MTX has high affinity with DHFR, and when it is internalized into cells, it can participate in the metabolic cycle of FA and inhibit the formation of DHFR, preventing the reduction of dihydrofolate to tetrahydrofolate, and can terminate DNA and RNA biosynthesis. MTX permeates into cytoplasm, which can lead to death of tumor cells, thus achieving anti-tumor effect. However, MTX has the characteristics of most antimetabolites, i.e., no tissue selectivity, high dose, large toxic side effects, etc. The active targeting of MTX to lesions by using nano-drug carriers has been the focus of attention of researchers, and the administration mode provides a new approach for MTX targeted therapy.
Hyaluronic acid (HyaluronicAcid, HA) has good biocompatibility, is nontoxic and harmless by the us FDA, is often used as a human body internal filling body, and its derivatives are often used as drug carrier materials, and hyaluronic acid can participate in a number of critical and complex biological functions through its receptor protein CD44 on cell membranes. It is reported that CD44 is over-expressed on the surfaces of many tumor cells to different degrees, and a new development direction is provided for the design of a targeted drug-carrying system. CD44 is a glycoprotein that is ubiquitous on mammalian cell surfaces and is overexpressed in a variety of solid tumors (e.g., pancreatic, breast, and lung cancers, etc.). Hyaluronic acid is a main CD44 binding molecule, and Chinese patent CN 108888775A, which utilizes the targeting capability of hyaluronic acid to effectively deliver drugs to tumor tissues (Hyaluronic acid targeting of CD44 for cancer therapy:from receptor biology to nanomedicine,Journal of Drug Targeting,Volume 23,2015,605-618)., discloses a self-assembled nano micelle of hyaluronic acid and methotrexate and a preparation method thereof, and the hyaluronic acid and the methotrexate are coupled and linked through a bridge (cystamine linkage of disulfide bonds). On one hand, hyaluronic acid can be specifically combined with tumor cells, so that the polymer micelle has targeting property, and can be loaded into focus positions in a targeted manner, and on the other hand, the glutathione responsiveness of disulfide bonds is utilized, so that the controlled release of the drug is realized. The method for carrying the methotrexate by coating the polyamide-amine with hyaluronic acid in Chinese patent CN 107049955A has better multistage targeting, but has larger toxic and side effects and complex preparation. Chinese patent CN 110237266A discloses a method for preparing hyaluronic acid-alendronate sodium-methotrexate nanoparticle, which prepares hyaluronic acid-alendronate sodium-methotrexate conjugate by covalent connection method of amide bond and ester bond, the conjugate can treat cancer cell in a targeting way, and the conjugate is limited in targeting bone tumor due to the fact that alendronate sodium is easy to adsorb to bone tissue.
Mangiferin is a natural polyphenol compound with pharmacological activity, and has good anti-inflammatory effect, antiallergic performance, antitumor and antioxidant activities. The mangiferin has wide application range, and can be used for treating diabetes, neurodegenerative diseases and preventing aging symptoms. At present, no literature report on the preparation of antitumor drugs by coupling mangiferin with methotrexate exists in China.
Disclosure of Invention
The invention aims to provide a hyaluronic acid-mangiferin-methotrexate anti-tumor coupled drug with excellent targeting and low toxic and side effects and a preparation method thereof.
The technical scheme for realizing the purpose of the invention is as follows:
the preparation method of the hyaluronic acid-mangiferin-methotrexate antitumor coupling drug comprises the following steps:
Step 1, dissolving Hyaluronic Acid (HA) in dimethyl sulfoxide (DMSO), adding a DMSO solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and 4-Dimethylaminopyridine (DMAP), stirring to activate carboxylic acid, adding Mangiferin (MA), continuing stirring to react until the reaction is complete, dialyzing and freeze-drying to obtain a hyaluronic acid-mangiferin (HA-MA) conjugate;
And 2, dissolving methotrexate in dimethyl sulfoxide (DMSO), adding a DMSO solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 4-dimethylaminopyridine, stirring to activate carboxylic acid, adding a hyaluronic acid-mangiferin conjugate, continuing stirring to react to completion, dialyzing and freeze-drying to obtain the hyaluronic acid-mangiferin-methotrexate antitumor conjugated drug (HA-MA-MTX).
Preferably, in the step 1, the mass ratio of the hyaluronic acid to the mangiferin is 1:2.
Preferably, in the step 1, the stirring reaction time is 1h, the stirring reaction time is 24h, and the freeze drying time is 24h.
Preferably, in step 2, the mass ratio of the hyaluronic acid-mangiferin conjugate to methotrexate is 1:4.
Preferably, in step 2, the mass ratio of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide to 4-dimethylaminopyridine is 2:1.
Compared with the prior art, the invention has the following advantages:
(1) According to the invention, mangiferin and methotrexate are combined with hyaluronic acid through ester bonds, the hyaluronic acid can be combined with CD44 receptor overexpressed in cancer cells, so that the tumor cell targeting is realized, meanwhile, the macromolecular structure of the mangiferin can also be used as a drug carrier for carrying the methotrexate, the mangiferin not only exerts the medicinal value of the mangiferin, but also has synergistic effect with the hyaluronic acid, the targeted anti-tumor effect of the drug is improved, the toxic and side effects of the methotrexate are further reduced, and the biocompatibility, bioavailability and degradability of the drug are improved.
(2) In the invention, the self structure among three raw materials of hyaluronic acid, mangiferin and methotrexate does not need to be coupled through a bridge (disulfide bond cystamine link), and the coupled medicine has stable structure and simple preparation method.
Drawings
Fig. 1 is a schematic diagram of the synthesis of the hyaluronan-mangiferin-methotrexate system in examples;
FIG. 2 is a nuclear magnetic resonance spectrum of HA, MA, MTX, HA-MA, HA-MTX, HA-MA-MTX conjugates prepared in the examples;
FIG. 3 is a Fourier IR spectrum of HA, MA, MTX, HA-MA, HA-MTX, HA-MA-MTX conjugates prepared in the examples;
FIG. 4 is a graph showing particle size distribution and morphology of HA-MA, HA-MTX, and HA-MA-MTX NPs in examples;
FIG. 5 is a chart showing the viable cell death staining of HA, MA, MTX, HA-MA, HA-MTX, HA-MA-MTX prepared in the examples after K7 cancer cell culture;
FIG. 6 is a graph showing the experimental results of cck-8 of HA, MA, MTX, HA-MA, HA-MTX, and HA-MA-MTX prepared in the examples after co-culturing K7 cancer cells;
FIG. 7 is a chart showing the viable cell death staining of HA, MA, MTX, HA-MA, HA-MTX, HA-MA-MTX prepared in the examples after co-culture of MC3T3-E1 normal cells;
FIG. 8 is a graph showing the experimental results of cck-8 of HA, MA, MTX, HA-MA, HA-MTX, and HA-MA-MTX prepared in the examples after co-culturing MC3T3-E1 normal cells.
Detailed Description
The invention will be described in further detail with reference to specific embodiments and drawings.
Examples
Preparation of HA-MTX conjugate 42mg MTX was dissolved in 3mL DMSO, 75mg EDC and 46mg DMAP were added, the carboxylic acid was activated by stirring, and then 50mg HA and 3mL DMSO were added for esterification. The solution was wrapped with aluminum foil to avoid light, allowed to react well for 48h, dialyzed for 2d and freeze-dried for 24h to give HA-MTX conjugate.
Preparation of HA-MA conjugates and HA-MA-MTX conjugates:
(1) 200mg of HA was dissolved in 60mL of DMSO mixed with 800mg of EDC and 400mg of DMAP, mixed and stirred for 1h, then 400mg of MA was added to the reaction mixture, stirred for 24h and dialyzed for 2d, and lyophilized to give HA-MA conjugate.
(2) 400Mg of MTX was dissolved in 60 mM DMOS mixed with 800mg of EDC and 400mg of DMAP, 100mg of HA-MA was added after stirring reaction, stirring was continued for 24 hours, dialysis was continued for 2d and freeze-drying was performed for 24 hours, to obtain HA-MA-MTX conjugate.
Fig. 1 is a schematic diagram of the synthesis of a hyaluronic acid-mangiferin-methotrexate system, and the structural formula of the HA-MA-MTX conjugate is shown in the figure.
FIG. 2 is a nuclear magnetic resonance spectrum of HA, MA, MTX, HA-MA, HA-MTX, and HA-MA-MTX conjugates, whose chemical structures can be determined. The acetyl (-NHCOCH 3) content in HA is 1.85ppm, and the glycoside H content is 3.0-4.0ppm. MA has characteristic peaks at 7.04ppm, 3.38ppm and 0.97 ppm. The weak characteristic peak of HA-MTX spectrum at 6.8-8.6ppm corresponds to aromatic protons of MTX, and N-acetyl group (1.85 ppm) and glycoside H (3.0-4.0 ppm) of HA are also shown in the spectrum, compared with MTX spectrum, confirming successful connection of MTX with HA. Characteristic peaks of 6.8-8.6ppm corresponding to aromatic protons of MTX indicate successful coupling of MTX to HA-MA conjugate, indicating successful preparation of HA-MA-MTX conjugate.
FIG. 3 is a Fourier IR spectrum of HA-MA-MTX conjugate. HA HAs a characteristic transmittance at 1625cm -1(-CO-)、1125cm-1(C-O-C)、1050cm-1 (-C-OH), MA HAs a characteristic transmittance at 2920cm -1(-CH2),1720cm-1(-C＝O),1250cm-1 (Ar-O-Ar) and 1050cm -1 (-C-OH), and MTX HAs a characteristic transmittance at 3500cm -1(-COOH),2960cm-1(-CH3),1720cm-1(-C＝O),1600cm-1 and 1500cm -1 and 820cm -1 (para-benzene). FT-IR peaks at 1600cm -1 and 1500cm -1 were found in the IR spectrum of MTX and HA-MTX conjugates due to telescoping benzene ring, indicating successful coupling of MTX to hyaluronic acid. Characteristic peaks of MTX and MA appear in the spectrum of HA-MA-MTX at the same time, which indicates that HA-MA-MTX coupling is successful.
FIG. 4 is a representation of the particle size distribution and morphology of the synthesized HA-MA (A, B), HA-MTX (C, D) and HA-MA-MTX (E, F) NPs using Atomic Force Microscopy (AFM). The nanoparticles are spherical and have a size of about 100 nm. These self-assembled nanoparticles consist of hydrophilic groups such as OH, COOH of the MA, MTX or combined internal hydrophobic core and HA polysaccharide chains. The hydrophobic molecules of MA and MTX form the inner core of the structure to act as a drug library. The outer hydrophilic shell of glycosaminoglycan HA can specifically target cancer cells through its CD44 binding capacity.
FIG. 5 shows the live-dead staining patterns of HA (A), MA (B), MTX (C), HA-MA (D), HA-MTX (E) and HA-MA-MTX (F) after co-culturing K7 cancer cells, and shows that MTX, HA-MTX and HA-MA-MTX can effectively inhibit proliferation of K7 cancer cells.
FIG. 6 is a graph showing the results of cck-8 test of HA, MA, MTX, HA-MA, HA-MTX, and HA-MA-MTX after co-culturing K7 cancer cells, respectively, showing that HA-MTX and HA-MA-MTX conjugate nanoparticles have inhibitory effect on tumor cell growth as free MTX, which is consistent with the experimental results of cck-8. With increasing concentration, the inhibition was significantly enhanced and HA-MA-MTX was more inhibitory than free MTX and HA-MTX. When the given drug concentration is 100 mug/mL, the inhibition effect of HA-MA-MTX can reach about 72%, the MTX inhibition rate is about 60%, and the HA-MTX inhibition rate is about 65%. Therefore, the inhibition effect of HA-MA-MTX is higher than that of free MTX and HA-MTX for K7 cancer cells, which indicates that the addition of MA can further improve the tumor inhibition effect of HA-MTX conjugate.
FIG. 7 shows the live and dead staining patterns of HA (A), MA (B), MTX (C), HA-MA (D), HA-MTX (E) and HA-MA-MTX (F) after the MC3T3-E1 normal cells are co-cultured, and the results show that MTX, HA-MTX and HA-MA-MTX can kill the normal cells to a certain extent, but the HA-MA-MTX conjugate kills fewer normal cells, namely HAs small toxic and side effects, and the addition of MA can further reduce the toxic and side effects of HA-MA-MTX on the normal tissue cells compared with the HA-MTX.
FIG. 8 is a graph showing the cck-8 test results of HA, MA, MTX, HA-MA, HA-MTX and HA-MA-MTX after co-culturing with MC3T3-E1 normal cells, showing that free MTX significantly reduces the viability of normal cells, and HAs large toxic and side effects, and when the given drug concentration is 100 μg/mL, the survival rate of MC3T3-E1 cells is about 57%, 62% and 68%, respectively, wherein the cell survival rate under the action of HA-MA-MTX conjugate nanoparticles is higher than that of free MTX and HA-MTX drugs. The results show that compared with HA-MTX, the HA-MA-MTX nano particles can further reduce toxic and side effects of MTX on normal cells.

Claims (4)

1. The preparation method of the hyaluronic acid-mangiferin-methotrexate antitumor coupling drug is characterized by comprising the following steps:
Step 1, dissolving hyaluronic acid in dimethyl sulfoxide, adding a dimethyl sulfoxide solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 4-dimethylaminopyridine, stirring to activate carboxylic acid, adding mangiferin, continuously stirring to react until the mass ratio of the hyaluronic acid to the mangiferin is 1:2, dialyzing and freeze-drying to obtain a hyaluronic acid-mangiferin conjugate;
And 2, dissolving methotrexate in dimethyl sulfoxide, adding a dimethyl sulfoxide solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 4-dimethylaminopyridine, stirring to activate carboxylic acid, adding a hyaluronic acid-mangiferin conjugate, continuously stirring to react until the reaction is complete, dialyzing and freeze-drying to obtain the hyaluronic acid-mangiferin-methotrexate antitumor coupling medicine.
2. The method according to claim 1, wherein in step 1, the stirring reaction time is 1h, the continuous stirring reaction time is 24h, and the freeze-drying time is 24 h.
3. The method according to claim 1, wherein in the step 2, the mass ratio of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide to 4-dimethylaminopyridine is 2:1.
4. A hyaluronic acid-mangiferin-methotrexate anti-tumor conjugate medicament prepared according to any of the preparation methods of claims 1 to 3.
CN202210809819.7A 2022-07-11 2022-07-11 Hyaluronic acid-mangiferin-methotrexate anti-tumor conjugate drug and preparation method thereof Active CN115105606B (en)

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