CN110755631A - Compound for quickly treating depression and preparation method and application thereof - Google Patents
Compound for quickly treating depression and preparation method and application thereof Download PDFInfo
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- CN110755631A CN110755631A CN201911187887.9A CN201911187887A CN110755631A CN 110755631 A CN110755631 A CN 110755631A CN 201911187887 A CN201911187887 A CN 201911187887A CN 110755631 A CN110755631 A CN 110755631A
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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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y20/00—Nanooptics, e.g. quantum optics or photonic crystals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The invention relates to the field of medicines, in particular to a compound for quickly treating depression, a preparation method and application thereof. The composite provided by the invention improves the biocompatibility of the antidepressant through the BP nanosheet, greatly shortens the treatment time of depression under the irradiation of near-infrared light, has no obvious side effect, and has great potential in future clinical application.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a compound for quickly treating depression as well as a preparation method and application thereof.
Background
Depression is the leading cause of disability and suicide, and also a major contributing factor to the global overall disease burden, affecting 3 billion people worldwide. However, existing treatments for depression typically take weeks to months to achieve their antidepressant effect. Thus, there is an urgent need for improved therapeutic agents that can shorten the time to onset to achieve their antidepressant effects with lower toxicity.
With the rapid development of multidisciplinary nanomedicine and nanobiotechnology, a variety of nanocarriers for disease diagnosis and treatment have been developed. Among them, phosphorus-free layered semiconductor Black Phosphorus (BP) nanosheets have received wide attention due to their excellent biocompatibility, good biodegradability, near-infrared (NIR) -induced photothermal effect and drug-loading property.
Disclosure of Invention
The invention aims to solve the problem of overlong time for treating depression and provide a compound for quickly treating depression.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides a compound for quickly treating depression, which is prepared by compounding black phosphorus nanosheets and antidepressant drugs. Commonly used antidepressants are fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, preferably fluoxetine.
The invention also provides a preparation method of the compound for quickly treating depression, which comprises the following steps: dispersing the black phosphorus nanosheet and the antidepressant drug in physiological saline, stirring and compounding at normal temperature and in the dark, and centrifuging and washing to obtain the compound.
Further, the mass ratio of the black phosphorus nanosheet to the antidepressant is 1: 2-1: 20, preferably 1: 5.
Further, the stirring and compounding time is 20-30 h.
Compared with the prior art, the invention has the beneficial effects that:
(1) the BP nanosheet can improve the biocompatibility of antidepressant drugs such as fluoxetine and the like, and the antidepressant drugs are compounded with the BP nanosheet to enhance the capability of the antidepressant drugs in passing through a blood brain barrier;
(2) the BP-Fluoxetine compound can relieve the toxicity of high-concentration Fluoxetine on cells;
(3) the compound provided by the invention can increase the expression of hippocampal BDNF under the irradiation of near-infrared light, and reduce the excitability of amygdala PNs and mEPSC frequency;
(4) the compound provided by the invention greatly shortens the treatment time of depression under the irradiation of near infrared light, and has no obvious side effect.
Drawings
FIG. 1 shows Zeta potentials of black phosphorus nanosheets, Fluoxetine and BP-Fluoxetine;
FIG. 2 is an SEM or TEM image of black phosphorus nanosheets and BP-Fluoxetine, wherein a is an SEM image of the black phosphorus nanosheets, b is a TEM image of the black phosphorus nanosheets, and c and d are SEM images of BP-Fluoxetine;
FIG. 3 shows the release of Fluoxetine from BP-Fluoxetine under near infrared irradiation;
FIG. 4 shows cytotoxicity of black phosphorus nanosheets at different concentrations on four cells, U251, HUVEC, 4T1 and LLC;
FIG. 5 is a graph of the cytotoxicity of low concentrations of fluoxetine on HUVEC;
FIG. 6 shows the cytotoxicity of different concentrations of black phosphorus nanosheets, Fluoxetine, BP-Fluoxetine, BP-Flu-NIR, against HUVEC;
FIG. 7 is a diagram of a mouse coat scoring test sample;
FIG. 8 is a graph of the change in body weight of mice;
FIG. 9 is a behavioral test chart of mice, wherein a is Sucrose Preference Test (SPT), b is Forced Swim Test (FST), c is Tail Suspension Test (TST) and d is coat score test;
FIG. 10 is a graph showing the expression of mouse hippocampal BDNF, wherein a, b and c are the mouse BDNF mRNA expression level, representative BDNF and β -actin Western blot images and the relative levels of mouse BDNF proteins in each group after two weeks of treatment, and d, e and f are after four weeks of treatment.
FIG. 11 is a schematic diagram showing basolateral amygdala (BLA) neuronal whole cell recordings; displaying the bright field image recorded by the BLA-PNs; (from left to right)
FIG. 12 is a representative trace of the ignition pattern of the reaction of BLA-PNs to current injection (250pa, 1000 ms);
FIG. 13 is a plot of peak number of BLA-PNs as a function of injected current intensity for a four week treatment;
FIG. 14 is a representative trace of mEPSC extracted from each group of mice, j-m, left to right; n-q, plotting the cumulative profile of mepscs amplitude (n) and mepscs frequency (p); quantitative analysis (o and q) showed that the frequency of mepscs in stressed mice was elevated and subsequently eliminated by BP-Flu-NIR, whereas for free fluoxetine, the mepscs amplitude did not change significantly;
fig. 15 is a schematic showing basolateral amygdala (BLA) neuronal whole cell recordings that treatment with Flu or BP-Flu-NIR reduced the intrinsic excitability of BLA projection neurons for four weeks; representative traces of ignition pattern of pns reaction to current injection (250pa, 1000 msec); a summary plot of the number of spikes of the BLA-PNs as a function of the intensity of the injected current;
FIG. 16 is a graph showing that four weeks of treatment with fluoxetine or BP-Flu-NIR reduces excitatory synaptic transmission by BLA projection neurons; a-d, from left to right, representative traces of mepscs extracted from the non-stress + saline, stress + fluoxetine, and BP-Flu-NIR groups. Plotting the cumulative profile of mepscs amplitude (e) and mepscs frequency (g); (f and h) quantitative analysis showed that the frequency of mEPSC was increased in stressed mice, followed by elimination of BP-Flu-NIR and free-Flu, with no significant change in mEPSC amplitude.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Fluoxetine (Fluoxetine) is selected as a representative antidepressant drug and compounded with the BP nanosheet.
EXAMPLE preparation of BP-Fluoxetine complexes
Preparation of BP nanosheet
1g of sodium hydroxide solid was dispersed in 40mL of N-methyl-2-pyrrolidone (NMP) and sonicated for 5 minutes to obtain a saturated sodium hydroxide solution of wine red NMP. Thereafter, 20mg of BP powder was dispersed in the above solution and sonicated in an ice bath for 8 to 10 h. The resulting brown suspension was centrifuged at 1000rpm for 10 minutes to remove residual non-peeled particles, and the supernatant was collected and centrifuged at 10000rpm for 5 minutes to remove NMP. The collected precipitate was washed twice with ultrapure water, then lyophilized and stored in a refrigerator at 4 ℃ for further use.
Compounding of BP-Fluoxetine
10mg of BP nanosheet and 50mg of fluoxetine were dispersed in 10mL of physiological saline and stirred at ambient temperature in the dark for 24 hours. After centrifugation at 10000rpm, the collected precipitate was washed twice with ultrapure water. Thereafter, the BP-fluoxeine complex is redispersed in water for further use.
Test example-Structure of BP-Fluoxetine Complex
And analyzing the characteristics of the BP-Fluoxetine compound such as structure and the like through a Zeta potential, a scanning electron microscope and an EDS spectrum.
As shown in fig. 1, the Zeta potential of the adsorbed nanosheets decreased from-35 to +15mv, indicating that fluoxetine (Flu) was successfully adsorbed on the surface of the BP nanosheets by electrostatic interaction. Scanning Electron Microscope (SEM) images and EDS (EDS) spectrum results (figure 2) show that the particle size of the BP nanosheet is still about 200nm after Flu loading.
Experimental example BP-Fluoxetine Complex is cytotoxic
The cytotoxicity of BP-Fluoxetine was determined by the CCK-8 method. At 2X 10 per ml3Density of Individual cells were seeded in 96-well plates and cultured for 24 hours, followed by 100. mu.L of BP-Fluoxetine (25, 50, 100 and 200. mu.g mL) containing different concentrations-1) Fresh medium was replaced. After 72h of incubation, the medium was replaced with 10% CCK-8 medium, 100. mu.L of each well was added, followed by incubation for 2h and absorbance measurement at 450nm on a multifunctional microplate reader. The cytotoxicity calculation formula is as follows: cell viability ═ OD450 nm/sample/OD450 nm/control)×100％
As shown in FIG. 4, BP-Fluoxetine at 0-100. mu.g/mL did not have significant toxicity to U251, HUVEC, 4T1 and LLC cells. As shown in FIG. 5, Fluoxetine less than 6.25. mu.g/mL had no significant cytotoxic effect on HUVEC cells. However, when the concentration of Fluoxetine is more than 6.25. mu.g/mL, it can be observed that Fluoxetine has significant cytotoxicity to HUVEC cells, and the cytotoxicity of Fluoxetine can be alleviated by BP-Flu and BP-Flu-NIR (as shown in FIG. 6).
Experimental example Release of Fluoxetine from BP-Fluoxetine
Preparation of 3mL of 2mg mL-1BP-Fluoxetine, combined use with 808nm (2W cm)-2) Laser irradiation of (2). Every 2 minutes, 100. mu.L of the supernatant was put into a 96-well plate, and then 100. mu.L of ultrapure water was added to the solution. The absorbance of fluoxetine in the supernatant was measured using a microplate reader and the concentration of fluoxetine was calculated according to a standard curve.
As shown in FIG. 3, over 90% of Fluoxetine can be released from BP-Fluoxetine in NIR within 30 minutes.
Test example evaluation of therapeutic Effect of TetraBP-Fluoxetine Complex on mouse Depression
First, construction of mouse Depression model-mild stress (CUMS) with chronic unpredictable behavior
Male C57BL/6J male mice, 4 weeks old, were subjected to Chronic Unpredictable Mild Stress (CUMS) to obtain an animal model of depression. The following pressure sources were used: confined in plastic tubing, cage tilted, extinguished during lighting, illuminated at night, cold isolated, forced swimming. To prevent habituation and provide unpredictable function to the pressure sources, the 2 pressure sources described above were used randomly at different times each day. The CUMS program lasted 4 weeks.
Group treatment of mice
After completion of the animal model of depression, mice were divided into 8 groups (n ═ 10-15): (a) no stress + normal saline; (b) stress + saline; (c) stress + BP; (d) stress +808nmNIR laser irradiation; (e) stress + BP with 808nm laser irradiation; (f) stress + Fluoxetine; (g) stress + BP-Fluoxetine; (h) stress + BP with 808nm laser irradiationFluoxetine. Wherein the concentration of fluoxetine is 2.5mg mL-1BP-Fluoxetine concentration of 2.86mg mL-1Mice were injected daily with a dose of 100 μ L of drug. For the group with 808nm laser irradiation, rats were controlled within a temperature range of 40-45 ℃ for 5 minutes per day. Treatment lasted four weeks, with depressed mice treated accordingly daily.
Third, mouse behavior test
Sucrose Preference Test (SPT), Forced Swim Test (FST), Tail Suspension Test (TST) and jacket score test are included to measure depression-like behavior. Mice were behaviorally tested weekly during treatment and weighed.
Experimental results as shown in fig. 7, 8 and 9, the CUMS significantly reduced the body weight, physical state of Sucrose Preference Test (SPT) and coat, and increased the resting time in the Tail Suspension Test (TST) and Forced Swim Test (FST) of the mice compared to the control group, indicating that the mice had depression-like behavior.
After two weeks of treatment, free Flu and NIR-free BP-Flu did not alleviate the depressive behavior of the mice, whereas BP-Flu-NIR significantly alleviated the depressive behavior. Both free Flu and BP-Flu-NIR showed the expected antidepressant effect over four weeks of treatment. The result shows that the treatment time of the BP-Flu irradiated by 808nm laser is shortened compared with the traditional fluoxetine treatment. Fifth test example evaluation of the therapeutic Effect of BP-Fluoxetine Complex on mouse Depression from Biochemical and physiological changes of cells
Four groups of mice were further analyzed (n-4-5): (a) no stress + normal saline; (b) stress + saline; (c) stress + Fluoxetine; (d) stress + BP-Fluoxetine with laser irradiation at 808 nm. Wherein the concentration of fluoxetine is 2.5mg mL-1BP-Fluoxetine concentration of 2.86mg mL-1Mice were injected daily with a dose of 100 μ L of drug. For the group with 808nm laser irradiation, rats were controlled within a temperature range of 40-45 ℃ for 5 minutes per day. Treatment was continued for two and four weeks, respectively, with depressed mice being treated accordingly daily.
Measurement of mouse brain-derived neurotrophic factor (BDNF)
The expression of mouse hippocampal BDNF was determined using quantitative real-time polymerase chain reaction technique.
As shown in fig. 10, the CUMS significantly reduced mRNA expression of BDNF compared to the non-stressed control group, whereas expression of BDNF was significantly reversed after two weeks of BP-Flu-NIR treatment. Likewise, the protein level of BDNF in the hippocampus was the same as its mRNA expression level.
After four weeks of treatment, both BP-Flu-NIR and free Flu treatment blocked the CUMS-induced reduction in mRNA expression and protein levels of BDNF.
Second, measurement of mouse amygdala PNs excitability and mEPSC frequency
Whole cell patch clamp recordings were performed on amygdala from acute brain sections of mice to confirm the rapid antidepressant effect of BP-Flu-NIR (FIG. 11).
As shown in fig. 12, CUMS significantly increased the frequency of discharge in mice compared to non-stressed controls. Two-week BP-Flu-NIR treatment was effective in ameliorating the increase in frequency of mice discharge caused by CUMS, whereas free Flu failed to play a corresponding role in the two-week treatment period (fig. 12, fig. 13).
On the other hand, the increase in frequency of the minimal excitatory postsynaptic current (mepscs) induced by CUMS can also be blocked by BP-Flu-NIR, whereas free Flu therapy does not work (fig. 14). There was no significant change in mEPSC amplitude, indicating that CUMS enhanced presynaptic vesicle release after BP-Flu-NIR treatment, rather than enhancing postsynaptic response. Whereas BP-Flu-NIR and free Flu blocked CUMS-induced changes in intrinsic excitability (FIG. 15) and mEPSC frequency (FIG. 16) of BLA-PNs following four weeks of BP-Flu-NIR or free Flu treatment. The variation between these two groups of mice was comparable.
Taken together, treatment with BP-Flu-NIR induced antidepressant-like cellular changes including increased hippocampal BDNF expression, decreased amygdala PNs excitability and mepscs frequency after two weeks, whereas two weeks of free Flu treatment was ineffective, suggesting that BP-Flu-NIR is a rapid and effective antidepressant strategy.
Claims (8)
1. The compound for rapidly treating the depression is characterized by being compounded from black phosphorus nanosheets and antidepressant drugs.
2. The composition for the rapid treatment of depression according to claim 1, wherein said antidepressant is fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram.
3. The composition for the rapid treatment of depression according to claim 1, wherein said antidepressant is fluoxetine.
4. The method for preparing a compound for rapidly treating depression according to claim 1, wherein the compound is obtained by dispersing black phosphorus nanosheets and antidepressant drugs in physiological saline, stirring and compounding at normal temperature and in the dark, and then centrifuging and washing.
5. The preparation method of the compound for rapidly treating depression according to claim 4, wherein the mass ratio of the black phosphorus nanosheet to the fluoxetine is 1: 2-1: 20.
6. The preparation method of the compound for rapidly treating depression according to claim 5, wherein the mass ratio of the black phosphorus nanosheet to the fluoxetine is 1: 5.
7. The preparation method of the compound for the rapid treatment of the depression according to claim 2, wherein the stirring compound time is 20-30 h.
8. The use of a compound for the rapid treatment of depression according to claim 1, which is used for preparing a medicament for treating depression.
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| CN114366806A (en) * | 2021-12-16 | 2022-04-19 | 天津市泌尿外科研究所 | Nano-drug complex of nano-black phosphorus loaded SDF-1 and preparation method and application thereof |
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| CN106335885A (en) * | 2016-08-17 | 2017-01-18 | 深圳先进技术研究院 | Black phosphorus nanosheet and preparation method and application thereof |
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| CN114366806A (en) * | 2021-12-16 | 2022-04-19 | 天津市泌尿外科研究所 | Nano-drug complex of nano-black phosphorus loaded SDF-1 and preparation method and application thereof |
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