CN108904446B - Preparation method and application of drug-loaded nano-micelle responding to arterial plaque microenvironment - Google Patents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G75/00—Macromolecular compounds obtained by reactions forming a linkage containing sulfur with or without nitrogen, oxygen, or carbon in the main chain of the macromolecule
- C08G75/02—Polythioethers
- C08G75/06—Polythioethers from cyclic thioethers
- C08G75/08—Polythioethers from cyclic thioethers from thiiranes
Abstract
The invention discloses a preparation method and application of a drug-loaded nano-micelle responding to an arterial plaque microenvironment. The nano micelle is formed by self-assembly of two-block polymer containing hydrophilic polyethylene glycol and hydrophobic polypropylene sulfide. The PEG-PPS micelle can respond to Reactive Oxygen Species (ROS) of the plaque to disintegrate, so that ROS at the focus part can be consumed by the PEG-PPS micelle to realize effective inhibition, and meanwhile, the micelle is also used as a drug carrier for stimulating response, so that loaded drug Andro is quickly released to reduce inflammatory reaction at the focus part, and the effect of remarkably enhancing the plaque treatment is achieved. The method for realizing the anti-inflammatory effect by drug release and relieving oxidative stress by virtue of the oxidative responsiveness of the carrier provides a promising innovative treatment strategy for atherosclerosis, and has a wide application prospect.
Description
Technical Field
The invention relates to the field of nano medicine, in particular to a preparation method and application of a drug-loaded nano-micelle capable of responding to arterial plaque microenvironment, and particularly relates to a preparation method and application of an andrographolide-loaded nano-micelle capable of responding to arterial plaque microenvironment.
Background
Atherosclerosis is a chronic inflammatory disease that is widely affected worldwide and causes a variety of serious complications, including hypertension, angina pectoris, and limb ischemia, among others. Currently available therapeutic strategies focus primarily on the regulation of lipid metabolites rather than inflammation control, and furthermore, as statins for the current common treatment of atherosclerosis, side effects such as myopathy and diabetes may be caused. Therefore, new strategies are urgently needed for the treatment of atherosclerosis.
It is well known that oxidative stress is involved in the development of atherosclerosis. On the one hand, Low Density Lipoprotein (LDL) retained in the intima is readily oxidized by Reactive Oxygen Species (ROS) to oxidized low density lipoprotein (oxLDL), a critical step in the formation of atherosclerotic plaques. The oxLDL produced induces and promotes the expression of various chemokines and promotes the recruitment of monocytes and ultimately their differentiation into macrophages. On the other hand, ROS can directly cause intimal damage, driving the progression and worsening of atherosclerosis. The intimal damage directly causes the over-expression of chemotactic inflammatory factors such as cytochemotactic protein-1 (MCP-1) and interleukin (IL-6), further causes the migration of monocytes and leukocytes to the damaged part, and can cause the secretion of more inflammatory cytokines and promote the development of atherosclerotic plaques to form a malignant cycle. Thus, inflammation and oxidative stress are two important factors in the pathogenesis of atherosclerosis, and modulation of both may provide new strategies for plaque treatment.
Based on the critical influence of the inflammatory response in atherosclerosis, a number of potent anti-inflammatory drugs have recently been investigated. Andrographolide (Andro) is a diterpenoid lactone compound, and can block a Nuclear Factor (NF) -kB pathway to have strong anti-inflammatory activity. However, the Andro is difficult to be clinically applied and popularized due to the limitation of poor water solubility. At present, nano drug delivery systems such as micelles have great potential in the aspects of improving the utilization rate of hydrophobic drugs, reducing toxic and side effects, improving treatment effects and the like. On the other hand, nano-drugs have the advantage of passive targeting, can attach to damaged blood vessels, cross dysfunctional vascular endothelium, and remain on atherosclerotic plaques. Therefore, the nano-micelle can be used as a carrier of andrographolide to realize effective treatment of arterial plaque.
However, the nanomicelles for atherosclerotic microenvironment are relatively rare in the prior art, and only a few of the nanomicelles for atherosclerotic microenvironment have the following defects: firstly, the problem that the medicine can not be well avoided to leak in the blood circulation and can be quickly released after reaching the target position can not be well solved, and secondly, the nano micelle only plays the role of a medicine carrying tool.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides the drug-loaded nano-micelle responding to the microenvironment of the arterial plaque, the drug-loaded nano-micelle can respond to the special stimulation of the pathological part of the plaque to release drugs (such as andrographolide), and in addition, the drug-loaded nano-micelle can also effectively induce the regression of the atherosclerotic plaque to play a role in adjuvant therapy.
The invention also aims to provide a preparation method of the drug-loaded nano-micelle responding to the arterial plaque microenvironment.
The invention further aims to provide application of the drug-loaded nano-micelle in the microenvironment response of the arterial plaque in preparation of drugs for treating atherosclerosis.
In order to achieve the purpose, the invention is realized by the following scheme:
a drug-loaded nano-micelle responding to arterial plaque microenvironment is formed by self-assembly of a diblock polymer containing a hydrophilic section polyethylene glycol (PEG) and a hydrophobic section polypropylene sulfide (PPS), wherein the molecular weight of the polyethylene glycol is 1kDa to 5kDa, and the molecular weight of the polypropylene sulfide is 2kDa to 10 kDa.
The polypropylene sulfide is used as a hydrophobic chain segment of the micelle, and can be oxidized into a hydrophilic polysulfone structure in the presence of ROS, so that the disintegration of the micelle and the release of the medicament are realized; meanwhile, hydrophilic chain segment polyethylene glycol is introduced to increase the stability and biocompatibility of the nano micelle.
In order to obtain nano-sized (less than 150nm, especially 117.9 +/-23.7 nm) micelles which can better penetrate through injured endothelial cell gaps and can be used for efficiently loading drugs (especially andrographolide), the molecular weight of polyethylene glycol selected as the block polymer is preferably 2000 Da, and the molecular weight of polypropylene sulfide is preferably 6000 Da.
A preparation method of a drug-loaded nano-micelle responding to arterial plaque microenvironment comprises the following steps:
s1, synthesizing sulfonated PEG by using PEG-OH as a raw material;
s2, using sulfonated PEG as a raw material, and reacting the sulfonated PEG with potassium thioacetate in methanol to synthesize thioacetic PEG;
s3, initiating ring-opening polymerization of propylene sulfide by using thioacetic acid-esterified PEG as an initiator and sodium methoxide as a catalyst to obtain a PEG-PPS block polymer.
As a preferred embodiment, the specific steps of S1 for synthesizing sulfonated PEG from PEG-OH as raw material include dissolving PEG-OH in anhydrous chloroform, adding DMAP, triethylamine and p-toluenesulfonyl chloride at 0 deg.C, stirring at room temperature for 12 h, precipitating in a large amount of diethyl ether, filtering and drying.
Is prepared by self-assembling polyethylene glycol-polypropylene sulfide (PEG-PPS) loaded with a hydrophobic anti-inflammatory micromolecule drug andrographolide (Andro).
The invention claims application of the drug-loaded nano-micelle responding to the arterial plaque microenvironment in preparation of drugs for treating atherosclerosis.
A medicine for treating atherosclerosis is prepared by loading andrographolide on the medicine-carrying nano micelle. The medicine can consume ROS of arterial plaque in the process of nano micelle carrier releasing medicine, and combine the anti-inflammatory effect of andrographolide, so as to generate the treatment effect of enhancing atherosclerosis.
In a preferred embodiment, the diameter of the nano-drug is less than 150nm, so that the enrichment of the damaged part of the blood vessel can be realized and the nano-drug can penetrate through the damaged endothelium to reach the pathological region of the plaque.
In a preferred embodiment, the diameter of the nano-drug is 117.9 ± 23.7 nm.
As a preferred embodiment, after obtaining the block polymer, the feeding ratio of andrographolide to polymer is controlled to be 1:10 by ultrasonically inducing the assembly of the polymer and the drug, so as to obtain the maximum drug loading and the optimal nano-drug size.
Compared with the prior art, the nano-drug has the following beneficial effects:
the invention provides a nano micelle with arterioplaque microenvironment response, which can effectively avoid the leakage of drugs in the delivery process and can respond to the microenvironment of a focus part to quickly release the drugs after reaching a target part. Particularly, the ROS consumption at the focus part can be caused when the arterial plaque is released, and the effect of enhancing the curative effect is achieved by combining the treatment of the anti-inflammatory drug. The carrier can respond to environmental stimulus to enhance the curative effect or provide a new idea for treating atherosclerosis.
Drawings
FIG. 1 is a block polymer synthesis scheme and structural changes after Reactive Oxygen Species (ROS) treatment.
FIG. 2A is a TEM image of the nano-drug; b is a TEM image of the nano-drug after being treated by hydrogen peroxide (0.3%) for 24 h; c is the particle size distribution diagram of the nano-drug; d is a fluorescence curve of the FDA-loaded nano micelle at different time after being treated by hydrogen peroxide (0.3%).
Fig. 3 shows the uptake of the FDA-loaded nanomicelles by RAW 264.7 cells at different times.
FIG. 4 is the evaluation of the effect of nano-drugs on the inhibition of the expression of inflammatory factors IL-6 and MCP-1; indicates significant differences (.)P﹤0.05，**P﹤0.01，***P﹤0.001）。
FIG. 5 is the intracellular oxidation level after nano-drug treatment of RAW 264.7 cells; and (3) upper row: control, LPS and LPS + MC; and (3) lower row: LPS + Adro and LPS + A-MC.
Detailed Description
The invention is further illustrated by the following figures and examples in conjunction with the description. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Experimental procedures, in which specific conditions are not indicated in the examples below, are generally carried out according to conditions conventional in the art or as recommended by the manufacturer. Any insubstantial changes and substitutions made by those skilled in the art based on the present invention are intended to be covered by the claims.
EXAMPLE 1 Synthesis of Block Polymer
The synthesis of the polymer is shown in FIG. 1. Firstly, the sulfonated PEG is synthesized by taking PEG-OH as a raw material. Specifically, dissolving 7.0 g of PEG-OH by 50 mL of anhydrous chloroform, then adding 43 mg of DMAP, 0.73 mL of triethylamine and 1.0 g of p-toluenesulfonyl chloride at the temperature of 0 ℃, stirring at room temperature for 12 hours, precipitating the reaction solution in a large amount of anhydrous ether, filtering to obtain a solid, and drying in vacuum to obtain sulfonated PEG;
then sulfonated PEG is used as a raw material to react with potassium thioacetate in methanol to synthesize the thioacetic PEG. 4.0 g of sulfonated PEG was dissolved in 5 mL of methanol, 12 mL of triethylamine and 2.28 g of potassium thioacetate were added to react for 12 hours, the methanol was removed by rotary evaporation, the solid was redissolved with chloroform, and then washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in this order, and the separated organic layer was dried over anhydrous magnesium sulfate, precipitated in anhydrous ether, filtered and dried to obtain a product.
And finally, taking thioacetic PEG as an initiator and sodium methoxide as a catalyst to initiate ring-opening polymerization of propylene sulfide to obtain PEG-PPS. 1.0 g of thioacetized PEG was dissolved in 10 mL of tetrahydrofuran, and 30 mg of sodium ethoxide was added thereto and stirred at room temperature for 1 hour. Then the reaction solution was cooled to 0 ℃, 1.95 mL of propylene sulfide was added, and after 30 min, the cooling apparatus was removed and stirred at room temperature for 12 h. Subsequently, the reaction solution was added dropwise to 100 mL of deionized water under sonication, dialyzed in water for 2 days to remove tetrahydrofuran, and then lyophilized to obtain the final product.
To obtain the most desirable polymer block ratios, block polymers were synthesized with PPS molecular weights of 4000, 6000 and 8000 Da, respectively. And screening out a 6000 block.
Example 2 preparation and characterization of Nanoparticulates
20 mg of the block polymer prepared in example 1 and 2 mg of andrographolide were dissolved in a mixed solvent of 1.5 mL of DMSO and 0.5 mL of chloroform, and added dropwise to 20 mL of water under sonication. The chloroform was removed from the mixed solution by rotary evaporation, and then dialyzed against water for 24 hours using a 14 kDa dialysis bag, concentrated by ultrafiltration, and washed three times with water. The particle size detection result shows that the hydration diameter of the micelle is 117.9 +/-23.7 nm (figure 2C), and the potential result shows that the nano-drug is a uniform spherical structure and has the diameter of about 100 nm (figure 2A). To prove that the nano-drug has oxidation responsiveness, the nano-drug is treated by 0.3% hydrogen peroxide for 48 hours, and a sample after treatment is prepared and subjected to TEM detection, so that the nano-drug is changed into a random aggregation structure (figure 2B), which can be attributed to the disintegration of a micelle structure.
EXAMPLE 3 Nano-drug Oxidation sensitive Release qualitative Studies
In order to confirm that the Andro in the nano-drug can be released in response to an oxidative environment, Fluorescein Diacetate (FDA) is loaded in nano-micelles instead of the Andro for in vitro simulated release fluorescence detection. As shown in fig. 2D, the FDA fluorescence gradually increased with time after the addition of 0.3% hydrogen peroxide due to fluorescence unquenching by release of FDA from micelles.
Example 4 cellular uptake of Nanoparticulates
We used confocal experiments to evaluate the ability of the nano-drug to enter cells. The FDA-loaded nanopharmaceuticals (FDA-MC) were co-cultured with normal RAW 264.7 cells and LPS-induced RAW 264.7 cells, respectively (after LPS induction, an oxidative environment similar to arterial plaque was generated), as shown in fig. 3, intracellular fluorescence was enhanced with the increase of incubation time, and the FDA fluorescence of LPS-induced group was significantly higher than that of untreated group, also showing the ability of oxidative microenvironment to trigger micelle disassembly.
Example 5 Nanoparticulate inhibition of inflammatory factors and modulation of ROS
The expression of IL-6 and MCP-1 in RAW 264.7 cells after nano-drug treatment at a transcription level is evaluated by adopting a PCR (polymerase chain reaction) experiment, as shown in figure 4, LPS (LPS) groups prove that the expression of IL-6 and MCP-1 in RAW 264.7 cells at plaque parts can be obviously up-regulated, the up-regulation can be obviously inhibited after nano-micelle treatment, and particularly, the nano-drug (A-MC) loaded with android shows the best treatment effect. Similarly, the nano-drug also showed excellent ability to inhibit oxidative stress of arterial plaque (fig. 5).
Claims (8)
1. The application of the drug-loaded nano-micelle in the microenvironment response of the arterial plaque in the preparation of drugs for treating atherosclerosis is characterized in that the drug-loaded nano-micelle in the microenvironment response of the arterial plaque comprises a nano-micelle formed by self-assembly of a diblock polymer containing a hydrophilic segment polyethylene glycol and a hydrophobic segment polypropylene sulfide, wherein the molecular weight of the polyethylene glycol is 1kDa to 5kDa, the molecular weight of the polypropylene sulfide is 2kDa to 10kDa, and the diameter of the nano-micelle is within 150 nm.
2. Use according to claim 1, characterized in that the polyethylene glycol has a molecular weight of 2kDa and the polypropylene sulfide has a molecular weight of 6 kDa.
3. The use of claim 1, wherein the preparation method of the artery plaque microenvironment responsive drug-loaded nano-micelle comprises the following steps:
s1, synthesizing sulfonated PEG by using PEG-OH as a raw material;
s2, using sulfonated PEG as a raw material, and reacting the sulfonated PEG with potassium thioacetate in methanol to synthesize thioacetic PEG;
s3, initiating ring-opening polymerization of propylene sulfide by using thioacetic acid-treated PEG as an initiator and sodium methoxide as a catalyst to obtain PEG-PPS.
4. The use according to claim 3, wherein the step of S1 synthesizing sulfonated PEG from PEG-OH comprises dissolving PEG-OH in anhydrous chloroform, adding DMAP, triethylamine and p-toluenesulfonyl chloride at 0-5 deg.C, stirring at room temperature for 8-24h, precipitating in a large amount of ether, filtering and drying.
5. The use of claim 1, wherein the medicament for treating atherosclerosis is prepared from andrographolide loaded drug-loaded nanomicelles responsive to the arterioplaque microenvironment.
6. The use of claim 5, wherein the nanomedicine is within 150nm in diameter to achieve enrichment at the site of vascular injury and to reach the plaque pathology through the damaged endothelium.
7. The use of claim 6, wherein the diameter of the nanomedicine is 117.9 ± 23.7 nm.
8. The use of claim 5, wherein the feeding ratio of andrographolide to polymer is controlled to 1:10 to obtain maximum drug loading and optimal nano-drug size.
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| CN109880097B (en) * | 2019-01-24 | 2021-04-20 | 大连理工大学 | Polymerization method for preparing block copolymer by inserting alkyl thioether into bis (tri) thioester end-group polymer under base catalysis |
| CN110302396B (en) * | 2019-07-22 | 2021-07-09 | 吉林大学 | Multifunctional liposome based on hydrogen peroxide response and preparation method and application thereof |
| CN111617036A (en) * | 2020-06-22 | 2020-09-04 | 河南省人民医院 | Targeted controlled-release anti-arthritis medicinal preparation and preparation method thereof |
| KR102418116B1 (en) * | 2020-10-08 | 2022-07-06 | 강원대학교산학협력단 | Oxidation-Responsive Emulsion Stabilized With Amphiphilic Copolymer |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001085710A1 (en) * | 2000-05-05 | 2001-11-15 | Dr. Reddy's Research Foundation | Novel anticancer compounds: process for their preparation and pharmaceutical compositions containing them |
| WO2010068432A1 (en) * | 2008-11-25 | 2010-06-17 | Ecole Polytechnique Federale De Lausanne (Epfl) | Block copolymers and uses thereof |
| CN104415029A (en) * | 2013-08-20 | 2015-03-18 | 苏州雷纳药物研发有限公司 | Andrographolide polymer micelle, preparation method and medicinal application thereof |
| CN105997941A (en) * | 2016-05-14 | 2016-10-12 | 北京师范大学 | Amphipathic micelle nanometer capsule and preparing method and application thereof |
| CN106852958A (en) * | 2015-12-08 | 2017-06-16 | 韩丰河 | Combination and its preparation technology for preventing and treating atherosclerosis Chinese traditional medicine extract |
Family Cites Families (1)
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001085710A1 (en) * | 2000-05-05 | 2001-11-15 | Dr. Reddy's Research Foundation | Novel anticancer compounds: process for their preparation and pharmaceutical compositions containing them |
| WO2010068432A1 (en) * | 2008-11-25 | 2010-06-17 | Ecole Polytechnique Federale De Lausanne (Epfl) | Block copolymers and uses thereof |
| CN104415029A (en) * | 2013-08-20 | 2015-03-18 | 苏州雷纳药物研发有限公司 | Andrographolide polymer micelle, preparation method and medicinal application thereof |
| CN106852958A (en) * | 2015-12-08 | 2017-06-16 | 韩丰河 | Combination and its preparation technology for preventing and treating atherosclerosis Chinese traditional medicine extract |
| CN105997941A (en) * | 2016-05-14 | 2016-10-12 | 北京师范大学 | Amphipathic micelle nanometer capsule and preparing method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| New synthetic methodologies for amphiphilic multiblock copolymers of ethylene glycol and propylene sulfide;A. Napoli et al;《Macromolecules》;20011231;第34卷(第26期);第8913–8917页 * |
| Oxidation responsive polymeric vesicles;Napoli A et al;《Nature Materials》;20040331;第3卷;第183-189页 * |
| Protected Thiol-Polyethylene Glycol: A New Activated Polymer for Reversible Protein Modification;Woghiren,C et al;《Bioconjugate Chemistry》;19931231;第4卷(第5期);第314-318页 * |
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