CN110755406A - β -carotene-carrying hydrophilic nano-drug and application thereof in preparation of drug for treating cerebral ischemia-reperfusion injury - Google Patents

β -carotene-carrying hydrophilic nano-drug and application thereof in preparation of drug for treating cerebral ischemia-reperfusion injury Download PDF

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CN110755406A
CN110755406A CN201911077427.0A CN201911077427A CN110755406A CN 110755406 A CN110755406 A CN 110755406A CN 201911077427 A CN201911077427 A CN 201911077427A CN 110755406 A CN110755406 A CN 110755406A
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carotene
drug
nano
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李士勇
罗军
王晔
袁真
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Second Affiliated Hospital to Nanchang University
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a hydrophilic nano-drug carrying β -carotene and application thereof in preparing a drug for treating cerebral ischemia-reperfusion injury, wherein β -carotene is carried by high-molecular DSPE-PEG, so that the water solubility and stability of the nano-drug are improved, the aggregation of the nano-drug in the brain is improved by using a intrathecal injection method, and active oxygen is removed by using β -carotene, so that the oxidative stress injury after ischemia-reperfusion of the brain is effectively reduced, the nano-drug has important value in developing the medical application of β -carotene, and has important significance in treating and relieving the cerebral ischemia-reperfusion injury.

Description

β -carotene-carrying hydrophilic nano-drug and application thereof in preparation of drug for treating cerebral ischemia-reperfusion injury
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a β -carotene-carrying hydrophilic nano-medicine and application thereof in preparation of medicines for treating cerebral ischemia-reperfusion injury.
Background
The ischemic cerebrovascular disease has high morbidity, high disability rate and high fatality rate, and is a disease which seriously affects the human health. Early restoration of cerebral blood flow is the most effective means of treating patients with ischemic cerebrovascular disease, but is limited by a short "time window" of treatment, with only a few patients (less than 5%) being able to receive effective thrombolytic therapy. After the blood supply of most patients is restored, the generation of a large amount of active oxygen is rapidly caused, and the excessive active oxygen further accelerates the apoptosis of neurons and the damage of brain tissues, namely: cerebral ischemia reperfusion injury. Active oxygen is removed, oxidative stress injury is inhibited, neurons are protected, and the method is one of important strategies for treating ischemic cerebrovascular diseases.
The important point is that antioxidant nano-drugs have shown great advantages in treating ROS-related diseases, including treating cerebral apoplexy, septicemia, Parkinson's disease, etc. β -carotene is a necessary nutrient pigment for human body and is also a good antioxidant, however, β -carotene has the defects of insolubility in water, poor stability, easy oxidation, etc., which greatly limits the application of the antioxidant nano-drug in biological medicine, in addition, because of the limitation of blood brain barrier, intravenous injection β -carotene can not penetrate through the blood brain barrier to enter the brain, further limiting the application of the antioxidant nano-drug in treating ischemic cerebrovascular disease.
Therefore, the development of ideal cerebral ischemia protective agents and treatment strategies is very urgent and necessary.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a β -carotene carried hydrophilic nano-drug and application thereof in preparing a drug for treating cerebral ischemia-reperfusion injury, aiming at synthesizing a β -carotene carried nano-drug aiming at the self-defect of β -carotene, realizing high-efficiency brain aggregation, eliminating active oxygen and treating cerebral ischemia-reperfusion injury.
The invention is realized by the hydrophilic nano-drug carrying β -carotene, wherein the inner core of the nano-drug is β -carotene, and the outer surface of the nano-drug is PEG material dissolved in water.
Further, DSPE-PEG and β -carotene are dissolved in an organic solvent, ultrasonic crushing is carried out to form initial emulsion, the initial emulsion is added into an aqueous solution, ultrasonic emulsification is carried out again, the organic solvent is removed through reduced pressure evaporation to obtain nano particles, the nano particles are resuspended, washed and centrifuged by ultrapure water to obtain the β -carotene carried hydrophilic nano medicament.
Further, the concentrations of DSPE-PEG and β -carotene were 10mg/mL in the organic solvent.
Further, the organic solvent is dichloromethane.
Further, the diameter of the β -carotene-carrying hydrophilic nano-drug is between 180 and 200 nm.
The β -carotene-carrying hydrophilic nano-drug is applied to the preparation of drugs for treating cerebral ischemia-reperfusion injury.
Furthermore, the administration mode of the medicine for treating the cerebral ischemia-reperfusion injury is intrathecal injection.
As a preferable scheme, the preparation process of the β -carotene nano-drug carried comprises the following steps:
a) dissolving DSPE-PEG in dichloromethane at room temperature, wherein the concentration of the DSPE-PEG is 10 mg/mL;
b) β -carotene is dissolved in dichloromethane, and the mixture is stirred for 0.5 to 1 hour at room temperature to be fully dissolved, wherein the concentration of the mixture is 10 mg/mL;
c) 400uL of carotene dissolved in dichloromethane (10mg/mL) and β -carotene dissolved in dichloromethane (10mg/mL) were mixed, and subjected to ultrasonic treatment under ice bath conditions (power 450W) for a reaction time of 2 minutes to obtain a primary emulsion.
Carrying out second emulsification: 6ml of deionized water was added to the primary emulsion, and the mixture was subjected to ultrasonic treatment (power 450W) in an ice bath for 2 minutes to obtain an emulsion.
Obtaining the nano-drug dissolved in water: free dichloromethane was removed using a rotary evaporator at 37 ℃.
In summary, the advantages and positive effects of the invention are:
the invention utilizes high molecular DSPE-PEG to carry β -carotene, increases the water solubility and stability of the nano-drug, utilizes a method of intrathecal injection to increase the aggregation of the nano-drug in the brain, utilizes β -carotene to remove active oxygen, effectively reduces the oxidative stress injury after ischemia-reperfusion of the brain, and has important significance for treating and relieving the ischemia-reperfusion injury of the brain.
Compared with the prior art, the β -carotene-carrying antioxidant nano-drug disclosed by the invention has good active oxygen scavenging capacity and high-efficiency scavenging capacity for hydrogen peroxide, hydroxyl free radicals and superoxide anions, and by intrathecal injection, the nano antioxidant can be effectively gathered in the central nervous system, can scavenge excessive active oxygen in the brain, can alleviate oxidative stress injury, and has important value and significance for treating cerebral ischemia-reperfusion injury.
Drawings
FIG. 1 is NPβ-caroteneThe size of the nano-drug measured by dynamic light scattering dispersed in PBS;
FIG. 2 is NPβ-caroteneRemoval of H2O2Efficiency;
FIG. 3 is NPβ-caroteneHydroxyl radical scavenging efficiency;
FIG. 4 is NPβ-caroteneSuperoxide anion removal efficiency;
FIG. 5 is NPβ-caroteneDistribution in the mouse nervous system following intrathecal injection;
FIG. 6 is NPβ-caroteneTreating mice with cerebral ischemia-reperfusion injury, reducing the volume of injured brain tissue;
FIG. 7 is NPβ-caroteneFunctional evaluation of mice treated with cerebral ischemia-reperfusion injury.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, and the equipment and reagents used in the examples and test examples are commercially available without specific reference. The specific embodiments described herein are merely illustrative of the invention and are not intended to be limiting.
The invention discloses a β -carotene-carrying hydrophilic nano-drug and application thereof in preparation of a drug for treating cerebral ischemia-reperfusion injury, and the specific application is shown in the following examples.
Example 1 preparation and Performance testing of a drug for the treatment of cerebral ischemia-reperfusion injury
Through a double emulsification method, DSPE-PEG is used as a carrier material to prepare the entrapping NPβ-caroteneWherein the amount of the polymer DSPE-PEG is 40mg and the amount of β -carotene added is 1 mg.
The specific method comprises the steps of dissolving DSPE-PEG and β -carotene in 0.5mL of dichloromethane, adding β -carotene solution, forming initial emulsion under ultrasonic wave (output power of 450 watts for 30 seconds) of a probe type ultrasonic crusher (VC130 type, sonic, USA), adding the initial emulsion into 5mL of aqueous solution, carrying out ultrasonic emulsification again (output power of 450 watts for 2 minutes), volatilizing the organic solvent under reduced pressure (1000 Pa) by using a rotary evaporator, centrifuging (4 ℃, 30000 Xg for 1 hour), collecting nanoparticles, carrying out resuspension for 2 times by using ultrapure water, carrying β -carotene by centrifuging, washing, collecting samples, and detecting the diameter of the obtained nanoparticles to be between 180 and 200 nm.
Or the preparation method and the substance concentration can be slightly adjusted, such as:
a) dissolving DSPE-PEG in dichloromethane at room temperature, wherein the concentration of the DSPE-PEG is 10 mg/mL;
b) β -carotene is dissolved in dichloromethane, and the mixture is stirred for 0.5 to 1 hour at room temperature to be fully dissolved, wherein the concentration of the mixture is 10 mg/mL;
c) 400uL of carotene dissolved in dichloromethane (10mg/mL) and β -carotene dissolved in dichloromethane (10mg/mL) were mixed, and subjected to ultrasonic treatment under ice bath conditions (power 450W) for a reaction time of 2 minutes to obtain a primary emulsion.
Carrying out second emulsification: 6ml of deionized water was added to the primary emulsion, and the mixture was subjected to ultrasonic treatment (power 450W) in an ice bath for 2 minutes to obtain an emulsion.
Obtaining the nano-drug dissolved in water: free dichloromethane was removed using a rotary evaporator at 37 ℃.
The nano-drug (NP) carrying β -carotene prepared by the first method is treated by Dynamic Light Scattering (DLS) technologyβ-carotene) The size and surface potential of the nano-drug dispersed in water are detected, and the result is shown in figure 1, and the nano-drug can be stably dispersed in the water phase.
Detection of NP at different concentrations Using the ABTS +. free radical Decoloration assayβ-caroteneThe result of the scavenging efficiency of free radicals is shown in FIG. 2, and the scavenging rate is as high as 33.6% when the concentration of β -carotene is 80 μ M.
According to the instructions of the kit, HORAC is used for detecting the hydroxyl radical scavenging efficiency of nano-drugs carrying β -carotene with different concentrations, and the result is shown in figure 3. the detection result shows that the nano-drugs carrying β -carotene has higher hydroxyl radical scavenging performance, the scavenging efficiency is related to the concentration, and when the concentration of β -carotene is 80 mu M, the scavenging rate is as high as 61.2%.
According to the kit use instruction, the SOD kit (Sigma-Aldrich, USA) is used for detecting the superoxide anion removal efficiency of the nano-drug carrying β -carotene with different concentrations, and the result is shown in figure 4. the detection result shows that the nano-drug carrying β -carotene has higher superoxide anion removal performance, the removal efficiency is related to the concentration, and the removal rate is as high as 64.4% when the concentration of β -carotene is 80 mu M.
Example 2 experiment for treating mouse cerebral ischemia-reperfusion injury
1. Study of in vivo drug distribution
C57 mice (10-12 weeks) were selected and had an average body weight of 26-28g, purchased from Wintolite, Beijing.
The experimental method comprises the steps of injecting nano-drug carrying β -carotene into a sheath after mice are anesthetized by isoflurane inhalation, wherein the dose is 0.5
mg/kg. was analyzed 0.5, 6, 12 hours after injection to analyze the distribution of β -carotene-carrying nano-drugs in vivo, and at 6, 12 hours to analyze the distribution of drugs in living brain tissue.
The experimental results are shown in fig. 5, and it can be known from the experimental results that the nano-drug of the hydrophilic β -carotene has a high aggregation amount in the brain, and still has a very high aggregation amount in 6 and 12 hours.
2. Cerebral ischemia reperfusion injury animal model
And C57BL/6 mice with the weight of about 28-30 g. After mice are anesthetized, the skin is incised at the neck, the left common carotid artery, the internal carotid artery and the external carotid artery are separated in a blunt manner, and the wires are placed for later use. And (3) punching a dead knot at the position of the external carotid artery far away from the bifurcation of the common carotid artery, punching a loose knot at the position close to the bifurcation of the common carotid artery, cutting a small opening in the external carotid artery between the two knots, inserting a wire plug, pulling out the wire plug after 60 minutes, and putting the mouse after the operation in a 25 ℃ incubator. 1 hour after the ligation, the mice were injected with PBS or NP by intrathecal injection, respectivelyβ-carotene. The experiments were divided into 4 groups: sham (only internal and external carotid arteries were exposed, but not ligated), sham (1 hour after sham, 10 μ L volume NP was injectedβ-carotene) And, injury group: injury group (1 hour after cerebral ischemia-reperfusion injury, 10. mu.L volume PBS injection), treatment group (1 hour after cerebral ischemia-reperfusion injury, 10. mu.L volume NP injection)β-carotene)
TTC staining and relative size of infarct area calculation: 3 days after ischemia reperfusion injury, the brain was sacrificed by decapitation, serial coronal brain slices with a thickness of 2mm were prepared and immersed in newly prepared 2% TTC (2, 3, 5-triphenyltetrazolium chloride) solution and incubated at 37 ℃ for 45min in the dark. After taking the picture, the percentage of infarct area to total area was measured using image analysis software ImageJ. As shown in FIG. 6, ischemia-reperfusion injury caused significant brain tissue damage with a volume of about 42.1. + -. 5.9, NPβ-caroteneThe lesion volume in the treatment group was 25.4 ± 3.6. The results show that NPβ-caroteneThe treatment can effectively relieve ischemia reperfusion injuryVolume of brain tissue damage caused by injury.
Neurological score (mNSS score), neurological function scores were performed on different groups of mice 3 days after injury, with a total score of 18, including: tail lifting test, walking test with rat on floor, feeling test, placing test (vision and touch test), proprioception test (deep feeling, pressing rat paw to table edge to stimulate limb muscle), and balance beam test. The higher the score, the more severe the damage. As shown in FIG. 7, significant neurological impairment, NP, occurred in the PBS-treated groupβ-caroteneCan effectively relieve nerve dysfunction caused by ischemia reperfusion injury.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (7)

1. A hydrophilic nano-drug carrying β -carotene, wherein the nano-drug has an inner core of β -carotene and an outer surface of PEG material dissolved in water.
2. The β -carotene-carrying hydrophilic nano-drug according to claim 1, wherein the DSPE-PEG and β -carotene are dissolved in an organic solvent and subjected to ultrasonication to form an initial emulsion, the initial emulsion is added into an aqueous solution and subjected to ultrasonic emulsification again, the organic solvent is removed through reduced pressure evaporation to obtain nanoparticles, and the nanoparticles are resuspended, washed and centrifuged with ultrapure water to obtain the β -carotene-carrying hydrophilic nano-drug.
3. The β -carotene-carrying hydrophilic nano-drug of claim 2, wherein the concentrations of DSPE-PEG and β -carotene in the organic solvent are both 10 mg/mL.
4. The β -carotene-carrying hydrophilic nano-drug according to claim 2, wherein the organic solvent is dichloromethane.
5. The β -carotene carrying hydrophilic nano-drug according to claim 2, wherein the β -carotene carrying hydrophilic nano-drug has a diameter of 180-200 nm.
6. Use of the β -carotene-carrying hydrophilic nano-drug of any one of claims 1-5 in the preparation of a medicament for treating cerebral ischemia-reperfusion injury.
7. The use of the β -carotene-carrying hydrophilic nano-drug of claim 6, wherein the preparation of the drug for treating cerebral ischemia-reperfusion injury is administered via intrathecal injection.
CN201911077427.0A 2019-11-06 2019-11-06 β -carotene-carrying hydrophilic nano-drug and application thereof in preparation of drug for treating cerebral ischemia-reperfusion injury Pending CN110755406A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111937861A (en) * 2020-08-17 2020-11-17 南昌大学第二附属医院 Sevoflurane ischemia reperfusion device and using method

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Application publication date: 20200207