CN109394695B - Self-oxygen-supply liposome and preparation method and application thereof - Google Patents
Self-oxygen-supply liposome and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a liposome capable of self-supplying oxygen, a preparation method and application thereof, wherein ammonium bicarbonate (NH) is encapsulated in the liposome4HCO3) Calcium peroxide nanoparticles (CaO)2NP) and aza borofluoride complex dipyrromethene dye (Azo-BODIPY). Wherein, the Azo-BODIPY is used as a photosensitizer and a photothermal reagent, and can induce the ammonium bicarbonate encapsulated in the liposome hydrophilic layer to decompose and release carbon dioxide under the excitation of light with the wavelength of 622-885nm, and further react with CaO2NP reaction produces oxygen, thus has guaranteed the oxygen releases more rapidly and lastingly, has overcome the hypoxic microenvironment in the tumour to the influence of therapeutic effect. The liposome can be used as a novel self-oxygen-supply nano diagnosis and treatment platform and can be applied to high-efficiency photodynamic therapy of living tumor tissues.
Description
Technical Field
The invention belongs to the technical field of inorganic biological functional materials, and particularly relates to a liposome capable of supplying oxygen automatically, and a preparation method and application thereof.
Background
Cancer is a general term for a large group of malignant tumors, cancer cells grow in vivo indefinitely and indefinitely, and various toxins are released while nutrients in the body are consumed, so that various diseases are caused, and one of important factors causing human death. How to diagnose and treat cancer as early as possible and reduce the death rate caused by cancer is a problem which is urgently needed to be solved in the medical field.
Currently, the conventional cancer treatment means are mainly surgical resection, chemotherapy, and radiotherapy. Although these treatments are direct and effective, they have significant disadvantages: surgical resection cannot completely remove cancer cells that have spread to adjacent tissues, causing inevitable deterioration; chemotherapy and radiotherapy are invasive, weak in specificity, high in side effect and capable of damaging normal cells. In this context, the attention of scientists is drawn to photodynamic therapy, which is a therapeutic means that uses photosensitizer molecules to absorb specific photon energy and generate reactive oxygen species to directly or indirectly damage target tissues, thereby killing cancer cells. Because the photosensitizer is triggered by the photosensitizer under the condition of illumination, high-precision control on time and space can be realized, and meanwhile, the photodynamic therapy has the advantages of small invasiveness, suitability for participating in cooperative therapy and the like, and is gradually accepted by scientists in recent years, so that the further development of cancer treatment is promoted.
However, photodynamic therapy, while promising, still faces several difficulties and challenges. The photodynamic therapy effect is closely related to the oxygen concentration in tissues, and a hypoxic microenvironment in tumors is inevitable, so that the singlet oxygen quantum yield is seriously influenced, and the application of photodynamic therapy in actual clinic is limited. In addition, photosensitizers consume oxygen during use, and the oxygen partial pressure inside the tumor decreases, leading to an increased burden on therapy. Therefore, how to increase the oxygen concentration and improve the photodynamic therapy effect in the hypoxic microenvironment in the living tumor becomes a key problem to be solved in the field of photodynamic therapy.
In conclusion, it is important to develop a novel material which can supply oxygen by itself, has low toxicity and good biocompatibility, and can be used for treating cancer by photodynamic therapy.
Disclosure of Invention
The invention aims to provide a liposome capable of supplying oxygen automatically, and discloses a preparation method and application thereof. The liposome can spontaneously and rapidly generate oxygen under a specific light excitation condition, overcomes the influence of hypoxic microenvironment in tumors on photodynamic therapy, and has good application prospect in the aspect of photodynamic therapy.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: the invention relates to a self-oxygen-supply liposome which can spontaneously and rapidly generate oxygen under the excitation condition of light with the wavelength of 622-885nm and comprises NH4HCO3、CaO2NP and Azo-BODIPY moieties, CaO2The final NP content was 0.629mg/mL, the final Azo-BODIPY content was 0.156 mg/mL;
wherein, the structure of the Azo-BODIPY is as follows:
wherein R is1，R2＝CnH2n+1，n＝1，2，3…17；
Wherein X is halogen.
A preparation method of liposome capable of supplying oxygen automatically comprises the following specific preparation steps:
the method comprises the following steps: CaO (CaO)2Preparation of NP:
adding CaCl2Dissolving in ultrapure water, adding prepared ammonia water solution, PEG200 and H2O2The solution is stirred and centrifuged after the reaction is finished, and CaO is obtained2NP；
Step two: preparation of Azo-BODIPY:
the synthetic route for Azo-BODIPY is as follows:
wherein R is1,R2＝CnH2n+1，n＝1，2，3…17；
Wherein X is halogen;
wherein Et is-CH2CH3；
Wherein NIS ═ N-iodosuccinimide;
the specific synthetic steps of the Azo-BODIPY are as follows:
a) dissolving the 2 in ethanol, stirring and dissolving, adding the 1 and the prepared NaOH solution, stirring and reacting, and performing suction filtration to obtain 3;
b) dissolving the 3 in methanol, stirring and dissolving, adding nitromethane and diethylamine, stirring and reacting, neutralizing reaction liquid to be neutral after the reaction is stopped, extracting, washing an organic layer, drying, concentrating under reduced pressure, and recrystallizing to obtain 4;
c) adding 4 into butanol for dissolving, adding ammonium acetate, stirring for reaction, cooling to room temperature after the reaction is stopped, concentrating under reduced pressure, filtering, and recrystallizing to obtain 5;
d) dissolving 5 in dichloromethane, stirring and dissolving, cooling to 0-5 ℃ in an ice water bath, dropwise adding a dichloromethane solution containing triethylamine into the solution, then adding a dichloromethane solution containing boron trifluoride-diethyl ether, moving to room temperature, stirring and reacting, keeping the whole reaction system in a nitrogen protection state all the time, washing after the reaction is finished, drying, concentrating under reduced pressure, separating by column chromatography, and recrystallizing to obtain 6;
e) dissolving 6 and NIS in CHCl3And CH3Stirring and reacting in the mixed solution of COOH, extracting reaction liquid after the reaction is finished, and performing chromatographic separation on an organic phase column to obtain Azo-BODIPY;
step three: containing CaO2NP, Azo-BODIPY, and NH4HCO3The preparation of the liposome of (4):
weighing DPPC, cholesterol, DSPE-PEG 5000, and Azo-BODIPY, dissolving in chloroform, adding CaO2Distilling NP in alcohol under reduced pressure, removing solvent to obtain lipid layer film, and adding prepared NH4HCO3The solution is prepared by mixing a solvent and a solvent,and (4) carrying out ultrasonic treatment and centrifugation to obtain the target liposome.
Further, a self-oxygenating liposome of the present invention may be used for the production of oxygen in aqueous solution.
Further, a self-oxygenating liposome of the present invention may be used for the production of oxygen in cells.
Further, the self-oxygen-supply liposome can be used for imaging tumor cells.
Further, a self-oxygenating liposome of the present invention may be used in photodynamic therapy.
The invention has the beneficial effects that:
the invention discloses a liposome capable of self-supplying oxygen, a preparation method and application thereof, wherein the liposome comprises NH4HCO3、CaO2NP and Azo-BODIPY, wherein the Azo-BODIPY is used as photosensitizer and photothermal reagent, and can induce the decomposition of ammonium bicarbonate encapsulated in the hydrophilic layer of liposome to release carbon dioxide under the excitation of specific wavelength light, and further react with CaO2NP reaction produces oxygen, thus has guaranteed the oxygen releases more rapidly and lastingly, overcome the hypoxic microenvironment in the tumor to the influence of therapeutic effect. The liposome can be used as a novel self-oxygen-supply nano diagnosis and treatment platform, can be applied to high-efficiency photodynamic therapy of living tumor tissues, and has a good application prospect in the aspect of photodynamic therapy.
Drawings
FIG. 1 is a transmission electron micrograph of liposomes obtained in example 2 of the present invention;
FIG. 2 is a graph showing the amount of change in dissolved oxygen in a liposome dispersion before and after irradiation with light, obtained in example 3 of the present invention;
FIG. 3 is a graph of the amount of change in the absorption peak at 400nm under normoxic and hypoxic conditions obtained in example 4 of the present invention;
FIG. 4 is a diagram of confocal imaging in living cells under normoxic and hypoxic conditions obtained in example 5 of the present invention.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the following further describes the technical solution of the present invention with reference to the drawings and the embodiments.
Example 1
Preparation of liposomes
The method comprises the following steps: CaO (CaO)2Preparation of NP:
(I) weighing 3g of CaCl2Adding 30mL of ultrapure water into a reaction bottle for dissolving;
(II) adding 15mL of 1M ammonia water solution, and dropwise adding 94mL of PEG200 solution at a stirring speed of 500 r/min;
(III) 15mL of 30% H was added2O2Solution (one drop per 20 s);
(IV) stirring and reacting for 1h after the dropwise addition is finished;
(V) after the reaction is finished, taking the suspension for centrifugation, wherein the centrifugation conditions are as follows: rotating at 10000rpm for 5min, separating to obtain CaO2NP。
Step two: preparation of Azo-BODIPY:
the synthetic route for Azo-BODIPY is as follows:
the synthesis steps are as follows:
1) weighing 1.10g 2 in a flask, adding 10mL of ethanol, stirring for dissolving, then adding 1.03g 1, dropwise adding 4mL of 10% NaOH aqueous solution into the flask under the condition of rapid stirring, stirring at 30 ℃ for reaction for 9 hours, after the reaction is finished, performing suction filtration, washing a filter cake with water, then washing with a mixed solution of ethanol and water, and drying to obtain a solid product 3, wherein the yield is about 82%;
1H NMR(400MHz,CDCl3)(ppm):8.02(d,J＝7.2Hz,2H),7.77(d,J＝15.6Hz,1H),7.58(d,J＝8.4Hz,2H),7.43(d,J＝15.6Hz,1H),6.96(d,J＝8.8Hz 2H),6.91(d,J＝7.6Hz2H),4.08-3.97(m,4H),1.88-1.74(m,4H),1.49-1.25(m,12H),0.91(t,J＝13.6Hz,6H).
2) weighing 1.67g of 3 into a flask, adding 10mL of methanol, stirring for dissolving, adding 1.25g of nitromethane and 749.69mg of diethylamine, and stirring for reacting for 7 hours; after the reaction is finished, neutralizing the reaction liquid with dilute hydrochloric acid to be neutral, extracting dichloromethane, washing an organic layer with water and saturated sodium chloride solution in sequence, drying with anhydrous magnesium sulfate, concentrating under reduced pressure, and recrystallizing with an anhydrous ethanol/petroleum ether mixed solvent to obtain a solid product 4 with the yield of 67%;
1H NMR(400MHz,CDCl3)(ppm):7.88(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),6.90(d,J＝8.3Hz,2H),6.83(d,J＝7.6Hz,2H),4.85-4.58(m,2H),4.18-4.11(m,1H),4.00(t,J＝12.8Hz,2H),3.90(t,J＝12.8Hz,2H),3.41-3.28(m,2H),1.82-1.72(m,4H),1.50-1.28(m,12H),0.88(t,J＝10.8Hz,6H).
3) weighing 1.29g of 4 in a flask, adding 7mL of butanol, stirring for dissolving, adding 7.41g of ammonium acetate solid, heating to 80 ℃, condensing for refluxing, and stirring for reacting for 12 hours; after the reaction is finished, cooling the reaction liquid to room temperature, concentrating the reaction liquid to be one fourth of the original volume under reduced pressure, filtering the reaction liquid, and recrystallizing the reaction liquid by using absolute ethyl alcohol to obtain 5 with the yield of 32 percent;
1H NMR(400MHz,CDCl3)(ppm):8.02(d,J＝8.8Hz,4H),7.84(d,J＝8.8Hz,4H),7.01(d,J＝8.3Hz,4H),6.99(s,2H),6.94(d,J＝12.8Hz,4H),4.07-3.99(m,8H),1.88-1.77(m,8H),1.55-1.45(m,8H),1.42-1.33(m,16H),0.97-0.89(t,J＝6.8Hz,12H).
4) weighing 372.00mg 5 in a three-mouth reaction bottle, adding 15mL of dry dichloromethane, stirring and dissolving, cooling in an ice water bath, dropwise adding 4mL of dry dichloromethane solution containing 489.20mg of freshly distilled triethylamine into the solution at 0-5 ℃, dropwise and slowly adding a solution containing 973.17mg of boron trifluoride-diethyl ether and 5mL of dry dichloromethane, after dropwise addition, moving to room temperature, stirring and reacting for 24 hours, wherein the whole reaction system is always in nitrogen protection; after the reaction is finished, washing the reaction solution with water, washing with a saturated sodium chloride solution, drying with anhydrous magnesium sulfate, concentrating under reduced pressure, separating by column chromatography, and recrystallizing with ethanol to obtain 6 with a yield of 70%;
1H NMR(400MHz,CDCl3)(ppm):8.08(d,J＝2.0Hz,4H),8.06(d,J＝2.0Hz,4H),7.02(d,J＝2.2Hz,4H),6.99(d,J＝2.2Hz,4H),6.95(s,2H),4.08-4.03(m,8H),1.88-1.79(m,8H),1.45-1.32(m,24H),0.98-0.96(m,12H).
5) 275.00mg 6 and 76.14mg NIS were weighed into a flask and dissolved in 15mL CHCl3And 5mL CH3Stirring the mixed solution of COOH at room temperature for 12h, and reacting with CH after the reaction is finished2Cl2And H2And extracting the reaction solution by using O, and performing chromatographic separation on an organic phase column to obtain Azo-BODIPY with the yield of 87%.
1H NMR(400MHz,CDCl3)(ppm):7.83(d,J＝8.8Hz,4H),7.67(d,J＝8.9Hz,4H),7.01-6.95(m,8H),4.07-3.98(m,8H),1.88-1.78(m,8H),1.55-1.35(m,24H),0.98-0.91(m,12H).
Step three, preparing the liposome:
(I) weighing 5mg of DPPC, 1.8mg of cholesterol and 3.2mg of DSPE-PEG 5000 in a reaction bottle;
(II) weighing 1mg of Azo-BODIPY, dissolving in 2mL of chloroform, and adding the solution into the reaction bottle;
(III) adding 200. mu.L of CaO2Distilling the NP solution in ethanol (10mg/mL) under reduced pressure to remove the solvent to obtain a lipid membrane;
(IV) adding 2.7M NH to the lipid layer membrane4HCO310mL of solution and 30s of ultrasonic treatment;
(V) centrifuging the suspension under the following centrifugation conditions: rotating at 12000rpm for 10min at 15 deg.C, centrifuging, and dispersing 5mL ultrapure water to obtain target liposome.
Example 2
Transmission electron microscopy images of liposomes
The prepared liposome is shot by a transmission electron microscope, and the specific test steps are as follows: 20 mu L of sample solution with the concentration of 0.2mg/mL is dripped on a copper net, and the shape test is carried out after the sample is dried. As shown in FIG. 1, it can be seen that the liposome has good dispersibility in aqueous solution, and the particle size is about 80nm, which is favorable for entering cells and further provides oxygen supply possibility for organisms.
Example 3
Testing of dissolved oxygen variation before and after illumination
An 80. mu.g/mL liposome dispersion was prepared, and the solvent was ultrapure water. After 20min, the amount of change in dissolved oxygen in the dispersion was measured on the basis of the original apparatus by irradiation with a 730nm laser. The obtained image of the amount of change of dissolved oxygen before and after illumination is shown in fig. 2, and it can be seen from the image that the amount of change of oxygen in the solution is not obvious before illumination, and the increase of the oxygen content in the solution is obviously accelerated within a certain time after the 730nm laser is used for illumination. The experimental result shows that the synthesized liposome can accelerate the generation of oxygen under the condition of optical excitation with specific wavelength, and therefore, the liposome can be well used for photodynamic therapy.
Example 4
In the singlet oxygen generation experiments, 3-Diphenylisobenzofuran (DPBF) was used as an indicator. A solution of DPBF (200. mu.M) in dimethyl sulfoxide (DMSO) was mixed with the liposomes to be tested (80. mu.g/mL) at 730nm, 50mW/cm2The amount of change in the absorption peak of DPBF at 400nm per unit time under irradiation with light of (1) is observed to determine the generation of singlet oxygen and, further, the self-oxygenation of liposomes. The experiment is divided into a normal oxygen group and a hypoxic group, the experimental result is shown in figure 3, and it can be seen from the figure that under the specific light irradiation, the change amounts of the absorption peak values at 400nm of the normal oxygen group and the hypoxic group in the unit time are almost the same, which shows that the liposome has good self-oxygen supply capability under the hypoxic condition. Therefore, the liposome can be well used for photodynamic therapy.
Example 5
Application of liposome in living cell imaging experiment
Culturing human cervical cancer cells (HeLa) in DMEM medium containing liposomes (80. mu.g/mL) containing 5% CO at 37 deg.C2After 2 hours of incubation in the air, 2, 7-dichlorodihydrogenfluorescent yellow diacetic acid (DCFH-DA) (1 mu M) is added, the culture is continued for 15min, and the PBS buffer solution is washed for an imaging experiment, wherein the experiment is divided into a normoxic group and a hypoxic group. As can be seen from FIG. 4, the illumination (730nm, 50 mW/cm)2) After 6min, the Reactive Oxygen Species (ROS) content of the hypoxic group increased significantly and lasted longer, while the ROS content of the normoxic group increased more slowly. Experimental results show that the liposome can well generate ROS under the hypoxic condition and the special wavelength illumination excitation, and can be applied to photodynamic therapy.
The foregoing illustrates and describes the principles, general features, and advantages of the present invention. However, the above description is only an example of the present invention, the technical features of the present invention are not limited thereto, and any other embodiments that can be obtained by those skilled in the art without departing from the technical solution of the present invention should be covered by the claims of the present invention.
Claims (2)
1. A self-oxygen-supply liposome is characterized in that the liposome spontaneously and rapidly generates oxygen under the condition of light excitation with the wavelength of 622-885nm, and NH is contained in the liposome4HCO3、CaO2NP and Azo-BODIPY;
wherein, the structure of the Azo-BODIPY is as follows:
wherein R is1，R2＝CnH2n+1，n＝1，2，3…17；
Wherein X is halogen.
2. The method for preparing the liposome capable of self-supplying oxygen according to claim 1, which comprises the following steps:
the method comprises the following steps: CaO (CaO)2Preparation of NP:
adding CaCl2Dissolving in ultrapure water, adding prepared ammonia water solution, PEG200 and H2O2The solution is stirred and centrifuged after the reaction is finished, and CaO is obtained2NP；
Step two: preparation of Azo-BODIPY:
the synthetic route for Azo-BODIPY is as follows:
wherein Et is-CH2CH3；
Wherein NIS ═ N-iodosuccinimide;
the specific synthetic steps of the Azo-BODIPY are as follows:
a) dissolving the 2 in ethanol, stirring and dissolving, adding the 1 and the prepared NaOH solution, stirring and reacting, and performing suction filtration to obtain 3;
b) dissolving the 3 in methanol, stirring and dissolving, adding nitromethane and diethylamine, stirring and reacting, neutralizing reaction liquid to be neutral after the reaction is stopped, extracting, washing an organic layer, drying, concentrating under reduced pressure, and recrystallizing to obtain 4;
c) adding 4 into butanol for dissolving, adding ammonium acetate, stirring for reaction, cooling to room temperature after the reaction is stopped, concentrating under reduced pressure, filtering, and recrystallizing to obtain 5;
d) dissolving 5 in dichloromethane, stirring and dissolving, cooling to 0-5 ℃ in an ice water bath, dropwise adding a dichloromethane solution containing triethylamine into the solution, then adding a dichloromethane solution containing boron trifluoride-diethyl ether, moving to room temperature, stirring and reacting, keeping the whole reaction system in a nitrogen protection state all the time, washing after the reaction is finished, drying, concentrating under reduced pressure, separating by column chromatography, and recrystallizing to obtain 6;
e) dissolving 6 and NIS in CHCl3And CH3Stirring and reacting in the mixed solution of COOH, extracting reaction liquid after the reaction is finished, and performing chromatographic separation on an organic phase column to obtain Azo-BODIPY;
step three: containing CaO2NP, Azo-BODIPY, and NH4HCO3The preparation of the liposome of (4):
weighing DPPC, cholesterol, DSPE-PEG 5000 and Azo-BODIPY, dissolving in chloroform, adding CaO2Distilling NP in alcohol under reduced pressure, removing solvent to obtain lipid layer film, and adding prepared NH4HCO3And (4) carrying out ultrasonic treatment and centrifugation on the solution to obtain the target liposome.
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