CN107233314B - Composite phospholipid thermosensitive liposome with double-target-region simultaneous drug delivery effect and preparation method and application thereof - Google Patents
Composite phospholipid thermosensitive liposome with double-target-region simultaneous drug delivery effect and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a composite phospholipid thermosensitive liposome with double-target-region simultaneous drug delivery effects, and a preparation method and application thereof. The folic acid modified cyclodextrin drug-loaded inclusion compound is applied to prepare the inclusion compound, then the folic acid modified cyclodextrin inclusion compound and free drugs are respectively loaded into an inner water phase and a lipid bilayer of the composite phospholipid thermosensitive liposome, the liposome at a target position is triggered by heating to release the free drugs and the drug-loaded folic acid modified cyclodextrin inclusion compound during antitumor application, the free drugs mainly act on interstitium outside tumor cells, the drug-loaded folic acid modified cyclodextrin inclusion compound actively delivers drugs in a targeted manner through receptor mediation to enter the tumor cells, and finally the dual-target region simultaneous drug delivery of the tumor interstitium and the tumor cells is realized, and the optimal treatment effect can be realized by flexibly adjusting the drug ratio in the free drugs and the folic acid modified cyclodextrin inclusion compound. The invention is especially suitable for the anti-tumor application of traditional Chinese medicine complex components or monomer components with multiple effects, and has wide application prospect in the research aspect of anti-tumor novel drug delivery systems.
Description
Technical Field
The invention belongs to the field of pharmacy, relates to a targeting preparation, and a preparation method and application thereof, and particularly relates to a composite phospholipid thermosensitive liposome with double target areas and a simultaneous drug delivery effect, and a preparation method and application thereof.
Background
The traditional Chinese medicine components generally have multiple effects, namely 'multi-target point synergistic effect', the targets are often located in different target areas, and the requirements on the dosage of different target areas are often different, so that the multiple target areas are required to deliver the medicine at the same time, and the regulation of the medicine delivery ratio can be realized among different target areas.
The liposome and the inclusion compound belong to the category of new preparation technology, and can improve the drug delivery effect. In recent years, the active targeting modification technology of cyclodextrin is developed rapidly, and active targeting drug delivery of the drug-loaded cyclodextrin inclusion compound into cells (mainly tumor cells) can be realized by connecting ligands such as folic acid on the surface of cyclodextrin. However, since inclusion is performed only by physical action, the drug-loaded cyclodextrin inclusion compound is easy to leak the drug in blood circulation after administration, and cyclodextrin has a certain renal targeting property, thereby severely limiting the targeting effect.
The inclusion liposome is prepared by loading the drug into cyclodextrin to prepare the inclusion compound, and then loading the inclusion compound liposome into liposome. Compared with the inclusion compound, the inclusion compound liposome has better targeting property and stability; compared with liposome, the drug-loaded inclusion compound in the inclusion compound liposome is positioned in an internal water phase, so that the drug is more stable, and the cyclodextrin is also a good freeze-drying protective agent. Therefore, inclusion compound liposome is a more efficient carrier, and can use lipid bilayer and internal water phase 'dual drug loading', but can not realize multi-target zone simultaneous drug delivery.
Therefore, there is a need to develop new targeted formulations to improve the effect of simultaneous drug delivery in multiple target regions, and simultaneously improve the drug loading effect and stability of the vector.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention provides a composite phospholipid thermosensitive liposome which comprises an internal water phase, a lipid bilayer, an actively targeted drug-loaded folic acid modified cyclodextrin inclusion compound in the internal water phase of the liposome and free drugs in the lipid bilayer.
According to the present invention, the phospholipid thermosensitive liposome may be one or more of phospholipids such as Dipalmitoylphosphatidylcholine (DPPC), hydrogenated soybean phospholipids, stealth material DSPE-PEG2000 (distearoylphosphatidylethanolamine-polyethylene glycol), single-chain phospholipid MSPC or cholesterol.
According to the invention, the drug-loaded folic acid modified cyclodextrin inclusion compound can be formed by loading a lipophilic drug or a mixture thereof into folic acid modified cyclodextrin.
Preferably, the lipophilic drug is preferably a lipophilic drug with an oil-water partition coefficient of more than 10, such as one or more of zedoary turmeric oil, curcumenol, germacrone, beta-elemene, curdione, curcumin and demethoxycurcumin.
According to the invention, the free drug may be a drug which is not included with cyclodextrin, such as the lipophilic drugs mentioned above.
As an example of the invention, after loading zedoary turmeric oil, curcumenol, germacrone, beta-elemene or curdione into folic acid modified cyclodextrin inclusion compound, the folic acid modified cyclodextrin inclusion compound and free drug which are encapsulated with the zedoary turmeric oil, curcumenol, germacrone, beta-elemene or curdione are respectively loaded into the inner water phase and the lipid bilayer of the phospholipid thermosensitive liposome.
According to the invention, the proportion of the drug-loaded folic acid modified cyclodextrin inclusion compound and the free drug can be adjusted according to the administration requirement, and preferably, the molar ratio of the free drug to the drug-loaded folic acid modified cyclodextrin inclusion compound is 0.1-5: 1.
The invention also provides a preparation method of the composite phospholipid thermosensitive liposome, which comprises the following steps:
1) dissolving folic acid in dimethyl sulfoxide, adding a catalyst for reaction, adding an amino-beta-cyclodextrin pyridine solution with the concentration of 0.1-0.5 g/mL, and continuously stirring to react to obtain a solid. Dissolving the solid in water, standing, filtering, concentrating, precipitating, washing the precipitate, and drying to obtain folic acid modified cyclodextrin;
2) preparing a drug-loaded folic acid modified cyclodextrin inclusion compound by taking a lipophilic drug and the folic acid modified cyclodextrin obtained in the step 1);
3) loading the drug-loaded folic acid modified cyclodextrin inclusion compound obtained in the step 2) and free drugs into the liposome by adopting a membrane material.
Preferably, in the step 1), the molar ratio of the amino-beta-cyclodextrin to the folic acid can be (1-5): 1. The catalyst may be one or more of N-hydroxysuccinimide and N, N-dicyclohexylcarbodiimide in a molar ratio to amino- β -cyclodextrin of 2.4 (1-5), for example using N-hydroxysuccinimide, N-dicyclohexylcarbodiimide and amino- β -cyclodextrin in a molar ratio of 1.2:1.2 (1-5).
According to the invention, the reaction of the amino-beta-cyclodextrin and the folic acid with the catalyst is preferably carried out for 1-48 hours at a temperature of not higher than 50 ℃ in an inert gas, for example, the folic acid and the catalyst are reacted for 3 hours at room temperature under nitrogen, the amino-beta-cyclodextrin is added and stirred for 48 hours, and the temperature is controlled to 45 ℃ to continue the reaction for 2 hours.
The precipitation may be carried out by adding the concentrated concentrate to a poor solvent for the folate-modified cyclodextrin, such as acetone, for example, by dropwise addition to acetone.
According to the present invention, in step 2),
the molar ratio of the lipophilic drug to the folic acid modified cyclodextrin is 0.2-5: 1.
Preferably, the drug-loaded folic acid modified cyclodextrin inclusion compound is prepared by a saturated aqueous solution method or a grinding method.
According to the present invention, in step 3),
the phospholipid thermosensitive liposome has the definition as described above, for example, dipalmitoyl phosphatidylcholine in a weight ratio of 8: 1-3: 0.5-2: 0.2-1: hydrogenated soybean phospholipids: stealth material DSPE-PEG2000 (distearoylphosphatidylethanolamine-polyethylene glycol): single-chain phospholipid MSPC as membrane material comprises dipalmitoyl phosphatidylcholine (DPPC), Hydrogenated Soybean Phospholipid (HSPC), stealth material DSPE-PEG2000 and single-chain phospholipid MSPC at a molar ratio of 67.6:18.4:4: 10.
The molar ratio of the drug-loaded folic acid modified cyclodextrin inclusion compound to the free drug can be 1: 0.1-5.
The invention also provides application of the composite phospholipid thermosensitive liposome, which is used for preparing antitumor drugs, such as antitumor drugs with double-target-region simultaneous drug delivery effects.
Advantageous effects
Compared with the prior art, the composite phospholipid thermosensitive liposome simultaneously encapsulating the free drug and the folic acid modified drug-loaded cyclodextrin inclusion compound can simultaneously act on tumor cells and tumor stroma, and the anti-tumor effect is enhanced. Meanwhile, in the prior art, the fat-soluble medicine can only be encapsulated in a lipid bilayer of the liposome, but the composite phospholipid thermosensitive liposome provided by the invention can be simultaneously encapsulated in the lipid bilayer in a free medicine form and in an internal water phase in a cyclodextrin inclusion compound form, so that the medicine loading effect and the stability of the carrier are also obviously improved. After the composite phospholipid thermosensitive liposome is administrated, free medicines and active targeting cyclodextrin inclusion compounds are released at a target position. The free drug mainly acts on tumor stroma, and the active targeting cyclodextrin inclusion compound enters tumor cells through the mediation of a folic acid receptor, so that the simultaneous drug delivery of the tumor stroma and the tumor cells in double target areas is realized. And the proportion of the two can be flexibly adjusted to obtain the optimal treatment effect.
Drawings
Fig. 1 shows the release rate of the curcumenol complex phospholipid thermosensitive liposome (n-3) at different temperatures in example 6.
Fig. 2 shows the in vitro antitumor effect of the zedoary turmeric oil complex phospholipid thermosensitive liposome encapsulated in example 7 (n-5).
Detailed Description
The compounds of the present invention, methods for their preparation and their use are described in further detail in the following examples. The following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the examples are all commercially available products or can be prepared by known methods.
Example 1 preparation of a Complex phospholipid thermosensitive Liposome with Dual target regions for Simultaneous drug delivery
1) Dissolving 1 part of folic acid in dimethyl sulfoxide, adding 1.2 parts of N-hydroxysuccinimide (NHS) and 1.2 parts of N, N-Dicyclohexylcarbodiimide (DCC), reacting for 3 hours under the protection of nitrogen and magnetic stirring in dark place, adding 1 part of amino-beta-cyclodextrin dissolved in 8ml of pyridine, continuing stirring for 48 hours, and continuing stirring for 2 hours at 45 ℃. And (3) evaporating most of the solvent under reduced pressure, dissolving the obtained solid in 300ml of distilled water, standing for 12 hours at 4 ℃, filtering, evaporating the filtrate under reduced pressure to 15ml, dropwise adding the filtrate into 300ml of acetone, stirring for 2 hours, taking the precipitate, washing the acetone, and drying in vacuum overnight to obtain the folic acid modified cyclodextrin.
2) Preparing the drug-loaded active targeting inclusion compound by mixing the curcumenol and the folic acid modified cyclodextrin according to the molar ratio of 1:1 and adopting a saturated aqueous solution method. Dissolving folic acid modified cyclodextrin in water to obtain saturated solution, dissolving curcumenol in anhydrous ethanol, dropwise adding folic acid modified cyclodextrin saturated aqueous solution, stirring at 50 deg.C to volatilize ethanol, standing to room temperature, filtering with 0.45 μm filter membrane, and freeze drying the filtrate to obtain curcumenol-loaded folic acid modified cyclodextrin clathrate.
3) Taking dipalmitoyl phosphatidylcholine (DPPC): hydrogenated Soybean Phospholipids (HSPC): stealth material DSPE-PEG 2000: the single-chain phospholipid MSPC (molar ratio is 67.6:18.4:4:10) is used as a membrane material, curcumenol and the lipid are dissolved in absolute ethyl alcohol together, the folic acid modified cyclodextrin inclusion compound carrying the curcumenol is dissolved in a water phase, the ethanol phase is injected into the water phase under the condition of magnetic stirring, the ethanol is volatilized after stirring for 1h at 60 ℃, the particle size is reduced by ultrasonic, and the composite phospholipid thermosensitive liposome simultaneously encapsulating the curcumenol folic acid modified cyclodextrin inclusion compound and the free curcumenol is obtained. Wherein the ratio of free curcumenol to curcumenol in the folic acid modified cyclodextrin inclusion compound is 1: 1.
Example 2 preparation of Complex phospholipid thermosensitive liposomes having Simultaneous Dual target delivery Effect
Referring to the preparation procedure of example 1, unlike example 1, the ratio of folic acid to amino β -cyclodextrin was 1: 2; the loaded medicine is zedoary turmeric oil; the proportion of the zedoary turmeric oil and folic acid modified cyclodextrin in preparing the inclusion compound is 5: 1; the ratio of free zedoary turmeric oil in the liposome to zedoary turmeric oil in the folic acid modified cyclodextrin inclusion compound is 1: 2.
Example 3 preparation of Complex phospholipid thermosensitive liposomes having Simultaneous Dual target delivery Effect
Referring to the preparation procedure of example 1, in contrast to example 1, the ratio of folic acid to amino β -cyclodextrin was 0.2: 1; the loaded medicine is beta-elemene; the proportion of beta-elemene and folic acid modified cyclodextrin in preparing the inclusion compound is 2: 1; the ratio of free beta-elemene in the liposome to beta-elemene in the folic acid modified cyclodextrin inclusion compound is 1: 5.
Example 4 preparation of Complex phospholipid thermosensitive liposomes having Simultaneous Dual target delivery Effect
Referring to the preparation procedure of example 1, unlike example 1, the ratio of folic acid to amino β -cyclodextrin was 1: 5; the loaded medicine is germacrone; the proportion of germacrone to folic acid modified cyclodextrin in preparing the inclusion compound is 1: 5; the ratio of free germacrone in the liposome to germacrone in the folate-modified cyclodextrin inclusion compound is 2:1.
Example 5 preparation of Complex phospholipid thermosensitive liposomes having Simultaneous Dual target delivery Effect
Referring to the preparation procedure of example 1, unlike example 1, the ratio of folic acid to amino β -cyclodextrin was 1: 1; the loaded medicine is curdione; the proportion of curdione to folic acid modified cyclodextrin in preparing the inclusion compound is 0.5: 1; the ratio of free curdione in the liposome to curdione in the folic acid modified cyclodextrin inclusion compound is 1: 3.
Example 6 study on temperature-sensitive Release degree of Curcumol-encapsulated phospholipid composite thermosensitive liposomes
The temperature-sensitive release degree of the composite phospholipid thermosensitive liposome encapsulating the curcumenol folic acid modified cyclodextrin inclusion compound and the free curcumenol prepared in the example 1 is studied. The release medium is pH 7.4 isotonic phosphate buffer solution (formula containing 137mmol/L NaCl, 3mmol/L KCl, 8mmol/L NaHPO)4、1mmol/LKH2PO4). Adding the curcumenol complex phospholipid thermosensitive liposome into 100ml release medium, magnetically stirring at constant temperature and different temperature, sampling at different time points, ultrafiltering with ultrafiltration tube with molecular weight cutoff of 100K, collecting ultrafiltrate, measuring curcumenol concentration by HPLC, and calculating release degree, as shown in figure 1, it can be seen thatThe curcumenol folic acid modified cyclodextrin inclusion compound can rapidly pass through an ultrafiltration membrane, and the composite phospholipid thermosensitive liposome is rapidly and completely released at 42 ℃ and is slowly released at the body temperature of 37 ℃, so that the composite phospholipid thermosensitive liposome has good temperature-sensitive release performance.
Example 7 cytotoxicity Studies of Zedoariae rhizoma oil-encapsulated phospholipid composite thermosensitive liposomes
Cytotoxicity study was carried out on the zedoary turmeric oil-encapsulated phospholipid thermo-sensitive liposome prepared in example 2. Human cervical cancer cell Hela cells highly expressed by a folic acid receptor are used as test objects, zedoary turmeric oil with different concentrations and encapsulated zedoary turmeric oil composite phospholipid thermosensitive liposome are added, the temperature is heated for 1h at 42 ℃, then the incubation is carried out for 24h, the tumor cell activity is measured by adopting an MTT method, the inhibition rate is calculated, and the result is shown in figure 2, so that the in-vitro anti-tumor cells of the encapsulated zedoary turmeric oil composite phospholipid thermosensitive liposome are far higher than that of free zedoary turmeric oil.
Example 8 study of antitumor Effect of beta-elemene-encapsulated phospholipid composite thermosensitive liposomes
The β -elemene composite phospholipid heat-sensitive liposome prepared in the embodiment 2 of the invention and β -elemene are used for research of anti-tumor effect, human cervical carcinoma cell Hela cells with high folic acid receptor expression are adopted, and the axilla of a nude mouse is inoculated until the tumor size exceeds 150mm3The administration is started later, the intravenous administration is carried out once a day, the dose is 100mg/kg, the administration is continuously carried out for 5 days, the tumor part is heated for 1 hour at 42 ℃ after the administration, the animal is killed at 7 days after the administration, the tumor part is weighed, the inhibition rates are calculated, the inhibition rates of β -elemene and β -elemene composite phospholipid thermosensitive liposome are 34.66 percent and 67.96 percent respectively, and the anti-tumor effect of the β -elemene composite phospholipid thermosensitive liposome is improved by nearly one time.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. The composite phospholipid thermosensitive liposome is characterized by comprising an internal water phase, a lipid bilayer, an actively targeted drug-loaded folic acid modified cyclodextrin inclusion compound in the internal water phase of the liposome and free drugs in the lipid bilayer;
the phospholipid thermosensitive liposome is selected from dipalmitoyl phosphatidylcholine with the weight ratio of 8: 1-3: 0.5-2: 0.2-1: hydrogenated soybean phospholipids: stealth material DSPE-PEG 2000: single-chain phospholipid MSPC; wherein, the phospholipid thermosensitive liposome is used as a membrane material, and the liposome is loaded with a drug-loaded folic acid modified cyclodextrin inclusion compound and free drugs;
the drug-loaded folic acid modified cyclodextrin inclusion compound is formed by loading lipophilic drugs or a mixture thereof into folic acid modified cyclodextrin; the folic acid modified cyclodextrin inclusion compound is prepared by the following method: dissolving folic acid in dimethyl sulfoxide, adding a catalyst for reaction, adding an amino-beta-cyclodextrin pyridine solution with the concentration of 0.1-0.5 g/mL, continuously stirring to obtain a solid, dissolving the solid in water, standing, filtering, concentrating, precipitating, washing the precipitate, and drying to obtain folic acid modified cyclodextrin; the mol ratio of the amino-beta-cyclodextrin to the folic acid is (1-5) to 1;
the free drug is the lipophilic drug without being included by cyclodextrin;
the lipophilic drug is one or more selected from zedoary turmeric oil, curcumenol, germacrone, beta-elemene and curdione;
the molar ratio of the free drug to the drug-loaded folic acid modified cyclodextrin inclusion compound is 0.1-5: 1.
2. The complex phospholipid thermosensitive liposome of claim 1, wherein the folic acid-modified cyclodextrin inclusion compound encapsulating the zedoary turmeric oil, the curcumenol, the germacrone, the beta-elemene or the curdione and the free drug are loaded into the inner water phase and the lipid bilayer of the phospholipid thermosensitive liposome, respectively, after loading the zedoary turmeric oil, the curcumenol, the germacrone, the beta-elemene or the curdione into the folic acid-modified cyclodextrin inclusion compound.
3. The method for preparing a complex phospholipid thermosensitive liposome according to claim 1 or 2, comprising the steps of:
1) dissolving folic acid in dimethyl sulfoxide, adding a catalyst for reaction, adding an amino-beta-cyclodextrin pyridine solution with the concentration of 0.1-0.5 g/mL, continuously stirring to obtain a solid, dissolving the solid in water, standing, filtering, concentrating, precipitating, washing the precipitate, and drying to obtain folic acid modified cyclodextrin; wherein the molar ratio of the amino-beta-cyclodextrin to the folic acid is (1-5):1, and the molar ratio of the catalyst to the amino-beta-cyclodextrin is 2.4: (1-5); the catalyst is one or more of N-hydroxysuccinimide and N, N-dicyclohexylcarbodiimide; the amino-beta-cyclodextrin, the folic acid and the catalyst react for 1 to 48 hours at the temperature of not higher than 50 ℃ in inert gas;
2) preparing a drug-loaded folic acid modified cyclodextrin inclusion compound by taking a lipophilic drug and the folic acid modified cyclodextrin obtained in the step 1) through a saturated aqueous solution method or grinding; wherein the molar ratio of the lipophilic drug to the folic acid modified cyclodextrin is 0.2-5: 1;
3) loading the drug-loaded folic acid modified cyclodextrin inclusion compound obtained in the step 2) and free drugs into liposome by adopting a membrane material; wherein the dipalmitoyl phosphatidylcholine is used in a weight ratio of 8: 1-3: 0.5-2: 0.2-1: hydrogenated soybean phospholipids: stealth material DSPE-PEG 2000: blending and stirring single-chain phospholipid MSPC to obtain a membrane material; the molar ratio of the drug-loaded folic acid modified cyclodextrin inclusion compound to the free drug is 1: 0.1-5.
4. Use of the composite phospholipid thermosensitive liposome according to claim 1 or 2 for preparing an antitumor drug having a dual-target region simultaneous drug delivery effect.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101809039A (en) * | 2007-09-28 | 2010-08-18 | 那诺蒂克株式会社 | Cyclodextrin compound modified with folic acid, process for production thereof, drug delivery agent for targeting drug delivery system, pharmaceutical composition, and imaging agent |
| CN101926962A (en) * | 2010-08-20 | 2010-12-29 | 南京中医药大学 | Hydroxypropyl-beta-cyclodextrin inclusion liposome of zedoary turmeric oil and preparation method thereof |
| JP2014133809A (en) * | 2013-01-10 | 2014-07-24 | Kumamoto Univ | Novel nucleic acid delivery system using aphanothece sacrum polysaccharide body low molecular compound, manufacturing method of nucleic acid delivery carrier using the system |
| CN103520726B (en) * | 2013-10-21 | 2015-03-11 | 郑州大学 | Preparation method of invisible thermosensitive liposome as well as application of drug delivery system of invisible thermosensitive liposome in tumor treatment drugs |
-
2017
- 2017-05-08 CN CN201710318449.6A patent/CN107233314B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101809039A (en) * | 2007-09-28 | 2010-08-18 | 那诺蒂克株式会社 | Cyclodextrin compound modified with folic acid, process for production thereof, drug delivery agent for targeting drug delivery system, pharmaceutical composition, and imaging agent |
| CN101926962A (en) * | 2010-08-20 | 2010-12-29 | 南京中医药大学 | Hydroxypropyl-beta-cyclodextrin inclusion liposome of zedoary turmeric oil and preparation method thereof |
| JP2014133809A (en) * | 2013-01-10 | 2014-07-24 | Kumamoto Univ | Novel nucleic acid delivery system using aphanothece sacrum polysaccharide body low molecular compound, manufacturing method of nucleic acid delivery carrier using the system |
| CN103520726B (en) * | 2013-10-21 | 2015-03-11 | 郑州大学 | Preparation method of invisible thermosensitive liposome as well as application of drug delivery system of invisible thermosensitive liposome in tumor treatment drugs |
Non-Patent Citations (1)
| Title |
|---|
| 具有温敏释放特性的钙黄绿素复合磷脂脂质体的处方优化;何超芹 等;《中国药学杂志》;20131231;第48卷(第23期);第2022-2025页 * |
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