CN110898010A - Glutathione-sensitive bone-targeted liposome and preparation method thereof - Google Patents
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Abstract
The invention discloses a glutathione-sensitive bone-targeted liposome and a preparation method thereof, wherein the bone-targeted liposome is modified with an amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol on a phospholipid bilayer skeleton of the liposome. The invention is prepared by modifying glutathione-sensitive bone targeting materials in the liposome, not only can target bone tissues, but also can embed disulfide bonds into the liposome, and can be rapidly broken in rich tumor cells of glutathione so as to release drugs.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a glutathione-sensitive bone-targeted liposome and a preparation method thereof.
Background
The bone tumor includes bone in situ tumor, bone metastasis tumor, leukemia and other diseases. Because bone tissues have the problems of higher hardness, lower blood flow, poor permeability and the like, chemotherapy medicaments generally hardly reach a target site, and the medicaments usually need to be administered systemically to reach effective treatment concentration in the bone tissues, so that the treatment efficiency of the medicaments is reduced, and certain toxic and side effects on other normal tissues are generated.
Cytarabine belongs to a water-soluble medicine, has a short half-life period in vivo, needs to be administered in a large amount if an anti-tumor effect is achieved, and can cause certain damage to normal tissues when the medicine is taken orally or injected to reach an action part difficultly. To overcome this difficulty, two problems need to be solved, firstly the delivery of the drug to the site of bone disease and secondly the rapid release of the drug at the site of the lesion. Thus, there is a need in formulation design to both target the drug to the bone and secondly to allow rapid release of the drug in the specific focal environment.
Disclosure of Invention
The invention aims to provide a cytarabine lipidosome bone targeting preparation and a preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
a bone targeting liposome sensitive to glutathione is characterized in that amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol is modified on a phospholipid bilayer skeleton of the liposome;
the structural formula of the amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol is shown as a formula I:
wherein m =10-100 and n = 10-100.
Further, the amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol is prepared by the following steps:
step 1, adding cystamine hydrochloride into dichloromethane, adding triethylamine as an acid-binding agent, dropwise adding cholesterol formyl chloride under the protection of ice bath and nitrogen, stirring for reaction, filtering after the reaction is finished, performing rotary evaporation, and redissolving with dimethylformamide to obtain cystamine-cholesterol;
step 2, dissolving hyaluronic acid in formamide, adding catalysts 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT) for activation, then adding alendronate sodium, stirring for reaction, dialyzing a product, and freeze-drying to obtain alendronate sodium-hyaluronic acid;
and 3, dissolving alendronate sodium-hyaluronic acid in formamide, adding catalysts 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT) for activation, then adding cystamine-cholesterol, stirring for reaction, dialyzing the product, and freeze-drying to obtain the alendronate sodium-hyaluronic acid.
Further, cytarabine is entrapped in the liposome.
The preparation method of the glutathione-sensitive bone-targeted liposome comprises the following steps:
taking lecithin, cholesterol and PEG to prepare a blank liposome according to a film dispersion method, and then incubating a cytarabine solution and the blank liposome to obtain a cytarabine liposome; and then incubating the amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol and the cytarabine liposome together to obtain the bone targeting liposome.
The preparation method of the glutathione-sensitive bone-targeted liposome comprises the following steps: preparing blank bone targeted liposome by taking lecithin, cholesterol, PEG and amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol according to a film dispersion method, and then incubating with cytarabine solution to obtain the bone targeted liposome.
The invention has the following advantages:
1. the invention utilizes liposome to wrap the cytarabine, which can prevent the drug from being metabolized by the organism quickly, thereby increasing the long circulation of the drug in the body.
2. The invention has certain targeting property and can accumulate at bone parts, thereby reducing the toxic and side effects of other tissues.
3. The liposome of the invention contains glutathione-sensitive disulfide bonds at the hydrophobic end, and the drug can be quickly released after reaching the target site, thereby achieving the purpose of killing tumor cells.
Drawings
Fig. 1 is a schematic structural diagram of a bone targeting liposome.
Figure 2 shows the degree of hydroxyapatite adsorption of cytarabine bulk drug and bone targeting liposomes.
Detailed Description
Nano-drugs have been widely used in cancer therapy in recent years, and a conventional targeting nano-formulation generally consists of three parts, a target, a carrier and a chemotherapeutic drug. In 1986, Pierce first proposed a bone targeting concept: the pharmaceutical formulation has a tendency to tend to and aggregate at the bone site. Common targets for bone targeting include tetracyclines, bisphosphonates, and polyglycolics, among others. Among the targets, alendronate sodium is a type of bisphosphonate which can inhibit bone resorption, and researches show that oxygen atoms on two phosphate groups in the structure of the bisphosphonate can be chelated with calcium ions in a main component (hydroxyapatite) of bone, so that the affinity to the bone tissue and calcified tissue is shown.
A large amount of glutathione exists in the tumor cells, the concentration of the glutathione is about 100-1000 times of that of extracellular glutathione, and the huge concentration difference provides usable value for the application of disulfide bond materials. The disulfide bond can be rapidly broken at the place with higher glutathione content, so that the nano preparation is rapidly expanded, and the effect of rapidly releasing the medicine is finally achieved.
The liposome-encapsulated small molecule drug is a common medicinal carrier, which can effectively prevent the drug from being metabolized prematurely so as to prolong the in vivo circulation of the drug, and on the other hand, the drug can be gathered at a tumor part due to the EPR effect.
The hyaluronic acid is a high molecular polymer, and is a high-grade polysaccharide composed of units of D-glucuronic acid and N-acetylglucosamine, as shown in the following formula, the D-glucuronic acid and the N-acetylglucosamine are connected by β -1, 3-glycosidic bond, the disaccharide units are connected by β -1, 4-glycosidic bond,
hyaluronic acid is a glycosaminoglycan widely existing in intercellular substance, and has high safety and modifiability. In addition, a great deal of research reports that the hyaluronic acid has the function of actively targeting the CD44 protein in tumor cells and is a good biological carrier.
In the invention, an amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol (ALN-HA-CYS-Chol) is designed, the structural formula is shown as formula I, hyaluronic acid is used as a basal nucleus, amino groups of alendronate sodium and part of carboxyl groups in the hyaluronic acid form amide bonds under the action of a catalyst, and meanwhile, cystamine connected with cholesterol and other carboxyl groups in the hyaluronic acid form amide bonds under the action of the catalyst. In the embodiment of the present invention, since the low molecular weight hyaluronic acid has the advantages of good penetration, easy absorption and degradation, etc., the hyaluronic acid with the molecular weight of about 10000 is selected for modification.
Further, an amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol (ALN-HA-CYS-Chol) is modified on the surface of the liposome, as shown in figure 1, hydrophobic end cholesterol (Chol) is inserted into the liposome, alendronate sodium (ALN) leaks out of the surface of the liposome so as to show bone targeting property and can be targeted to bone tissues, and the material contains disulfide bonds which can be embedded into the liposome and can be rapidly broken in tumor cells rich in glutathione so as to release drugs.
In the embodiment of the invention, cytarabine is selected as a model drug and is entrapped in the liposome.
The preparation method of the drug-loaded liposome can adopt a post-insertion method, firstly preparing blank liposome, carrying the drug, and then adding ALN-HA-CYS-Chol for modification. Meanwhile, the ALN-HA-CYS-Chol modified blank bone targeting liposome can be directly prepared by adopting a pre-insertion method, and then the medicine is loaded.
The invention will be further illustrated with reference to the following specific examples. The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. The materials, reagents and the like used in the following examples are commercially available unless otherwise specified, and techniques not described in detail are performed according to standard methods well known to those skilled in the art. The reagents and the like referred to in this application are commercially available or otherwise publicly available, and are intended to be exemplary only and not exclusive to the present invention. Other suitable tools or biological materials may be substituted, respectively. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
The amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol (ALN-HA-CYS-Chol) is prepared by an organic synthesis method, wherein part of carboxyl groups of hyaluronic acid are modified with alendronate sodium as a target, and other carboxyl positions of hyaluronic acid are modified with cystamine-cholesterol. The specific synthetic process is as follows:
(1) synthetic intermediate alendronate sodium-hyaluronic acid (ALN-HA): dissolving hyaluronic acid (400 mg, 0.5mmol, D-glucuronic acid/N-acetyl-D-glucosamine) in formamide, heating for dissolving, cooling, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT), slowly dropwise adding a solution of alendronate sodium (106 mg, 0.25 mmol), reacting for 24h, dialyzing, freezing, and freeze-drying to obtain white solid powder;
(2) synthesis of intermediate cholesterol-cystamine (Cys-Chol): adding cystamine (1520 mg, 10 mmol) into a three-necked bottle, adding dichloromethane serving as a solvent, using triethylamine as an acid-binding agent, slowly dropwise adding cholesterol formyl chloride (44.9 mg, 1 mmol) into the bottle under the protection of nitrogen, reacting overnight, filtering, extracting, performing column chromatography and the like, and dissolving a product (33.2 mg) in dimethylformamide;
(3) synthesis of alendronate sodium-hyaluronic acid-cystamine-cholesterol (ALN-HA-Cys-Chol): ALN-HA (100 mg0.125mmol, D-glucuronic acid/N-acetyl-D-glucopamine) is dissolved in formamide, heated to dissolve, after cooling, EDCI and HOBT are added to activate, Cys-Chol (281.9 mg, 0.5 mmol) is added to react for 24h at room temperature, and then dimethylformamide and water are respectively used for dialysis and freeze-drying to obtain white solid powder.
Example 1
Weighing 160 mg of soybean lecithin, 16 mg of cholesterol and 5 mg of PEG, placing the soybean lecithin, 16 mg of cholesterol and 5 mg of PEG in a 100 mL eggplant-shaped bottle, adding 20 mL of dichloromethane for dissolving, carrying out spin-drying at the temperature of 48 ℃ at the rotating speed of 50 r/min, then adding 10 mL of water for membrane washing, carrying out ultrasonic treatment on a probe for 30 min to obtain a blank liposome, and then carrying out co-incubation and dialysis on the blank liposome and a cytarabine solution (40 mg/mL and 10 mL) to obtain the cytarabine liposome. Taking 1mL of cytarabine liposome in a penicillin bottle, preparing 2 mg/mL of bone targeting material ALN-HA-CYS-Chol in the penicillin bottle, heating and incubating at the incubation temperature higher than the phase transition temperature of the liposome, cooling, and sequentially passing through filters of 0.45 mu m and 0.22 mu m to obtain the bone targeting liposome.
Example 2
Weighing 160 mg of soybean lecithin, 16 mg of cholesterol, 5 mg of PEG and 20mg of bone targeting substances, placing the bone targeting substances into an eggplant-shaped bottle, adding 20 mL of dichloromethane for dissolving, carrying out spin-drying at the rotating speed of 50 r/min at 48 ℃, then adding 10 mL of water for membrane washing, carrying out ultrasonic treatment on a probe for 30 min to obtain blank bone targeting liposomes, then carrying out co-incubation on the blank bone targeting liposomes and a cytarabine solution (40 mg/mL and 10 mL), and finally dialyzing to remove free cytarabine to obtain the bone targeting cytarabine liposome.
Example 3
Weighing 160 mg of soybean lecithin, 16 mg of cholesterol, 5 mg of PEG and 20mg of bone targeting substances, dissolving in tetrahydrofuran, slowly dripping the bone targeting substances into 10 mL of PBS and continuously stirring, obtaining bone targeting blank liposomes after the tetrahydrofuran is volatilized, and finally, incubating an aqueous solution (40 mg/mL and 10 mL) of cytarabine and the blank liposomes together and dialyzing to obtain the cytarabine bone targeting liposomes.
Example 4
Weighing 160 mg of soybean lecithin, 16 mg of cholesterol and 5 mg of PEG, dissolving in tetrahydrofuran, slowly dripping the soybean lecithin, 16 mL of cholesterol and 10 mL of PEG into PBS, continuously stirring, volatilizing the tetrahydrofuran to obtain blank liposome, co-incubating cytarabine aqueous solution (40 mg/mL and 10 mL) and the blank liposome to obtain cytarabine liposome, placing 1mL of cytarabine liposome in a penicillin bottle, preparing 2 mg/mL of bone targeting material ALN-HA-CYS-Chol in the penicillin bottle, heating and co-incubating at an incubation temperature higher than the phase transition temperature of the liposome, cooling, and sequentially passing through 0.45 mu m and 0.22 mu m filters to obtain the bone targeting liposome.
Taking the bone targeting liposome (the concentration is 1mg/mL and the calculation is carried out by converting the bone targeting liposome into cytarabine) prepared in the example 1 and a cytarabine bulk drug, then respectively diluting the bone targeting liposome with PBS (phosphate buffer solution), measuring the absorbance of the cytarabine in the solution as V1, then weighing hydroxyapatite with a certain content in the PBS, incubating and stirring the hydroxyapatite in the PBS, after a certain time, taking a proper amount of the solution, centrifuging the supernatant, measuring the absorbance of the solution as V2, and expressing the bone targeting rate as R = (V1-V2)/V1.
The result of bone targeting efficiency is shown in fig. 2, wherein a is cytarabine bulk drug, and B is bone targeting liposome, and it can be seen that the bone targeting liposome can significantly improve the accumulation degree of cytarabine in hydroxyapatite compared with free drug.
The bone targeting liposome prepared by the invention can target the drug to the bone for drug release, improve the drug treatment efficiency and reduce the toxic and side effects. Has certain application prospect in clinic and market.
Claims (5)
1. A glutathione-sensitive bone-targeted liposome, which is characterized in that: the phospholipid bilayer skeleton of the liposome is modified with an amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol;
the structural formula of the amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol is shown as a formula I:
wherein m =10-100 and n = 10-100.
2. The bone-targeting liposome of claim 1, wherein: the amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol is prepared by the following steps:
step 1, adding cystamine hydrochloride into dichloromethane, adding triethylamine as an acid-binding agent, dropwise adding cholesterol formyl chloride under the protection of ice bath and nitrogen, stirring for reaction, filtering after the reaction is finished, performing rotary evaporation, and redissolving with dimethylformamide to obtain cystamine-cholesterol;
step 2, dissolving hyaluronic acid in formamide, adding catalysts 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride and 1-hydroxybenzotriazole for activation, then adding alendronate sodium, stirring for reaction, dialyzing a product, and freeze-drying to obtain alendronate sodium-hyaluronic acid;
and 3, dissolving alendronate sodium-hyaluronic acid in formamide, adding catalysts 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride and 1-hydroxybenzotriazole for activation, then adding cystamine-cholesterol, stirring for reaction, dialyzing a product, and freeze-drying to obtain the alendronate sodium-hyaluronic acid composite gel.
3. The bone-targeting liposome of claim 1, wherein: the liposome is loaded with cytarabine.
4. The method for preparing the glutathione-sensitive bone-targeting liposome of claim 1, wherein the glutathione-sensitive bone-targeting liposome comprises the following steps: the method comprises the following steps:
taking lecithin, cholesterol and PEG to prepare a blank liposome according to a film dispersion method, and then incubating a cytarabine solution and the blank liposome to obtain a cytarabine liposome; and then incubating the amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol and the cytarabine liposome together to obtain the bone targeting liposome.
5. The method for preparing the glutathione-sensitive bone-targeting liposome of claim 1, wherein the glutathione-sensitive bone-targeting liposome comprises the following steps: the method comprises the following steps: preparing blank bone targeted liposome by taking lecithin, cholesterol, PEG and amphiphilic material alendronate sodium-hyaluronic acid-cystamine-cholesterol according to a film dispersion method, and then incubating with cytarabine solution to obtain the bone targeted liposome.
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Cited By (3)
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| CN113476426A (en) * | 2021-06-29 | 2021-10-08 | 大连工业大学 | Preparation of double-targeting functional factor delivery system based on hyaluronic acid and application of double-targeting functional factor delivery system in inflammatory bowel disease |
| CN113521032A (en) * | 2021-07-16 | 2021-10-22 | 南京基树医药科技有限公司 | Preparation method and application of bone targeting nano-reagent containing glaucocalyxin A |
| CN115554420A (en) * | 2022-10-17 | 2023-01-03 | 中国科学院长春应用化学研究所 | Paramagnetic magnetic resonance contrast agent and preparation method and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113476426A (en) * | 2021-06-29 | 2021-10-08 | 大连工业大学 | Preparation of double-targeting functional factor delivery system based on hyaluronic acid and application of double-targeting functional factor delivery system in inflammatory bowel disease |
| CN113476426B (en) * | 2021-06-29 | 2023-11-24 | 大连工业大学 | Preparation of hyaluronic acid-based dual-targeting functional factor delivery system and application of hyaluronic acid-based dual-targeting functional factor delivery system in inflammatory bowel disease |
| CN113521032A (en) * | 2021-07-16 | 2021-10-22 | 南京基树医药科技有限公司 | Preparation method and application of bone targeting nano-reagent containing glaucocalyxin A |
| CN115554420A (en) * | 2022-10-17 | 2023-01-03 | 中国科学院长春应用化学研究所 | Paramagnetic magnetic resonance contrast agent and preparation method and application thereof |
| CN115554420B (en) * | 2022-10-17 | 2023-08-08 | 中国科学院长春应用化学研究所 | Paramagnetic magnetic resonance contrast agent and preparation method and application thereof |
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