Method for modifying Mg-Al layered double hydroxide drug-loaded particles through one-step method

Abstract

The invention relates to a method for modifying Mg-Al layered double hydroxide drug-loaded particles by a one-step method, which comprises the following steps: preparing wet Mg-Al layered double hydroxide by hydrothermal reaction, preparing a sulfydryl modifier, and adding a modification solution into the wet Mg-Al layered double hydroxide for modification to obtain the modified Mg-Al layered double hydroxide. And then adding temozolomide to obtain the Mg-Al layered double hydroxide medicine carrying material. The Mg-Al layered double hydroxide is modified by adopting a trimercaptopropylmethoxysilane one-step method, the operation is simple, the experimental environment is not complicated, the controllability in the reaction process is good, and the modified Mg-Al layered double hydroxide has relatively high drug loading capacity.

Description

Technical Field

[0001] The invention belongs to the technical field of inorganic nanomaterial preparation, and particularly relates to a one-step preparation method of modified Mg-Al layered double hydroxide drug-loaded particles. Background Art

[0002] Gliomas, accounting for 50% to 60% of intracranial tumors, are the most common brain tumor in adults. They are characterized by high morbidity, mortality, recurrence, and cure rates, making them the most detrimental type of central nervous system tumor. Due to their diffuse growth, gliomas cannot be completely removed surgically. Therefore, most glioma treatments involve surgery followed by radiotherapy and chemotherapy. Temozolomide (TMZ), an oral DNA alkylating agent that penetrates the blood-brain barrier, is currently the first-line chemotherapy drug for gliomas. However, chemotherapeutic efficacy in gliomas is suboptimal, primarily due to TMZ's short half-life in the body, low effective drug concentrations reaching the tumor site after circulating through the bloodstream, and a lack of target selectivity. Long-term systemic administration can also cause toxic side effects such as nausea and vomiting. The use of drug-loaded composite formulations can address the non-targeting issues of traditional drugs and significantly reduce TMZ's side effects. However, current TMZ delivery systems, such as liposomes and nanocapsules, have low drug loading efficiencies, making them difficult to achieve clinical application.

[0003] Over the past decade, layered double hydroxides (LDHs) have been increasingly used as drug carrier materials. LDHs, composed of two or more metal elements, are hydroxides with a layered crystal structure similar to hydrotalcite. Their lamellar structure carries a positive charge, with exchangeable anions between the layers and adjustable interlayer spacing. Therefore, drugs are inserted into the interlayers to form drug / LDH nanohybrids. Due to the electrostatic interactions, hydrogen bonding, and steric hindrance between the drug and the layers, effective controlled release of the drug is possible, making drug / LDH nanohybrid controlled-release systems promising for promising applications. However, the insertion of electrically neutral and hydrophobic drug molecules is difficult, making it challenging to prepare drug / LDH nanomaterials with ideal drug loading capacities.

[0004] Prior art CN107552007B synthesizes mercapto-modified magnesium-aluminum layered double hydroxide using (3-mercaptopropyl)trimethoxysilane as a crosslinker and sodium dodecyl sulfate-intercalated magnesium-aluminum layered double hydroxide as a carrier. The reaction, carried out under nitrogen protection and at elevated temperature for 24 hours, is complex and tedious, and the reaction process is difficult to control. You et al. used surfactants to embed poorly soluble HCPT into the hydrophobic channels of modified LDH, but the drug content was low. Summary of the Invention

[0005] The purpose of the present invention is to provide a one-step method for modifying Mg-Al layered double hydroxide drug-loaded particles to address the problems of low drug encapsulation efficiency of existing TMZ carriers, difficulty in achieving clinical application value, and difficulty in inserting electrically neutral and hydrophobic drug molecules into LDH. The method has the advantages of simple synthesis process, easy operation, low production cost, and high drug loading capacity.

[0006] The technical solution of the present invention is: a one-step method for modifying Mg-Al layered double hydroxide drug-loaded particles, the specific steps of which are as follows:

[0007] (1) Synthesis of wet Mg-Al layered double hydroxide

[0008] Weighing magnesium inorganic salt, aluminum inorganic salt and urea into a container, adding deionized water, stirring and dissolving to obtain a mixed solution, transferring the mixed solution to a hydrothermal reactor under air environment, placing it in a constant temperature oven for hydrothermal reaction to obtain a uniformly suspended layered double hydroxide suspension, removing the reactor after the reaction is completed, pouring the reactants into a centrifuge tube, centrifuging, and washing to prepare a wet Mg-Al layered double hydroxide;

[0009] (2) Introduction of thiol modifier

[0010] Weigh a certain amount of the wet Mg-Al layered double hydroxide obtained in step (1) and place it in a container; add ethanol, deionized water, and a thiol modifier according to a certain mass ratio; add an acidic solution to adjust the pH of the mixed solution to acidic; after sufficient reaction, pour the reactant into a centrifuge tube, centrifuge, wash, and vacuum freeze-dry to obtain thiol-modified Mg-Al layered double hydroxide;

[0011] (3) Preparation of Mg-Al layered double hydroxide drug-loaded materials

[0012] A certain amount of temozolomide is weighed and dissolved in deionized water to obtain a drug solution, the thiol-modified Mg-Al layered double hydroxide obtained in step (2) is dispersed in the drug solution, an alkaline solution is added to adjust the pH of the mixed solution to alkaline, the mixed solution is directly poured into a centrifuge tube, centrifuged, and washed to obtain a Mg-Al layered double hydroxide drug-loaded material.

[0013] Preferably, the magnesium inorganic salt described in step (1) is magnesium chloride or magnesium nitrate; the aluminum inorganic salt is aluminum chloride hexahydrate or aluminum nitrate; and the molar ratio of the magnesium inorganic salt, the aluminum inorganic salt and urea is 1:(0.11-0.20):(4.90-5.24).

[0014] Preferably, the stirring speed in step (1) is 1000-1500 r / min, and the stirring time is 1-3 h.

[0015] Preferably, the reaction temperature of the hydrothermal reactor in step (1) is 120-160° C., the reaction time is 24-36 h, the centrifugal speed is 5000-10000 rpm, and the washing times are 3-4 times.

[0016] Preferably, the mercapto modifier described in step (2) is one or more of 3-mercaptopropylmethoxysilane, mercaptopropionic acid or mercaptoacetic acid; the mass ratio of wet Mg-Al layered double hydroxide, water, ethanol and mercapto modifier is 1: (0.5-2): (9.4-15.8): (0.2-1.1).

[0017] Preferably, the acidic solution in step (2) is one or a mixture of hydrochloric acid aqueous solution, sulfuric acid aqueous solution or nitric acid aqueous solution; the acidic solution adjusts the pH value of the mixed solution to 4-6.

[0018] Preferably, the centrifugal speed in step (2) is 3000-10000 rpm; and the washing times are 3-4 times.

[0019] Preferably, the alkaline solution in step (3) is one or more of a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution or a sodium carbonate aqueous solution; the alkaline solution adjusts the pH value of the mixed solution to 9-10.

[0020] Preferably, the mass ratio of temozolomide to the modified Mg-Al layered double hydroxide in the drug solution in step (3) is 1:(10-20).

[0021] Preferably, the centrifugal speed in step (3) is 6000-10000 rpm; the product separated by centrifugation is washed with sodium hydroxide aqueous solution for 3-4 times.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) The process is simple and controllable. The present invention adopts a one-step method to modify the Mg-Al layered double hydroxide, which is simple to operate, has a simple experimental environment, and has good controllability during the reaction process.

[0024] (2) The modified Mg-Al layered double hydroxide has a high drug loading capacity, up to 20% BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is a SEM image of the modified Mg-Al layered double hydroxide prepared in Example 1;

[0026] Figure 2 3 is an SEM image of the modified Mg-Al layered double hydroxide prepared in Example 2. DETAILED DESCRIPTION

[0027] The present invention is further described below through the following embodiments. It should be understood that the following embodiments are only used to illustrate the present invention, rather than to limit the present invention.

[0028] Example 1

[0029] To a beaker, add 56 ml of deionized water, 0.03 mol of magnesium chloride, 0.0033 mol of aluminum chloride hexahydrate, and 0.147 mol of urea. Place the beaker solution on a magnetic stirrer and stir at 1500 rpm for 1 hour to obtain a fully dissolved mixed solution. This mixed solution is then poured into a polytetrafluoroethylene-lined hydrothermal reactor, placed in an oven at 120°C, and allowed to react for 36 hours. The resulting solution is then poured into a centrifuge tube, centrifuged at 5000 rpm, and washed four times with deionized water to obtain a Mg-Al layered double hydroxide. To a beaker, add 4 g of wet Mg-Al layered double hydroxide, 2 g of deionized water, 37.872 g of ethanol, and 0.844 g of trismercaptopropylmethoxysilane. Adjust the solution to pH 4 with aqueous hydrochloric acid and stir at room temperature to dissolve. The solution is then poured into a centrifuge tube, centrifuged at 3000 rpm, washed four times with deionized water, and freeze-dried to obtain the modified Mg-Al layered double hydroxide. like Figure 1 As shown, the modified material has a distinct lamellar structure. 20 mg of the modified Mg-Al layered double hydroxide and 2 mg of temozolomide were placed in a container, deionized water was added, and after stirring to dissolve completely, sodium hydroxide aqueous solution was added to adjust the pH value of the mixed solution to 9.5. The solution was then vigorously stirred at room temperature. The mixed solution was then poured directly into a centrifuge tube and centrifuged at 6000 rpm. The separated product was washed four times with sodium hydroxide aqueous solution to obtain a Mg-Al layered double hydroxide drug-loaded material. Testing showed that the modified Mg-Al layered double hydroxide had a drug loading capacity of up to 10%.

[0030] Example 2

[0031] To a beaker, add 56 ml of deionized water, 0.03 mol of magnesium chloride, 0.006 mol of aluminum chloride hexahydrate, and 0.1572 mol of urea. Place the beaker solution on a magnetic stirrer and stir at 1000 rpm for 3 hours to obtain a fully dissolved mixed solution. This mixed solution is then poured into a polytetrafluoroethylene-lined hydrothermal reactor, placed in an oven at 160°C, and reacted for 24 hours. The resulting solution is then poured into a centrifuge tube, centrifuged at 10,000 rpm, and washed three times with deionized water to obtain a Mg-Al layered double hydroxide. To a beaker, add 4 g of wet Mg-Al layered double hydroxide, 8 g of deionized water, 63.12 g of ethanol, and 4.228 g of trismercaptopropylmethoxysilane. Adjust the solution to pH 6 with aqueous nitric acid and stir at room temperature to dissolve. The solution is then poured into a centrifuge tube, centrifuged at 10,000 rpm, washed three times with deionized water, and freeze-dried to obtain the modified Mg-Al layered double hydroxide. like Figure 2 As shown, the modified material has a distinct lamellar structure. 40 mg of the modified Mg-Al layered double hydroxide and 2 mg of temozolomide were placed in a container, deionized water was added, and after stirring to dissolve completely, sodium hydroxide aqueous solution was added to adjust the pH value of the mixed solution to 9. The solution was then vigorously stirred at room temperature. The mixed solution was then poured directly into a centrifuge tube and centrifuged at 6000 rpm. The separated product was washed three times with sodium hydroxide aqueous solution to obtain a Mg-Al layered double hydroxide drug-loaded material. Testing showed that the modified Mg-Al layered double hydroxide had a drug loading capacity of up to 15%.

[0032] Example 3

[0033] Add 56 ml of deionized water, 0.03 mol of magnesium chloride, 0.0047 mol of aluminum chloride hexahydrate, and 0.15 mol of urea to a beaker. Place the beaker solution on a magnetic stirrer and stir at 1250 rpm for 2 hours to obtain a fully dissolved mixed solution. Pour this mixed solution into a polytetrafluoroethylene-lined hydrothermal reactor, place it in an oven at 120°C, and react for 36 hours. Pour the solution after the hydrothermal reaction into a centrifuge tube, centrifuge it at 10,000 rpm, and wash it four times with deionized water to obtain a Mg-Al layered double hydroxide. Add 4 g of wet Mg-Al layered double hydroxide, 4 g of deionized water, 59.964 g of ethanol, and 4.228 g of trismercaptopropylmethoxysilane to a beaker. Adjust the solution to pH 4 with aqueous hydrochloric acid and stir to dissolve at room temperature. The solution was poured into a centrifuge tube, centrifuged at 10,000 rpm, washed with deionized water 4 times, and freeze-dried to obtain a modified Mg-Al layered double hydroxide. 40 mg of the modified Mg-Al layered double hydroxide and 2 mg of temozolomide were placed in a container, deionized water was added, and after stirring and dissolving completely, potassium hydroxide aqueous solution was added to adjust the pH value of the mixed solution to 10, and vigorously stirred at room temperature. The mixed solution was then poured directly into a centrifuge tube and centrifuged at 10,000 rpm. The separated product was washed 3 times with sodium hydroxide aqueous solution to obtain a Mg-Al layered double hydroxide drug-loaded material. Testing showed that the drug loading of the modified Mg-Al layered double hydroxide could reach 20%.

[0034] Example 4

[0035] To a beaker, add 56 ml of deionized water, 0.03 mol of magnesium nitrate, 0.0047 mol of aluminum nitrate, and 0.1496 mol of urea. Place the solution in the beaker on a magnetic stirrer and stir at 1250 rpm for 2 hours to obtain a fully dissolved mixed solution. This mixed solution is then poured into a polytetrafluoroethylene-lined hydrothermal reactor, placed in an oven at 120°C, and reacted for 36 hours. The resulting solution is then poured into a centrifuge tube, centrifuged at 6000 rpm, and washed three times with deionized water to obtain a Mg-Al layered double hydroxide. To a beaker, add 4 g of wet Mg-Al layered double hydroxide, 4 g of deionized water, 59.175 g of ethanol, and 2.6425 g of trismercaptopropylmethoxysilane. Adjust the solution to pH 5 with aqueous hydrochloric acid and stir at room temperature to dissolve. The solution is then poured into a centrifuge tube, centrifuged at 10000 rpm, washed four times with deionized water, and freeze-dried to obtain the modified Mg-Al layered double hydroxide. 40 mg of the modified Mg-Al layered double hydroxide and 2 mg of temozolomide were placed in a container, deionized water was added, and after stirring to dissolve completely, an aqueous sodium hydroxide solution was added to adjust the pH of the mixed solution to 10. The mixture was then vigorously stirred at room temperature. The mixed solution was then poured directly into a centrifuge tube and centrifuged at 10,000 rpm. The separated product was washed three times with an aqueous sodium hydroxide solution to obtain a Mg-Al layered double hydroxide drug-loaded material. Testing showed that the modified Mg-Al layered double hydroxide had a drug loading capacity of up to 10%.

[0036] Example 5

[0037] Add 56 ml of deionized water, 0.03 mol of magnesium chloride, 0.0046 mol of aluminum chloride hexahydrate, and 0.1499 mol of urea to a beaker. Place the beaker solution on a magnetic stirrer and stir at 1500 rpm for 1 hour to obtain a fully dissolved mixed solution. Pour the mixed solution into a polytetrafluoroethylene-lined hydrothermal reactor, place it in an oven at 150°C, and react for 30 hours. Pour the solution after the hydrothermal reaction into a centrifuge tube, centrifuge it at 10,000 rpm, and wash it four times with deionized water to obtain a Mg-Al layered double hydroxide. Add 4 g of wet Mg-Al layered double hydroxide, 4 g of deionized water, 59.175 g of ethanol, and 3.171 g of trismercaptopropylmethoxysilane to a beaker. Adjust the solution to pH 4 with aqueous hydrochloric acid and stir to dissolve at room temperature. The solution was poured into a centrifuge tube, centrifuged at 5000 rpm, washed with deionized water 4 times, and freeze-dried to obtain a modified Mg-Al layered double hydroxide. 40 mg of the modified Mg-Al layered double hydroxide and 2 mg of temozolomide were placed in a container, deionized water was added, and after stirring and dissolving completely, an aqueous sodium hydroxide solution was added to adjust the pH value of the mixed solution to 10, and vigorously stirred at room temperature. The mixed solution was then poured directly into a centrifuge tube and centrifuged at 10000 rpm. The separated product was washed 3 times with an aqueous sodium hydroxide solution to obtain a Mg-Al layered double hydroxide drug-loaded material. Testing showed that the drug loading capacity of the modified Mg-Al layered double hydroxide could reach 15%.

[0038] Example 6

[0039] To a beaker, add 56 ml of deionized water, 0.03 mol of magnesium chloride, 0.0047 mol of aluminum chloride hexahydrate, and 0.1496 mol of urea. Place the beaker on a magnetic stirrer and stir at 1250 rpm for 2 hours to obtain a fully dissolved mixed solution. Pour this mixed solution into a polytetrafluoroethylene-lined hydrothermal reactor, place it in an oven at 140°C, and react for 33 hours. The hydrothermal reaction solution is poured into a centrifuge tube, centrifuged at 10,000 rpm, and washed four times with deionized water to obtain a Mg-Al layered double hydroxide. To a beaker, add 4 g of wet Mg-Al layered double hydroxide, 4 g of deionized water, 47.34 g of ethanol, and 2.6425 g of trismercaptopropylmethoxysilane. Adjust the solution to pH 4 with aqueous hydrochloric acid and stir at room temperature to dissolve. The solution was poured into a centrifuge tube, centrifuged at 10,000 rpm, washed with deionized water 4 times, and freeze-dried to obtain a modified Mg-Al layered double hydroxide. 40 mg of the modified Mg-Al layered double hydroxide and 2 mg of temozolomide were placed in a container, deionized water was added, and after stirring and dissolving completely, an aqueous sodium hydroxide solution was added to adjust the pH value of the mixed solution to 10, and vigorously stirred at room temperature. The mixed solution was then poured directly into a centrifuge tube and centrifuged at 10,000 rpm. The separated product was washed 3 times with an aqueous sodium hydroxide solution to obtain a Mg-Al layered double hydroxide drug-loaded material. Testing showed that the drug loading capacity of the modified Mg-Al layered double hydroxide could reach 18%.

Claims

1. A one-step method for modifying Mg-Al layered double hydroxide drug-loaded particles, the specific steps of which are as follows: (1) Synthesis of wet Mg-Al layered double hydroxide Weighing magnesium inorganic salt, aluminum inorganic salt and urea into a container, adding deionized water, stirring and dissolving to obtain a mixed solution, transferring the mixed solution to a hydrothermal reactor under air environment, placing it in a constant temperature oven for hydrothermal reaction to obtain a uniformly suspended layered double hydroxide suspension, removing the reactor after the reaction is completed, pouring the reactants into a centrifuge tube, centrifuging, and washing to prepare a wet Mg-Al layered double hydroxide; (2) Introduction of thiol modifier Weigh a certain amount of the wet Mg-Al layered double hydroxide obtained in step (1) and place it in a container; add ethanol, deionized water, and a thiol modifier according to a certain mass ratio; add an acidic solution to adjust the pH of the mixed solution to acidic; after sufficient reaction, pour the reactant into a centrifuge tube, centrifuge, wash, and vacuum freeze-dry to obtain thiol-modified Mg-Al layered double hydroxide; (3) Preparation of Mg-Al layered double hydroxide drug-loaded materials A certain amount of temozolomide is weighed and dissolved in deionized water to obtain a drug solution, the thiol-modified Mg-Al layered double hydroxide obtained in step (2) is dispersed in the drug solution, an alkaline solution is added to adjust the pH of the mixed solution to alkaline, the mixed solution is directly poured into a centrifuge tube, centrifuged, and washed to obtain a Mg-Al layered double hydroxide drug-loaded material.

2. The method according to claim 1, characterized in that The magnesium inorganic salt described in step (1) is magnesium chloride or magnesium nitrate; the aluminum inorganic salt is aluminum chloride hexahydrate or aluminum nitrate; and the molar ratio of the magnesium inorganic salt, the aluminum inorganic salt and urea is 1:(0.11-0.20):(4.90-5.24).

3. The method according to claim 1, characterized in that The stirring speed in step (1) is 1000-1500 r / min, and the stirring time is 1-3 h.

4. The method according to claim 1, characterized in that The reaction temperature of the hydrothermal reactor in step (1) is 120-160° C., the reaction time is 24-36 hours, the centrifugal speed is 5000-10000 rpm, and the washing times are 3-4 times.

5. The method according to claim 1, characterized in that The mercapto modifier described in step (2) is one or more of 3-mercaptopropylmethoxysilane, mercaptopropionic acid or mercaptoacetic acid; the mass ratio of wet Mg-Al layered double hydroxide, water, ethanol and mercapto modifier is 1: (0.5-2): (9.4-15.8): (0.2-1.1).

6. The method according to claim 1, characterized in that The acidic solution in step (2) is one or a mixture of hydrochloric acid aqueous solution, sulfuric acid aqueous solution or nitric acid aqueous solution; the acidic solution adjusts the pH value of the mixed solution to 4-6.

7. The method according to claim 1, characterized in that The centrifugal speed in step (2) is 3000-10000 rpm; the washing times are 3-4 times.

8. The method according to claim 1, characterized in that The alkaline solution described in step (3) is one or more of a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution or a sodium carbonate aqueous solution; the alkaline solution adjusts the pH value of the mixed solution to 9-10.

9. The method according to claim 1, characterized in that The mass ratio of temozolomide to the modified Mg-Al layered double hydroxide in the drug solution in step (3) is 1:(10-20).

10. The method according to claim 1, characterized in that The centrifugal speed in step (3) is 6000-10000 rpm; the product separated by centrifugation is washed with sodium hydroxide aqueous solution for 3-4 times.

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