CN116987211A - Benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative and preparation and application thereof - Google Patents
Benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative and preparation and application thereof Download PDFInfo
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- 229920001661 Chitosan Polymers 0.000 title claims abstract description 117
- 150000003242 quaternary ammonium salts Chemical class 0.000 title claims abstract description 99
- -1 hydroxypropyl Chemical group 0.000 title claims abstract description 85
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 239000002253 acid Substances 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 18
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 17
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 17
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 17
- 239000000661 sodium alginate Substances 0.000 claims abstract description 17
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 15
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims abstract description 15
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims abstract description 13
- 238000004132 cross linking Methods 0.000 claims abstract description 8
- 229940045110 chitosan Drugs 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 239000002245 particle Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 238000004108 freeze drying Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- RHXSYTACTOMVLJ-UHFFFAOYSA-N 1H-benzimidazole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=NC2=C1 RHXSYTACTOMVLJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- PUVAFTRIIUSGLK-UHFFFAOYSA-M trimethyl(oxiran-2-ylmethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1CO1 PUVAFTRIIUSGLK-UHFFFAOYSA-M 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 238000006116 polymerization reaction Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 16
- 239000002246 antineoplastic agent Substances 0.000 abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 2
- 150000002500 ions Chemical class 0.000 abstract 1
- 238000011068 loading method Methods 0.000 description 8
- 238000005538 encapsulation Methods 0.000 description 7
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 3
- 238000001000 micrograph Methods 0.000 description 3
- 239000002086 nanomaterial Substances 0.000 description 3
- 238000002798 spectrophotometry method Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 239000004971 Cross linker Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 231100001264 fatal toxicity Toxicity 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention belongs to the technical field of nano biological medicines, and particularly relates to a hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative containing benzimidazole acid, and preparation and application thereof. The nanometer gel of the target product containing the hydroxypropyl trimethyl chitosan quaternary ammonium salt of the benzimidazole acid is synthesized by adopting the hydroxypropyl trimethyl chitosan quaternary ammonium salt of the benzimidazole acid, carboxymethyl chitosan, sodium hyaluronate and sodium alginate as raw materials through an ion crosslinking method, the average grain diameter of the product is 255.61 nm-331.48 nm, and the Zeta potential is +32.72- +37.94 mV. The benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel prepared by the invention can encapsulate antitumor drugs and shows pH responsive release behavior, and is a carrier with good application value.
Description
Technical Field
The invention belongs to the technical field of nano biological medicines, and particularly relates to a hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative containing benzimidazole acid, and preparation and application thereof.
Background
Clinical chemotherapeutic drugs are drugs commonly used in the past and in the present to treat tumors. Chemotherapeutic drugs can increase survival rate of cancer patients, but have side effects such as rapid growth of drug-resistant cells and fatal toxicity, and a new therapeutic mode is urgently needed. Development of nanoparticles having strong tumor accumulating ability and antioxidant activity to deliver anticancer drugs to enhance therapeutic effects is urgently needed.
The preparation of chitosan quaternary ammonium salt is simple, and the process for preparing the nano gel capable of encapsulating anticancer drugs is very difficult. The difficulty is that the concentration ratio of chitosan quaternary ammonium salt and the cross-linking agent and the selection of the cross-linking agent are adopted to ensure that the prepared nano gel has reasonable particle size, potential and stability range.
Disclosure of Invention
The invention provides a hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative containing benzimidazole acid, and preparation and application thereof.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
a benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative has a structural formula:formula (1), wherein the average polymerization degree n is in the range of 100 to 150.
The preparation method of the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative comprises the following steps:
s1: reacting chitosan with 2, 3-epoxypropyl trimethyl ammonium chloride at 60-80 ℃ for 12-24h, precipitating with ethanol after the reaction, washing, centrifuging and filtering to obtain hydroxypropyl trimethyl chitosan quaternary ammonium salt;
s2: and (3) completely dissolving the hydroxypropyl trimethyl chitosan quaternary ammonium salt obtained by the reaction in water, and reacting with benzimidazole-2-formic acid at room temperature for 12-24 hours to obtain the hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative containing benzimidazole acid shown in the formula (1).
The molar ratio of the 2, 3-epoxypropyl trimethyl ammonium chloride to the chitosan is 4-6:1, a step of; the mole ratio of the benzimidazole-2-formic acid to the hydroxypropyl trimethyl chitosan quaternary ammonium salt is 1-2:1.
the application of the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative is that the derivative is applied to the gel as a drug carrier.
The derivative is mixed with carboxymethyl chitosan, sodium hyaluronate and sodium alginate, and the benzimidazolate hydroxypropyl trimethyl chitosan quaternary ammonium salt nano gel is synthesized through an ionic crosslinking method, and the application of the nano gel as a medicine carrier gel is provided.
The preparation method of the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel comprises the steps of mixing the derivative with carboxymethyl chitosan, sodium hyaluronate and sodium alginate respectively, and synthesizing the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel by an ionic crosslinking method;
wherein, the mol ratio of the benzimidazole-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt to the sodium hyaluronate is 8-10:1; the molar ratio of the benzimidazole-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt to the sodium alginate is 8-10:1.
The method comprises the following steps:
s1: dissolving 0.4-0.5g of hydroxypropyl trimethyl chitosan quaternary ammonium salt containing benzimidazole acid, 0.1-0.2g of carboxymethyl chitosan, 0.1-0.2g of sodium hyaluronate and 0.1-0.2g of sodium alginate in deionized water for standby;
s2: dripping 4.0-5.0mL of the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt aqueous solution into 1-2mL of carboxymethyl chitosan aqueous solution under the stirring condition, stirring for 20-25 minutes at room temperature after dripping, and freeze-drying to obtain the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel (I);
or, dropwise adding 4.0-5.0mL of the benzimidazole acid hydroxypropyl trimethyl chitosan quaternary ammonium salt-containing aqueous solution into 1-2mL of sodium hyaluronate solution under the stirring condition, stirring at room temperature for 20-25 minutes after the dropwise adding, and freeze-drying to obtain the benzimidazole acid hydroxypropyl trimethyl chitosan quaternary ammonium salt-containing nanogel (II);
or, dropwise adding 4.0-5.0mL of the benzimidazole hydroxypropyl trimethyl chitosan quaternary ammonium salt-containing aqueous solution into 1-2mL of sodium alginate solution under the stirring condition, stirring at room temperature for 20-25 minutes after the completion of the dropwise adding, and freeze-drying to obtain the benzimidazole hydroxypropyl trimethyl chitosan quaternary ammonium salt-containing nanogel (III);
s3: three kinds of quaternary ammonium salt nanogels containing the hydroxypropyl trimethyl chitosan benzimidazole acid are obtained through ionic crosslinking.
The nanometer gel containing the benzimidazole hydroxypropyl trimethyl chitosan quaternary ammonium salt prepared by the method has the particle size of 255.61nm-265.12nm, the potential of +32.72- +36.20 mV and the entrapment rate of 86.18-91.76 percent.
Use of said nanogel as a pharmaceutical carrier.
The invention has the following beneficial effects:
the chitosan quaternary ammonium salt nano gel can be obtained by utilizing an ionic crosslinking technology in one step, the particle size of the obtained gel is 255.61nm-265.12nm, and the potential is +32.72- +36.20 mV; the auxiliary ultrasonic device is not needed in the preparation process, and the problem that the nano structure can only be realized by a complex ultrasonic process when the prior art is used for preparing the nano structure is solved. The method reduces the difficulty of preparing the nano structure, saves the cost and provides a new technical scheme for preparing the nano gel.
The benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel prepared by the invention can encapsulate antitumor drugs and shows pH responsive release behavior, and is a carrier with good application value.
Drawings
FIG. 1 is an infrared spectrum of a quaternary ammonium salt of hydroxypropyl trimethyl chitosan containing benzimidazole acid, 1650 cm and 1580cm -1 Vibration absorption peaks for imidazole rings c=c and c=n bond extension, 1417, 1067 and 754cm -1 Is an imidazole ring C-H bond telescopic vibration absorption peak 1476 cm -1 The data above demonstrate successful synthesis of hydroxypropyl trimethyl chitosan quaternary ammonium salt containing benzimidazole acid as the absorption peak of trimethylammonium.
Fig. 2 is a transmission electron microscope image of a quaternary ammonium salt nanogel (i) containing hydroxypropyl trimethyl chitosan benzimidazole acid provided by the embodiment of the invention.
Fig. 3 is a transmission electron microscope image of a quaternary ammonium salt nanogel (ii) containing hydroxypropyl trimethyl chitosan benzimidazole acid provided by the embodiment of the invention.
Fig. 4 is a transmission electron microscope image of a quaternary ammonium salt nanogel (iii) containing hydroxypropyl trimethyl chitosan benzimidazole acid provided by the embodiment of the invention.
Detailed Description
The following description of the embodiments of the present invention is further provided in connection with the accompanying examples, and it should be noted that the embodiments described herein are for the purpose of illustration and explanation only, and are not limiting of the invention.
The molecular weight of the chitosan raw material adopted in the following examples is 3-5 ten thousand, and n=50-100.
Example 1
The compound contains the synthesis of benzimidazole hydroxypropyl trimethyl chitosan quaternary ammonium salt:
1) Preparation of hydroxypropyl trimethyl chitosan quaternary ammonium salt: 1.61g (10 mmol) of chitosan was weighed out and dissolved in 40 mL isopropanol and swollen for 3h at room temperature. And 8.0 g (50 mmol) of 2, 3-epoxypropyl trimethyl ammonium chloride is added, stirred for 24 hours at 80 ℃ under reflux, then ethanol is used for precipitation, washing and freeze drying, and 4.12g of hydroxypropyl trimethyl chitosan quaternary ammonium salt is obtained for standby.
2) Preparing benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt: 3.12 (g) (10 mmol) hydroxypropyl trimethyl chitosan quaternary ammonium salt is weighed and dissolved in 50mL water, then 1.62 (g) (10 mmol) benzimidazole-2-formic acid is added, stirring is carried out for 24 hours at room temperature, and after the reaction is finished, dialysis is carried out for 4 days, thus obtaining 3.32g hydroxypropyl trimethyl chitosan quaternary ammonium salt containing benzimidazole acid in the formula (1), wherein the average polymerization degree n=100-150 (see figure 1).
Example 2
Preparation of benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt gel (I):
weighing 0.4. 0.4g hydroxyl propyl trimethyl chitosan quaternary ammonium salt containing benzimidazole acid, dissolving in 100mL water,stirring to be uniform at room temperature, and filtering by a 0.45 mu m filter for later use; dissolving 0.1g of carboxymethyl chitosan in 50mL of water, stirring to be uniform at room temperature, and filtering by a 0.45 mu m filter for later use; the structural formula of the carboxymethyl chitosan is shown as a formula (2),(2),
the carboxymethyl chitosan aqueous solution of 1. 1mL is taken and dripped into 5mL of the hydroxypropyl trimethyl chitosan quaternary ammonium salt aqueous solution containing benzimidazole acid for 5 minutes, and then stirred at 800rpm for 20 minutes at 25 ℃. The opalescent solution is the benzimidazole hydroxypropyl trimethyl chitosan quaternary ammonium salt gel (I).
Example 3
Preparation of benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt gel (II):
weighing 0.4g hydroxyl propyl trimethyl chitosan quaternary ammonium salt containing benzimidazole acid, dissolving in 100mL water, stirring at room temperature until the quaternary ammonium salt is uniform, and filtering by a 0.45 mu m filter for later use; dissolving 0.1g of sodium hyaluronate in 50mL water, stirring at room temperature until the solution is uniform, and filtering the solution by a 0.45 mu m filter for later use; the structural formula of the sodium hyaluronate is shown as a formula (3),
formula (3).
Dripping the 1mL sodium hyaluronate aqueous solution into the 4 mL hydroxypropyl trimethyl chitosan quaternary ammonium salt aqueous solution containing benzimidazole acid for 5 minutes, and stirring at 800rpm for 20 minutes at 25 ℃. The opalescent solution is hydroxypropyl trimethyl chitosan quaternary ammonium salt gel (II) containing benzimidazole acid.
Example 4
Preparing benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt gel (III):
weighing 0.4g hydroxyl propyl trimethyl chitosan quaternary ammonium salt containing benzimidazole acid, dissolving in 100mL water, stirring at room temperature until the quaternary ammonium salt is uniform, and filtering by a 0.45 mu m filter for later use; dissolving 0.1g of sodium alginate in 50mL water, stirring at room temperature until the sodium alginate is uniform, and filtering the sodium alginate by a 0.45 mu m filter for later use; the structural formula of the sodium alginate is shown as formula (4),
formula (4).
Dripping 1mL of the sodium alginate aqueous solution into 4.5 mL of the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt aqueous solution for 5 minutes, and stirring at 800rpm for 20 minutes at 25 ℃. The opalescent solution is hydroxypropyl trimethyl chitosan quaternary ammonium salt gel (III) containing benzimidazole acid.
Application example 1
Characterization of the obtained gel containing the benzimidazole hydroxypropyl trimethyl chitosan quaternary ammonium salt
(1) The obtained hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogels containing benzimidazole acid are characterized by adopting a Dynamic Light Scattering (DLS) method. Placing 2.5. 2.5 mL nanogels in a cuvette, and measuring the particle size, potential and dispersion index values of the nanogels in a Litesizer 500 nanometer particle size meter (see Table 1);
TABLE 1 particle size, potential and dispersibility index of hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel containing benzimidazole acid
The characteristics of the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogels prepared in the embodiments 2,3 and 4 are shown in the table 1, the particle sizes of the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogels are 265.12 +/-4.88, 262.43 +/-7.08 and 255.61 +/-5.26 nm respectively, and the particle sizes are more than 100nm and less than 500 nm, so that damage to normal cells can be reduced, and the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogels can accurately enter focus cells to exert drug effects; the potential is greater than +30mV, which indicates that the stability of the nano gel is good; the dispersity index is less than 30%, which indicates that the prepared nano gel is uniformly distributed.
(2) Gel encapsulation efficiency and drug loading rate were measured using the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt obtained in example 1.
The method comprises the following specific steps:
1) 0.4g of the hydroxypropyl trimethyl chitosan quaternary ammonium salt containing benzimidazole acid of example 1 was taken and dissolved in 100ml of water. Dissolving 60 ug doxorubicin hydrochloride in 1mL of carboxymethyl chitosan water solution with the concentration of 2 mg/mL, slowly dripping the solution into the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt water solution, centrifuging the obtained solution at 12000rpm for 20min, taking a supernatant, measuring the absorbance at 480 nm by an ultraviolet spectrophotometry, and calculating the encapsulation efficiency and the drug loading rate of the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt gel (I) according to the following formula (see table 2);
2) 0.4g of the hydroxypropyl trimethyl chitosan quaternary ammonium salt containing benzimidazole acid of example 1 was taken and dissolved in 100ml of water. Dissolving 60 ug doxorubicin hydrochloride in 1mL of sodium hyaluronate solution with the concentration of 2 mg/mL, slowly dripping the solution into a solution containing the hydroxypropyl trimethyl chitosan quaternary ammonium salt of benzimidazole acid, centrifuging the obtained solution at 12000rpm for 20min, taking a supernatant, measuring the absorbance at 480 nm by an ultraviolet spectrophotometry, and calculating the encapsulation rate and the drug loading rate of the gel (II) containing the hydroxypropyl trimethyl chitosan quaternary ammonium salt of benzimidazole acid according to the following formula (see table 2);
3) 0.4g of the hydroxypropyl trimethyl chitosan quaternary ammonium salt containing benzimidazole acid of example 1 was taken and dissolved in 100ml of water. Doxorubicin hydrochloride 60 ug was dissolved in 1mL of sodium alginate solution with a concentration of 2 mg/mL, slowly added dropwise to a solution containing a quaternary ammonium salt of hydroxypropyl trimethyl chitosan of benzimidazole acid, the resulting solution was centrifuged at 12000rpm for 20min, the absorbance of the supernatant was measured at 480 nm by ultraviolet spectrophotometry, and the encapsulation and drug loading rates of the gel (iii) containing hydroxypropyl trimethyl chitosan of benzimidazole acid were calculated according to the following formula (see table 2).
Encapsulation efficiency = (total drug-free drug)/total drug x 100%
Drug loading rate = (total drug amount-free drug)/(total drug loading nanogel) x 100%
TABLE 2 encapsulation and drug loading rates of benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogels
As can be seen from Table 2, the prepared hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel containing benzimidazole acid has higher encapsulation rate and drug loading rate, improves the utilization rate of the anti-tumor drug and reduces the side effect of the anti-tumor drug.
The foregoing is merely an embodiment of the present invention, and it should be noted that modifications, such as changes in the structure and size of the nanogel, replacement of anionic crosslinker materials, changes in crosslinker concentration parameters, etc., may be made by those skilled in the art without departing from the inventive concept, and such modifications are also considered to be within the scope of the invention.
Claims (9)
1. A benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative is characterized in that: the structural formula of the derivative compound is as follows:formula (1), wherein the average polymerization degree n is in the range of 100 to 150.
2. A method for preparing a benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative according to claim 1, which is characterized in that:
s1: reacting chitosan with 2, 3-epoxypropyl trimethyl ammonium chloride at 60-80 ℃ for 12-24h, precipitating with ethanol after the reaction, washing, centrifuging and filtering to obtain hydroxypropyl trimethyl chitosan quaternary ammonium salt;
s2: and (3) completely dissolving the hydroxypropyl trimethyl chitosan quaternary ammonium salt obtained by the reaction in water, and reacting with benzimidazole-2-formic acid at room temperature for 12-24 hours to obtain the hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative containing benzimidazole acid shown in the formula (1).
3. The method for preparing the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative according to claim 2, which is characterized by comprising the following steps: the molar ratio of the 2, 3-epoxypropyl trimethyl ammonium chloride to the chitosan is 4-6:1, a step of; the mole ratio of the benzimidazole-2-formic acid to the hydroxypropyl trimethyl chitosan quaternary ammonium salt is 1-2:1.
4. use of the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt derivative according to claim 1, characterized in that: the use of said derivatives as a pharmaceutical carrier gel.
5. The use of a quaternary ammonium salt derivative of hydroxypropyl trimethyl chitosan containing benzimidazole acid according to claim 4, wherein: the derivative is mixed with carboxymethyl chitosan, sodium hyaluronate and sodium alginate, and the benzimidazolate hydroxypropyl trimethyl chitosan quaternary ammonium salt nano gel is synthesized through an ionic crosslinking method, and the application of the nano gel as a medicine carrier gel is provided.
6. A preparation method of a benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel is characterized by comprising the following steps: the derivative of claim 1 is respectively mixed with carboxymethyl chitosan, sodium hyaluronate and sodium alginate, and the benzimidazole acid hydroxypropyl trimethyl chitosan quaternary ammonium salt-containing nanogel is synthesized by an ionic crosslinking method;
wherein, the mole ratio of the benzimidazole-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt to the sodium hyaluronate is 8-10:1, a step of; the mole ratio of the benzimidazole-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt to the sodium alginate is 8-10:1.
7. the method for preparing the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel according to claim 6, which is characterized in that:
s1: dissolving 0.4-0.5g of hydroxypropyl trimethyl chitosan quaternary ammonium salt containing benzimidazole acid, 0.1-0.2g of carboxymethyl chitosan, 0.1-0.2g of sodium hyaluronate and 0.1-0.2g of sodium alginate in deionized water for standby;
s2: dripping 4.0-5.0mL of the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt aqueous solution into 1-2mL of carboxymethyl chitosan aqueous solution under the stirring condition, stirring for 20-25 minutes at room temperature after dripping, and freeze-drying to obtain the benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel (I);
or, dropwise adding 4.0-5.0mL of the benzimidazole acid hydroxypropyl trimethyl chitosan quaternary ammonium salt-containing aqueous solution into 1-2mL of sodium hyaluronate solution under the stirring condition, stirring at room temperature for 20-25 minutes after the dropwise adding, and freeze-drying to obtain the benzimidazole acid hydroxypropyl trimethyl chitosan quaternary ammonium salt-containing nanogel (II);
or, dropwise adding 4.0-5.0mL of the benzimidazole hydroxypropyl trimethyl chitosan quaternary ammonium salt-containing aqueous solution into 1-2mL of sodium alginate solution under the stirring condition, stirring at room temperature for 20-25 minutes after the completion of the dropwise adding, and freeze-drying to obtain the benzimidazole hydroxypropyl trimethyl chitosan quaternary ammonium salt-containing nanogel (III);
s3: three kinds of quaternary ammonium salt nanogels containing the hydroxypropyl trimethyl chitosan benzimidazole acid are obtained through ionic crosslinking.
8. A benzimidazole acid-containing hydroxypropyl trimethyl chitosan quaternary ammonium salt nanogel prepared by the method of claim 6, which is characterized in that: the particle size of the nano gel is 255.61nm-265.12nm, the potential is +32.72- +36.20 mV, and the entrapment rate is 86.18-91.76%.
9. Use of a nanogel according to claim 8 wherein: the use of said nanogel as a drug carrier.
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| CN102198053A (en) * | 2011-05-25 | 2011-09-28 | 江南大学 | Synthesis and application of similar quaternized chitosan sunscreen |
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| CN109762078A (en) * | 2019-04-09 | 2019-05-17 | 中国科学院烟台海岸带研究所 | A kind of hydroxypropyltrimethylammonium chloride chitosan-carboxylated polysaccharide complex salt and preparation method and application |
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| CN102198053A (en) * | 2011-05-25 | 2011-09-28 | 江南大学 | Synthesis and application of similar quaternized chitosan sunscreen |
| CN103965374A (en) * | 2014-04-28 | 2014-08-06 | 华南理工大学 | O-imidazate-N-trimethyl chitosan quaternary ammonium salt, as well as preparation method and application thereof |
| CN108623708A (en) * | 2018-06-01 | 2018-10-09 | 中国科学院烟台海岸带研究所 | A kind of chitosan quaternary ammonium salt and its preparation method and application containing halogenated acetic acids |
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