CN116966169A - Application of curcumin polyethylene glycol polypropylene sulfide micelle in preparation of medicines for treating heart reperfusion injury - Google Patents
Application of curcumin polyethylene glycol polypropylene sulfide micelle in preparation of medicines for treating heart reperfusion injury Download PDFInfo
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 title claims abstract description 60
- 229940109262 curcumin Drugs 0.000 title claims abstract description 43
- 239000000693 micelle Substances 0.000 title claims abstract description 35
- 235000012754 curcumin Nutrition 0.000 title claims abstract description 30
- 239000004148 curcumin Substances 0.000 title claims abstract description 30
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 28
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- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 25
- 239000004743 Polypropylene Substances 0.000 title claims abstract description 25
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 title claims abstract description 25
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- 206010063837 Reperfusion injury Diseases 0.000 title claims abstract description 20
- 229940079593 drug Drugs 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 title description 3
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- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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Classifications
-
- 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
- A61K31/12—Ketones
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
-
- 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
Abstract
The invention discloses application of curcumin polyethylene glycol polypropylene sulfide micelle in medicines for treating heart reperfusion injury, in particular heart reperfusion injury. The invention proves the great potential of the curcumin polyethylene glycol polypropylene sulfide micelle as a heart ischemia reperfusion injury treatment drug, firstly discloses the good protection curative effect of the curcumin polyethylene glycol polypropylene sulfide micelle on heart ischemia reperfusion, provides an effective novel potential alternative drug for heart reperfusion injury clinical prevention and treatment, expands the indication of the curcumin polyethylene glycol polypropylene sulfide micelle, and greatly improves the application potential and market prospect of the curcumin polyethylene glycol polypropylene sulfide micelle.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to application of curcumin polyethylene glycol polypropylene sulfide micelle in preparing a medicine for treating heart reperfusion injury.
Background
Ischemic heart disease (Ischemic heart disease, IHD) is a common cardiovascular disease that can cause irreversible myocardial damage. At present, the recovery of blood supply to the heart, namely reperfusion, is the most effective method for treating ischemic heart disease, and early reperfusion can quickly recover blood flow in myocardial ischemia areas, and the death rate can be reduced by about half. However, the recovery of oxygenated blood may cause greater injury than the initial ischemic injury, i.e., ischemia/reperfusion (I/R) injury. Cardiac I/R injury is a major cause of morbidity and mortality in patients with severe coronary artery disease. Despite the ongoing understanding of the molecular mechanisms of this pathological process, no specific targeted therapeutic strategy is currently available for the treatment of post-ischemic reperfusion injury. The mechanism and potential therapeutic targets of cardiac I/R injury remain to be further explored. Although several traditional small molecule therapies are available for the treatment of common cardiovascular diseases, the clinical need for acquired and inherited cardiovascular diseases is not met. Since the 1980 s, the potential of gene therapy in cardiac vessels has been revealed, and heart failure, arrhythmia, refractory angina pectoris, ischemic heart disease and the like have become potential targets for gene therapy, but clinical transformation of gene therapy for heart-related diseases has not been very successful. The key problem of limiting the progress of related researches is insufficient knowledge of the underlying pathophysiological mechanism and the lack of stable targeting delivery strategies, thereby severely restricting the development of novel clinical treatment schemes. Intensive research in this direction will provide new therapeutic strategies for treating heart diseases.
Excessive accumulation of reactive oxygen species (Reactive oxygen species, ROS) during cardiac ischemia reperfusion can lead to DNA strand breaks, protein denaturation, and lipid peroxidation, membrane lipid peroxidation leading to loss of membrane integrity, and mitochondrial dysfunction by increasing mitochondrial membrane permeability leading to ca2+ overload, further acceleration of ROS production leading to increased cardiomyocyte apoptosis and decreased myocardial function. Therefore, effective inhibition or scavenging of ROS is one of the important strategies for treating myocardial I/R injury. Curcumin is considered to have an antioxidant effect due to its structure containing a β -diketone group. Research shows that curcumin can reduce lipid peroxidation and relieve liver injury by improving the activities of various antioxidant enzymes. Therefore, the research on whether curcumin polyethylene glycol polypropylene sulfide (PPS-Cur) micelle plays a role in treating heart reperfusion injury is of great significance in fully developing clinical application of the curcumin polyethylene glycol polypropylene sulfide (PPS-Cur) micelle in heart diseases.
Disclosure of Invention
The invention aims to provide a new indication of curcumin polyethylene glycol polypropylene sulfide micelle. The curcumin polyethylene glycol polypropylene sulfide micelle can be used as a medicament for preventing and treating heart ischemia reperfusion injury, can effectively improve heart function and maintain normal heart structure, and provides a new alternative medicament for preventing and treating ischemia reperfusion injury.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention firstly provides application of curcumin polyethylene glycol polypropylene sulfide micelle in preparing a medicament for preventing and treating ischemia reperfusion injury, wherein the curcumin polyethylene glycol polypropylene sulfide micelle plays a role in preventing and treating heart ischemia reperfusion injury.
The invention also provides a method for preventing and treating ischemia reperfusion injury, and also comprises other ischemia reperfusion injury. Therefore, besides the prevention and treatment effects on the heart ischemia reperfusion injury, the application of the curcumin polyethylene glycol polypropylene sulfide micelle to the prevention and treatment of the ischemia reperfusion injury of other tissues and organs is also within the protection scope of the invention.
Further, the medicament comprises curcumin polyethylene glycol polypropylene sulfide micelles, which exist in free form or in the form of pharmaceutically acceptable compounds.
In the above application of the present invention, the medicament contains an effective dose of curcumin polyethylene glycol polypropylene sulfide micelle. An effective dose is a unit dosage form (e.g., a tablet, a needle, a pill, or a dose of drug) or a unit dose (e.g., a unit body weight dose) of a treated patient. In the present invention, the scope of the subject to be treated with the drug is mammalian, including human, canine, rodent, etc. The effective dose conversion of different animals can be based on equivalent dose conversion relationships of laboratory animals to humans in the art (see generally guidelines of drug administration such as FDA, SFDA, etc., the unit weight dose of humans can be deduced from the dose of laboratory animals, e.g., for commonly used laboratory animals, mice, the conversion relationship to adults is about 12:1 according to the above references.
In the present invention, in 8-week-old C57BL/6 male mice, the effective dose (in terms of content) for significantly treating myocardial ischemia reperfusion is 0.05 to 1.0mg/kg, preferably 0.2mg/kg.
Preferably, the adult effective dose is 0.6-12 mg/kg per day, preferably 2.4mg/kg, when the adult weight standard is set to 60kg according to the conversion relation between the mouse and the adult effective dose.
Preferably, the medicament further comprises other medicaments which protect tissue after reperfusion injury.
Preferably, the medicament further comprises a pharmaceutically acceptable carrier.
The carrier provided by the invention is a pharmaceutically acceptable carrier, and is characterized in that: one or more compatible solid or liquid filler or gel materials. They are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients.
Preferably, the carrier includes, but is not limited to: diluents, buffers, suspensions, emulsions, granules, encapsulates, excipients, fillers, binders, sprays, transdermal absorbents, humectants, disintegrants, absorption enhancers, surfactants, binders
Color agent, correctant or adsorption carrier.
The above-mentioned medicaments can be made into any pharmaceutically usable dosage form according to the need, preferably, the dosage form of the medicament is suitable for oral administration or injection; preferably, the dosage forms comprise oral liquid, injection, tablets, capsules and the like.
The beneficial effects are that:
the invention proves the great potential of the curcumin polyethylene glycol polypropylene sulfide micelle as a medicament for preventing and treating heart ischemia reperfusion, firstly discloses the protective effect of the curcumin polyethylene glycol polypropylene sulfide micelle on ischemia reperfusion myocardial cells, provides an effective novel potential alternative medicament for preventing and treating ischemia reperfusion injury, expands the indication of the curcumin polyethylene glycol polypropylene sulfide micelle, and greatly improves the application potential and market prospect of the curcumin polyethylene glycol polypropylene sulfide micelle.
Drawings
FIG. 1 shows the protective effect of PPS-Cur micelles on myocardial cells.
FIG. 2 is an in vivo study of the effect of PPS-Cur micelles on the level of oxidative stress in the heart of mice.
FIG. 3 PPS-Cur micelle reduced myocardial fibrosis in ischemia reperfusion mice.
Detailed Description
The following examples are illustrative of the invention and are not intended to limit the scope of the invention. Unless otherwise indicated, the technical means used in the examples are conventional means well known to those skilled in the art, and the reagents used are commercially available.
EXAMPLE 1 preparation of curcumin polyethylene glycol polysulfide propylene micelle
1. Experimental materials
Curcumin, polyethylene glycol polypropylene sulfide, methanol, chloroform and sterile water.
2. Experimental procedure
Polyethylene glycol polypropylene sulfide (PEG) synthesized by solvent evaporation method 2000 -PPS 5000 ) Loaded curcumin polymer micelle.
3. Experimental specific procedure
Curcumin dissolved in chloroform (0.2 mg/mL) and PEG dissolved in methanol were combined in a fume hood 2000 -PPS 5000 (1 mg/mL) mixing well, curcumin and PEG 2000 -PPS 5000 The mass ratio of (2) is 1:5; transferring the mixed solution into a 25mL eggplant-shaped bottle, sealing with sealant, and performing ultrasonic treatment in an ultrasonic oscillator for 5min to fully and uniformly mix the two solutions; fixing the eggplant-shaped bottle containing the mixed solution on a negative pressure rotary evaporator, and fully evaporating the solvent in the mixed solution in a water bath at 45 ℃; a layer of uniform film is arranged in the eggplant-shaped bottle after the solvent is evaporated, 1 mL sterile water is added into an ultra-clean bench to dissolve the film, and water bath is carried out for 30min at 60 ℃; the solution was transferred to sterile EP tubes, sealed and stored at 4 ℃ for later use.
Example 2 establishment of myocardial ischemia and hypoxia injury model
1. Experimental materials
Cardiomyocytes (H9C 2), fetal bovine serum, PBS, medium.
Experimental procedure
Culturing the cells in a serum-free culture medium, and inducing in a hypoxia environment to obtain the ischemia and hypoxia injury cell model.
3. Experimental method
H9c2 was inoculated into Dulbecco's Modified Eagle's Medium (DMEM) Medium containing 10% (v/v) Fetal Bovine Serum (FBS) at 37℃with 5% CO 2 Is cultured overnight in the environment of (2). The old medium was replaced with freshly prepared sugar-free serum-free medium, and the well plate was placed in an anoxic chamber (5% CO 2 /1% O 2 /94% N 2 ) Anaerobic culture was performed for 3 hours, and after the culture was replaced with a normal medium, the cells were transferred to a 37℃normoxic incubator for further culture for 4 hours.
4. Experimental results and conclusions
Ischemia and hypoxia induced cell injury, and the protective effect of micelle on myocardial cells was observed. First, the change of the active oxygen level of the cells was observed, and the fluorescence microscope showed that the fluorescence intensity of the cells of the protective group was significantly lower than that of the hypoxic group, and the same result was obtained by further detection using a flow cytometer (fig. 1).
Example 3 construction of cardiac ischemia reperfusion mouse model
1. Experimental materials
1, experimental animal: c57BL/6 mice, 8 week old male, body weight 20-24g, SPF grade, purchased from Shanghai Baitong laboratory animal technologies Co.
2, experimental reagent: sirius scarlet staining kit (purchased from wuhansai wile biotechnology limited).
2. Experimental procedure
The heart ischemia reperfusion model was established by ligating the left anterior descending branch of the mouse coronary artery. Opening the chest of the mouse to squeeze out the heart, ligating the left anterior descending branch of the coronary artery at the position of about 2mm below the left auricle, making a slipknot, observing the heart at the apex to turn white, loosening the slipknot 45min after closing the chest, and taking materials to dye sirius scarlet.
3. Experimental method
Male C57BL/6 mice with the weight of 20-24g are selected for constructing the heart ischemia reperfusion model about 8 weeks old. The mice were placed in a pre-anesthesia warehouse, induced anesthesia was performed using 3% isoflurane by volume (purchased from Ruiwod) at a flow rate of 1000ml/min, and after the mice were turned over and the specular reflection disappeared, they were removed and placed on a heated operating table at 37℃and maintained under anesthesia with 2% isoflurane at a flow rate of 1000ml/min and connected to an electrocardiogram. Dehairing the left chest to left armpit area of the mouse, cutting the skin at the 4 th-5 th intercostal position to form an incision of about 1cm, opening the chest cavity between the 4 th and 5 th intercostals, extruding the heart, ligating the left anterior descending branch of the coronary artery at the position about 2mm below the left auricle by using 6-0 silk thread, beating the slipknot, observing the color whitening of the heart at the apex of the heart, placing the heart back into the chest cavity, leaving the thread end of the slipknot outside the chest cavity, extruding air in the chest cavity, observing the ST elevation change of the electrocardiogram, and confirming the success of ischemia. After 45min, the slipknot is loosened, the wire is left in the heart and is not taken out, the ST section of the electrocardiogram is observed again, the success of the model establishment is confirmed, and the mice are put back into the rearing cage to wait for awakening.
4. Experimental results and conclusions
Compared to sham-operated groups, the changes in the oxidative stress related index of mice after 3 days of ischemia after perfusion injury were evident (fig. 2). Ischemia cardiac fibrosis was evident 14 days after perfusion injury (fig. 3). Indicating that ischemia develops obvious oxidative stress in the acute phase and obvious fibrosis in the convalescence phase in perfusion-damaged mice.
Example 4 protective Effect of curcumin polyethylene glycol-polypropylene sulfide micelle on cardiac ischemia reperfusion
1. Experimental materials
1, experimental animal: c57BL/6 mice, 8 week old male, body weight 20-24g, SPF grade, purchased from Shanghai Baitong laboratory animal technologies Co.
2, experimental reagent: sirius scarlet staining kit (purchased from wuhansai wile biotechnology limited).
2. Experimental procedure
A heart ischemia reperfusion model is established by ligating the left anterior descending branch of the coronary artery of the mouse, PPS-Cur micelles with different concentrations are injected into the body of the mouse through tail veins, and the oxidation stress level and the heart fibrosis level are observed.
3. Experimental method
The mice were divided into three groups, namely, a Sham operation (Sham) group, an Ischemia Reperfusion (IR) group and a PPS-Cur group (0.2 mg/kg), wherein the PPS-Cur group mice were injected with PPS-Cur micelle through the tail vein on the day of the ischemia reperfusion operation, and the other two groups were injected with the same dose of physiological saline. Three days after continuous injection, heart tissue from the ischemic area was taken to detect differences in mRNA and protein levels.
4. Experimental results and conclusions
Compared with the IR group, after PPS-Cur micelle is injected, the cell oxidative stress related genes, inflammation related genes and apoptosis related genes (figure 2) in the heart ischemia region of the mice are obviously improved. Further observations of changes in protein levels also gave consistent results (fig. 2). The results show that the PPS-Cur micelle can obviously reduce early myocardial cell injury caused by ischemia reperfusion of mice.
After sirius red staining, the heart fibrosis degree was evident in the IR group mice, while the heart fibrosis degree was reduced in the PPS-Cur micelle treatment group (FIG. 3). The PPS-Cur micelle can reduce myocardial cell death by improving myocardial cell oxidative stress level, and further reduce myocardial fibrosis degree to save heart function.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.
Claims (4)
1. Application of curcumin polyethylene glycol polypropylene sulfide micelle in preparing medicine for treating heart ischemia reperfusion injury.
2. The use according to claim 1, wherein the medicament is in the form of an oral or injectable dosage form, the oral dosage form being a powder, tablet, granule, capsule, oral liquid, emulsion or suspension.
3. The use according to claim 1, wherein the medicament further comprises other excipients.
4. The use according to claim 3, wherein the medicament further comprises a pharmaceutically acceptable carrier, which is a diluent, buffer, binder, wetting agent, disintegrant, surfactant, colorant, flavoring agent.
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