CN112138144B - Liposome containing active biological factor and preparation method thereof - Google Patents
Liposome containing active biological factor and preparation method thereof Download PDFInfo
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Abstract
The invention aims to provide a liposome containing active biological factors and a preparation method thereof, wherein the raw materials of the liposome are lecithin, cholesterol, phosphatidylethanolamine and the active biological factors, the active biological factors are preferably FGF-2, and the phosphatidylethanolamine is preferably dioleoylphosphatidylethanolamine; the liposome is prepared by a film dispersion method, has the advantages of high encapsulation efficiency, good stability and good biological activity, is suitable to be used as a carrier of active biological factors, and has great application and popularization values.
Description
Technical Field
The invention belongs to the field of active biological factors, and particularly relates to a liposome containing active biological factors and a preparation method thereof.
Background
Fibroblast growth factor is an important cytokine which has various physiological functions and plays an important role in life activities. The fibroblast growth factor family is currently known to comprise 23 members, with 30-80% homology between family members. Research on fibroblast growth factors has been focused on FGF-1 (a-FGF, acidic fibroblast growth factor), FGF-2 (b-FGF, basic fibroblast growth factor), FGF-13, FGF-21, etc.
FGF-2, namely basic fibroblast growth factor, is originally separated from bovine pituitary and brain tissue extracts and can promote division and proliferation of 2T3 cells, and subsequent researches show that FGF-2 is widely distributed in vivo, can be separated from pituitary, brain, hypothalamus, retina, adrenal gland, thymus, corpus luteum, kidney, heart, liver and placenta, and can also be expressed in various tumor tissues. The human FGF-2 gene is a single copy gene, is positioned on the short arm of chromosome 4, its total length is greater than 40kb, and its 5 'end and 3' end have non-coding sequence which can be used for regulating gene transcription, and its mRNA length is about 6802bp, and because of the difference of translation initiation sites it can produce a low Mr FGF-2 and 4 high Mr FGF-2.
FGF-2 is a multifunctional cytokine, such as it can promote mitosis of cells, induce angiogenesis, promote repair of damaged vascular endothelial cells, promote repair of soft tissue injury, promote repair of cartilage and bone tissue injury, promote repair and regeneration of nerve tissue, etc. In conclusion, the fibroblast growth factor, especially the basic fibroblast growth factor, has great clinical value and can be used for treating or assisting in treating various clinical diseases.
The half-life of exogenous active biomolecules such as fibroblast growth factors in vivo is short, for example, the half-life of FGF-2 in vivo is only 3-10min, and the effect of systemic or local administration cannot meet the clinical application requirement.
The existing fibroblast growth factor administration technology mainly focuses on the following aspects: heparin-regulated FGF drug release technology, namely heparin is combined to different carrier materials by a covalent grafting method to form a new material of a heparin-polymer compound, and then the FGF is entrapped or free heparin is directly mixed into the carrier materials in a non-covalent form, so that the release process of the drug FGF is influenced; FGF microspheres and nanospheres; an FGF liposome; FGF micelles; FGF hydrogels, and the like. Compared with liposome, heparin-controlled FGF drug release technology, FGF micelle, FGF hydrogel and other drug delivery technologies, the preparation steps are multiple, the technology is complex, the cost is high and the like, and the liposome is simple in preparation steps, low in cost and wide in clinical popularization prospect.
The liposome is prepared from phospholipid, cholesterol and other amphiphilic substances, a bilayer membrane forms one or more layers of hollow ultramicro spherical carrier dosage forms, the inside of the liposome is a closed vesicle with a water phase, and the liposome serving as a drug carrier can delay the release of drugs in vivo. However, the existing active biological factors, such as fibroblast growth factors, especially FGF-2 liposomes have the defects of low encapsulation efficiency, poor stability and the like, and the demand of further improvement exists.
Disclosure of Invention
In order to overcome the defects of low encapsulation efficiency and stability of the liposome of the active biological factor and easy reduction of biological activity in the prior art, the invention provides the liposome containing the active biological factor and the preparation method thereof.
Specifically, the invention provides a liposome containing an active biological factor, raw materials for preparing the liposome are lecithin, cholesterol, phosphatidylethanolamine and the active biological factor, and preferably the phosphatidylethanolamine is dioleoylphosphatidylethanolamine.
Further, the lecithin is one or more of soybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin and dipalmitoyl phosphatidylcholine, and is preferably soybean lecithin.
Further, the active biological factor is fibroblast growth factor, nerve growth factor, epidermal growth factor, insulin, preferably fibroblast growth factor, more preferably FGF-2.
Furthermore, the ratio of lecithin, cholesterol and dioleoyl phosphatidylethanolamine in the liposome is (by weight ratio) 10-20; the ratio is preferably 20.
Furthermore, the ratio of the lecithin, the cholesterol, the dioleoyl phosphatidylethanolamine and the active biological factor in the liposome is 10-20: 0.1 (weight ratio).
The invention also provides a preparation method of the liposome, and particularly relates to a method for preparing the liposome by a film dispersion method.
Further weighing required amount of lecithin, cholesterol, dioleoylphosphatidylethanolamine and active biological factors, putting into a eggplant-shaped bottle, and adding chloroform to completely dissolve; the chloroform in the solution is pumped out by a rotary evaporator through rotary evaporation, so that a layer of uniform lipid film is formed at the bottom and the inner wall of the eggplant-shaped bottle; place in a vacuum desiccator overnight to thoroughly remove the chloroform; adding 10% sucrose water solution, hydrating at room temperature for 30min to form semitransparent emulsion, extruding at room temperature, sieving with 0.22 μm microporous membrane for 5-10 times, and grading to obtain active biological factor liposome.
Furthermore, in the raw materials, the ratio of lecithin, cholesterol and dioleoyl phosphatidylethanolamine is (by weight ratio) 10-20; the ratio is preferably 20.
Furthermore, in the raw materials, the ratio of lecithin, cholesterol, dioleoyl phosphatidylethanolamine and active biological factors is (10-20): 0.1 (weight ratio).
Most further, the dosage of each raw material is as follows: 20mg of soybean lecithin, 5mg of cholesterol, 1.5mg of dioleoyl phosphatidylethanolamine and 100 mu g of active biological factor.
Advantageous effects
The liposome has high encapsulation efficiency and good stability, can well keep the activity of the active biological factor, and is suitable for long-term storage of the active biological factor; and the preparation method is used for identification, so that the industrial production and application of the active biological factor are facilitated.
Drawings
FIG. 1: transmission electron micrograph of FGF-2 liposome of the invention.
Detailed Description
The present invention is described in more detail below to facilitate an understanding of the present invention.
It should be understood that the terms or words used in the specification and claims should not be construed as having meanings defined in dictionaries, but should be interpreted as having meanings that are consistent with their meanings in the context of the present invention on the basis of the following principles: the concept of terms may be defined appropriately by the inventor for the best explanation of the invention.
The experimental procedures, for which specific conditions are not noted in the following examples, are generally carried out according to the routine experimental procedures in the art or according to the conditions recommended by the manufacturers.
Example 1: preparation of FGF-2 liposome by film dispersion method
The invention surprisingly discovers that the addition of phosphatidylethanolamine, particularly dioleoylphosphatidylethanolamine, into the liposome prepared from soybean lecithin and cholesterol can greatly improve the entrapment rate of the liposome to active biological factors and reduce the leakage rate of the liposome, and the stability of the liposome is also obviously improved.
Furthermore, preliminary experiments show that the liposome prepared by mixing soybean lecithin, cholesterol and dioleoyl phosphatidylethanolamine in a ratio of 10-20 (weight ratio) to 3-6 (weight ratio) has good shape, good stability, good encapsulation efficiency and other parameters, and is suitable for being used as a carrier of active biological factors.
Therefore, in this example, the liposome is prepared according to the above formulation, and the specific process parameters are as follows:
weighing 20mg of soybean lecithin, 5mg of cholesterol, 1.5mg of dioleoyl phosphatidylethanolamine and 100 mu g of FGF-2, putting into a solanaceous bottle, and adding chloroform to completely dissolve the materials; extracting chloroform from the solution by rotary evaporation by using a rotary evaporator, thereby forming a uniform lipid film on the bottom and the inner wall of the eggplant-shaped bottle; place in a vacuum desiccator overnight to thoroughly remove the chloroform; adding 10% sucrose water solution, hydrating at room temperature for 30min to form semitransparent emulsion, extruding at room temperature, sieving with 0.22 μm microporous membrane for 5-10 times, and grading to obtain FGF-2 liposome.
The transmission electron micrograph of the obtained liposome is shown in fig. 1.
The liposome prepared by the method is relatively complete and spheroidal, mainly has a single-chamber structure, has an average particle size of about 100.0nm, is mainly distributed between 65.45 and 136.55nm, has a zeta potential of-45.49 mV, namely an absolute value of the zeta potential is between 30 and 60mV, and is relatively stable.
Comparative example 1:
FGF-2 liposomes were prepared according to the following procedure: weighing 20mg of soybean lecithin, 5mg of cholesterol and 100 mu g of FGF-2, putting the soybean lecithin, the 5mg of cholesterol and the 100 mu g of FGF-2 into an eggplant-shaped bottle, and adding chloroform to completely dissolve the soybean lecithin, the cholesterol and the FGF-2; extracting chloroform from the solution by rotary evaporation by using a rotary evaporator, thereby forming a uniform lipid film on the bottom and the inner wall of the eggplant-shaped bottle; place in a vacuum desiccator overnight to thoroughly remove the chloroform; adding 10% sucrose water solution, hydrating at room temperature for 30min to form semitransparent emulsion, extruding at room temperature, sieving with 0.22 μm microporous membrane for 5-10 times, and grading to obtain FGF-2 liposome.
Comparative example 2:
FGF-2 liposomes were prepared according to the following steps: weighing 20mg of soybean lecithin, 5mg of cholesterol, 2mg of phosphatidyl glycerol and 100 mu g of FGF-2, putting the mixture into an eggplant-shaped bottle, and adding chloroform to completely dissolve the mixture; the chloroform in the solution is pumped out by a rotary evaporator through rotary evaporation, so that a layer of uniform lipid film is formed at the bottom and the inner wall of the eggplant-shaped bottle; the vacuum desiccator was placed overnight to thoroughly remove the chloroform; adding 10% sucrose water solution, hydrating at room temperature for 30min to form semitransparent emulsion, extruding at room temperature, sieving with 0.22 μm microporous membrane for 5-10 times, and grading to obtain FGF-2 liposome.
Test example:
1. determination of encapsulation efficiency
Placing 2mL of FGF-2 liposome in a 10mL quantitative bottle, diluting to the constant volume with dimethyl sulfoxide, diluting by 10 times with 95% ethanol, shaking up, quantifying by using HPLC, wherein the encapsulation efficiency calculation formula is as follows: encapsulation ratio (%) = (amount of FGF-2 encapsulated in liposome/total amount of FGF-2) × 100%.
2. Determination of the stability
Measuring a physical stability parameter KE by adopting a centrifugal spectrophotometry, sucking 1mL of FGF-2 liposome sample, placing the sample in a centrifuge tube for 10min at 3500rpm/min, centrifuging the sample, taking 0.3mL of liposome before centrifugation and supernatant after centrifugation, respectively adding phosphate buffer (pH 6.8) to dilute the sample to 5.0mL, measuring the absorbance of the sample at the wavelength of 500nm by taking the phosphate buffer as a blank, respectively measuring the absorbance values A0 and A before and after liposome centrifugation, calculating a stability parameter KE value, wherein the KE value is (A0-A)/A0 x 100%, and the smaller the KE value, the more stable the liposome is.
3. Determination of the leakage Rate
Separating FGF-2 liposome from free FGF-2 by Sephadex G-50 molecular exclusion chromatography, storing the suspension of the drug-loaded liposome at 4 deg.C, 25 deg.C and 37 deg.C respectively, and measuring the drug leakage rate by HPLC method, wherein the leakage rate (%) = (the amount of drug in liposome before placement-the amount of drug in liposome after placement)/the amount of drug in liposome is multiplied by 100%.
4. Determination of biological Activity
The biological activity of FGF-2 liposome is determined by adopting an MTT method, FGF-2 liposome or FGF-2 stock solution is diluted to 0.1mg/L by DMEM culture solution containing 0.5% serum, 100 microliter of the diluted FGF-2 stock solution is precisely absorbed and added into the 1 st hole, 4 times of dilution is carried out in sequence, 3 multiple holes are arranged at each dilution degree, the initial dose of the FGF-2 stock solution (standard substance) is 100U, blank liposome matrix control is arranged, the A value is determined at the position of 570nm by taking 630nm as a reference wavelength on an enzyme labeling instrument, and the biological activity of the FGF-2 liposome is calculated.
The results were as follows:
first, the encapsulation efficiency of liposomes at 4 ℃ storage conditions was specifically measured, and three samples were measured, and the change with time of the encapsulation efficiency of FGF-2 liposomes prepared in example 1 of the present invention and comparative examples 1-2 is shown in Table 1.
TABLE 1 variation of FGF-2 liposome encapsulation efficiency preserved at 4 ℃
As can be seen from the encapsulation efficiency results in Table 1, the FGF-2 liposome prepared in example 1 of the present invention achieves better encapsulation efficiency, and the encapsulation efficiency can be maintained at a higher level when stored at a low temperature of 4 ℃ for a long time, which is beneficial to the preservation of FGF-2.
Next, the stability of liposomes at 4 ℃ storage conditions was specifically measured, and three samples were measured, and the stability of FGF-2 liposomes prepared in example 1 of the present invention and comparative examples 1-2 as a function of time is shown in Table 2.
TABLE 2 variation of FGF-2 liposome stability when stored at 4 ℃
As can be seen from the stability results in table 2, the FGF-2 liposome prepared in example 1 of the present invention has better stability under low-temperature storage, and can be maintained at a higher level for a long period of time even when stored at low temperature for a long period of time, which is beneficial to the long-term storage of FGF-2.
The leakage rate and biological activity were measured in triplicate for a period of time at 4 ℃ and the results are shown in table 3:
table 3: changes in the leakage and biological Activity of FGF-2 liposomes when stored at 4 deg.C
As can be seen from the results of the changes in the permeability and biological activity of the liposomes shown in Table 3, the FGF-2 liposomes prepared in example 1 of the present invention have a lower permeability and a better biological activity under the condition of long-term low-temperature storage, which is advantageous for the long-term storage of FGF-2.
In summary, it is clear from the experimental data given in the above experimental examples that the liposome prepared from lecithin, cholesterol, dioleoylphosphatidylethanolamine and the active biological factor can obtain the best encapsulation efficiency and stability, and can maintain the biological activity of the active biological factor, thereby being beneficial to the industrial application of the active biological factor.
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention, and such modifications and adaptations are intended to be within the scope of the invention.
Claims (3)
1. A liposome comprising an active biological factor, wherein: raw materials for preparing the liposome comprise lecithin, cholesterol, phosphatidylethanolamine and active biological factors; the lecithin is soybean lecithin, and the phosphatidylethanolamine is dioleoyl phosphatidylethanolamine; the weight ratio of the soybean lecithin, the cholesterol, the dioleoyl phosphatidylethanolamine and the active biological factor in the liposome is 20.
2. A method for preparing the liposome of claim 1, wherein: preparing liposome by thin film dispersion method, weighing desired amount of soybean lecithin, cholesterol, dioleoylphosphatidylethanolamine, and active biological factor, placing into a bottle shaped like a eggplant, and adding chloroform to dissolve completely; the chloroform in the solution is pumped out by a rotary evaporator through rotary evaporation, so that a layer of uniform lipid film is formed at the bottom and the inner wall of the eggplant-shaped bottle; the vacuum desiccator was placed overnight to thoroughly remove the chloroform; adding 10% sucrose water solution, hydrating at room temperature for 30min to form semitransparent emulsion, extruding at room temperature, sieving with 0.22 μm microporous membrane for 5-10 times, and grading to obtain active biological factor liposome; the active biological factor is FGF-2.
3. The method of claim 2, wherein: wherein the dosage of each raw material is as follows: 20mg of soybean lecithin, 5mg of cholesterol, 1.5mg of dioleoyl phosphatidylethanolamine and 100. Mu.g of FGF-2.
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