CN115252558B - Multi-drug liposome system taking phosphatidyl drug as framework, and preparation method and application thereof - Google Patents
Multi-drug liposome system taking phosphatidyl drug as framework, and preparation method and application thereof Download PDFInfo
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- CN115252558B CN115252558B CN202211078734.2A CN202211078734A CN115252558B CN 115252558 B CN115252558 B CN 115252558B CN 202211078734 A CN202211078734 A CN 202211078734A CN 115252558 B CN115252558 B CN 115252558B
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- 125000001095 phosphatidyl group Chemical group 0.000 title claims abstract description 37
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- 150000002632 lipids Chemical class 0.000 claims abstract description 28
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- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
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- BHYOQNUELFTYRT-DPAQBDIFSA-N cholesterol sulfate Chemical compound C1C=C2C[C@@H](OS(O)(=O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 BHYOQNUELFTYRT-DPAQBDIFSA-N 0.000 description 1
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- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
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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
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses a multi-drug liposome system taking a phosphatidyl drug as a framework, and a preparation method and application thereof, wherein the preparation method comprises the following steps: respectively weighing phosphatidyl prodrug, synergic chemotherapeutic medicine, PEG-lipid complex and cholesterol to prepare a lipid composition; preparing a mixed lipid membrane; re-dissolving under low-power ultrasound, and then performing high-power ultrasound to obtain a crude nano preparation solution; preparing nanometer preparation with uniform particle diameter. The invention creatively utilizes the structural similarity of the phosphatidyl prodrug and the traditional phospholipid to prepare the lipoid nanometer preparation which does not need to add the phospholipid but also has a bilayer structure, and the preparation can respond to the hydrolysis triggered by the phospholipase D highly expressed at the tumor part, thereby achieving the purpose of specifically releasing two synergic chemotherapeutics at the tumor part, avoiding the treatment complexity caused by biological distribution of different pharmacokinetics in the combined administration and solving the problems of multi-drug delivery and safe and effective release in the anti-tumor treatment.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to a multi-drug liposome system taking a phosphatidyl drug as a framework, and a preparation method and application thereof.
Background
Chemotherapy remains the predominant method in clinical tumor treatment, generally exerting a cancer inhibiting effect by affecting the cell proliferation of tumor cells. Side effects of chemotherapeutic agents are the most important issue because traditional chemicals, such as various small molecule drugs, have non-specific cytotoxicity, including severe systemic toxicity, low levels of cellular uptake, and development of multi-drug resistance (MDR). These toxicities are generally determined by the nature of the drug itself, such as poor stability, low solubility, and rapid metabolism. To overcome these shortcomings, various drug delivery systems have been designed for chemotherapeutic drug delivery. Since a single anticancer drug or gene may not be sufficient to cope with tumor cells and their complex microenvironment, the combined use of multiple drugs is a common therapeutic regimen, e.g., drug-drug, drug-gene, gene-gene co-administration. In order to verify the synergistic effect between drugs, it is necessary to use a variety of statistical methods, such as multi-drug effect/Combination Index (CI) or equivalent line analysis.
Liposomes, which are the most mature nanocarriers, are often used for co-administration. However, it has disadvantages in that: 1) The drug loading capacity of the current liposome is generally lower than 10% (w/w%), and a large amount of carrier is needed to achieve the administration dosage, and systemic toxicity and serious anaphylactic reaction can be caused due to physical disintegration of the liposome in a human body, and the traditional liposome encapsulation strategy generally causes side effects and insufficient dosage to target cells; 2) Conventional liposomes cannot achieve targeted release.
Disclosure of Invention
The invention aims to provide a multi-drug liposome system taking a phosphatidyl drug as a framework, and a preparation method and application thereof, so as to solve the problems of low drug loading capacity, high side effect and incapability of targeted release when the liposome is used as a multi-drug delivery carrier in the prior art.
In order to solve the problems, the invention adopts the following technical scheme:
according to a first aspect of the present invention, there is provided a method for preparing a multi-drug liposome system using a phosphatidyl drug as a scaffold, comprising the steps of: s1, preparing a lipid composition: respectively weighing and mixing a phosphatidyl prodrug, a synergistic chemotherapeutic agent, a PEG-lipid complex and cholesterol to obtain a lipid composition; s2, preparing a mixed lipid membrane: dissolving the lipid composition in an organic solvent, and drying the organic solvent by decompression or nitrogen to obtain a mixed lipid membrane; s3, obtaining a crude nano preparation solution: the mixed lipid membrane is redissolved by using a buffer solution under low-power ultrasound, and then high-power ultrasound is carried out to obtain a crude nano preparation solution; s4, preparing a nano preparation by using an extruder: the crude nano preparation solution is prepared into nano preparation with uniform particle size by an extruder, namely a multi-drug liposome system taking phosphatidyl drugs as frameworks.
Preferably, in step S1, the phosphatidyl prodrug is selected from: phosphatidyl prodrugs such as phosphatidylmitoxantrone, phosphatidyldoxorubicin, phosphatidylcytarabine, or phosphatidylgemcitabine that are triggered by PLD in response to release; the synergistic chemotherapeutic agent is selected from the group consisting of: hydroxycamptothecin, irinotecan, paclitaxel, vincristine, etoposide, phorbol ester, or the like. It will be appreciated that in accordance with the present invention, the phosphatidyl prodrug and the co-chemotherapeutic agent may be formulated within the above ranges, optionally in each case, according to actual requirements.
It should be understood that the "phosphatidyl prodrug" in the present invention is formed by bonding a hydrophilic antitumor drug containing a primary alcohol and a phosphate compound through phosphorus-oxygen bond under the catalysis of phospholipase D, and the specific preparation process of the phosphatidyl prodrug can be referred to in patent application CN105963708A, and the phosphatidyl prodrug has amphipathy, forms a micelle by molecular self-assembly in an aqueous phase, and can be hydrolyzed to release the hydrophilic antitumor drug containing the primary alcohol under the catalysis of phospholipase D highly expressed in tumor tissue after the micelle enters the tumor tissue in a targeted manner.
Preferably, in step S1, the molar ratio of the phosphatidyl prodrug, the co-chemotherapeutic, the PEG-lipid complex and cholesterol is (9-11): (0.5-3): 1: (2-4).
According to a preferred embodiment of the present invention, in step S1, the lipid mixture comprises phosphatidyl mitoxantrone, hydroxycamptothecin, PEG-lipid complex, cholesterol, wherein the molar ratio of phosphatidyl mitoxantrone, hydroxycamptothecin, PEG-lipid complex, cholesterol is 10: (0.5-3): 1:3.
in step S2, the organic solvent is selected from: tetrahydrofuran, dichloromethane, ethanol, or the like.
In the step S3, the buffer solution is PBS phosphate buffer solution with pH of 6.5-7.5.
In step S3, the low-power ultrasound conditions are: continuously ultrasonic at 100W for 2-10 min; the high-power ultrasonic conditions are as follows: the ultrasonic wave of 250W is circulated for 60-120 times, and the time of each circulation is 10 seconds, wherein the ultrasonic wave is 5 seconds and the interval is 5 seconds.
Furthermore, the lipid composition not only comprises necessary added component materials of a basic structure, but also can select RGD, ANG, folic acid, transferrin, targeting monoclonal antibody and other functional modified materials, and traditional liposome materials such as phosphatidylethanolamine, deoxycholic acid, cholesterol sulfate and the like to adjust the performance.
According to a second aspect of the present invention, there is provided a multi-drug liposome system having a phosphatidyl drug as a scaffold, prepared by the preparation method as described above.
According to a third aspect of the present invention, there is provided the use of a multidrug liposome system having a phosphatidyl drug as a matrix in the manufacture of a medicament for the treatment of a tumor.
In the application, the multi-drug liposome system taking the phosphatidyl drug as the framework is prepared into the drug for treating the tumor, the multi-drug liposome system taking the phosphatidyl drug as the framework is self-assembled into the nano-liposome in the water phase, and after the nano-liposome enters the tumor tissue in a targeting way, the nano-liposome simultaneously releases two chemotherapeutic drugs with synergistic effect under the catalysis of the phospholipase D with high expression in the tumor tissue, so that the treatment complexity caused by the biodistribution of different pharmacokinetics in the combined administration is avoided, and the problems of multi-drug delivery and safe and effective release in the anti-tumor treatment are solved.
Preferably, the particle size of the nano-liposome is 100-180 nm.
According to a preferred scheme of the invention, a preparation method of a multi-drug liposome system taking phosphatidylmitoxantrone liposome as a framework is provided, and the preparation method comprises the following specific steps: weighing 44mg of phosphatidylmitoxantrone, 2000.33 mg of DSPE-mPEG, 1.47mg of hydroxycamptothecin and 4.4mg of cholesterol, adding 12ml of tetrahydrofuran, and performing ultrasonic treatment at normal temperature until the mixture is dissolved to obtain an oil phase; 20ml of 10mM PBS buffer solution (pH 6.5) was prepared as an aqueous phase; removing tetrahydrofuran in an oil phase by reduced pressure evaporation to obtain a dry lipid film, soaking the film in a water phase, continuously ultrasonic for 5 minutes to redissolve the lipid film at 100W, and after the solution is changed into a blue turbid solution, increasing ultrasonic power, and ultrasonic for 90 cycles at 250W, wherein the cycle time is 10 seconds each time, and ultrasonic for 5 seconds and intermittent for 5 seconds to obtain a crude nano preparation solution; finally, changing the crude nano preparation into nano preparation with uniform particle size by an extruder to obtain the multi-drug liposome system taking phosphatidylmitoxantrone liposome as a framework.
Further, we found in the study that the more stable the drug morphology, the smaller the liposome particle size, and the higher the encapsulation efficiency, when the PEG-lipid complex content in the phosphatidylmitoxantrone liposome is increased, but the higher the PEG-lipid complex content, the longer-term storage performance of the liposome is reduced. Preferably, therefore, the molar ratio of phosphatidylmitoxantrone, hydroxycamptothecin, PEG-lipid complex, cholesterol is 10: (0.5-3): 1:3.
furthermore, the liposome prodrug can also exchange phosphatidyl prodrugs such as phosphatidyl doxorubicin, phosphatidyl cytarabine, phosphatidyl gemcitabine and the like which can respond to release under the trigger of PLD.
Furthermore, the medicine hydroxycamptothecin can also be replaced by other anticancer medicines such as irinotecan, taxol, vincristine, etoposide, phorbol ester and the like.
The key invention is that the phosphatidyl prodrug is firstly selected as a delivery carrier to prepare a multi-drug liposome system, the phosphatidyl prodrug is an antitumor prodrug which is released in a targeting manner by enzymes in a tumor, and simultaneously has amphiphilicity and self-assembly capability of phospholipids, and can be used as a nano carrier to load other drugs, so that the multi-drug liposome nano system for the targeting release in the tumor is assembled. However, a similar technical solution for carrying a synergistic chemotherapeutic drug using a phosphatidyl prodrug as a backbone has never been disclosed in the prior art, and therefore the technical solution of the present invention should be unobvious.
According to the multi-drug liposome system taking the phosphatidyl drug as the framework, and the preparation method and the application thereof, the invention has the advantages compared with the prior art that:
1) The multi-drug delivery carrier prepared according to the invention takes the phosphatidyl prodrug as a framework, can respond to the hydrolysis triggered by the phospholipase D highly expressed in the tumor part, realizes the tumor part specific release of two chemotherapeutic drugs with synergistic effect, and solves the problems of multi-drug delivery and safe and effective release in anti-tumor treatment;
2) Because the phosphatidyl prodrug is not hydrolyzed and released in normal tissues, the nonspecific distribution of two chemotherapeutic drugs in the body is reduced, the two chemotherapeutic drugs are ensured to act on target cells at the same position at the same time, and the complexity of combined treatment caused by different pharmacokinetic biodistribution is avoided;
3) Because the carrier phosphatidyl prodrug is also a drug with anticancer activity, the total drug load in the multi-drug liposome system provided by the invention can exceed 50% (w/w%), thereby reducing the side effects related to excipients and improving the safety of the drug;
4) The invention realizes the phospholipase D triggering response release of various medicines in tumor tissues simultaneously, opens up a new idea for the development of medicines for treating tumors, and has good application prospect in clinical tumor treatment.
In summary, the multi-drug liposome system taking the phosphatidyl drug as the framework, and the preparation method and the application thereof provided by the invention have the advantages of high drug load, high safety and low side effect, can realize the specific release of two synergistic chemotherapeutics at the tumor part, and solve the problems of multi-drug delivery and safe and effective release in anti-tumor treatment.
Drawings
FIGS. 1A and 1B are graphs of particle size potential and encapsulation efficiency, respectively;
FIG. 2 is a diagram showing the morphology of the liposome of hydroxycamptothecin-phosphatidylmitoxantrone as observed by transmission electron microscopy;
FIG. 3 is a graph showing the results of hydroxycamptothecin-phosphatidylmitoxantrone liposomes releasing entrapped drug in response to phospholipase D hydrolysis;
FIG. 4 shows the cytotoxicity results of phosphatidylmitoxantrone, hydroxycamptothecin-phosphatidylmitoxantrone liposomes on MCF-7, respectively.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that the following examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
EXAMPLE 1 preparation of hydroxycamptothecin-phosphatidylmitoxantrone liposomes
Weighing 44mg of phosphatidylmitoxantrone, 2000.33 mg of DSPE-mPEG, 1.47mg of hydroxycamptothecin and 4.4mg of cholesterol, adding 12ml of tetrahydrofuran, and performing ultrasonic treatment at normal temperature until the mixture is dissolved to obtain an oil phase; 20ml of 10mM PBS buffer solution (pH 6.5) was prepared as an aqueous phase; removing tetrahydrofuran in the oil phase by reduced pressure evaporation to obtain a dry lipid film, then soaking the film in a water phase, continuously ultrasonic for 5 minutes to redissolve the lipid film at 100W, and after the solution is changed into a blue turbid solution, increasing ultrasonic power, and ultrasonic for 90 cycles at 250W, wherein each cycle time is 10 seconds, and ultrasonic for 5 seconds and intermittent for 5 seconds to obtain a crude nano preparation solution. Finally, changing the crude nano preparation into nano preparation with uniform particle size by an extruder to obtain HCPT-PMA, and storing the HCPT-PMA in a refrigerator at 4 ℃ in a dark place.
EXAMPLE 2 preparation of paclitaxel-phosphatidylmitoxantrone liposomes
Weighing 44mg of phosphatidylmitoxantrone, 2000.33 mg of DSPE-mPEG, 3.65mg of paclitaxel and 4.4mg of cholesterol, adding 12ml of tetrahydrofuran, and performing ultrasonic treatment at normal temperature until the materials are dissolved to obtain an oil phase; 20ml of 10mM PBS buffer solution (pH 6.5) was prepared as an aqueous phase; removing tetrahydrofuran in the oil phase by reduced pressure evaporation to obtain a dry lipid film, then soaking the film in a water phase, continuously ultrasonic for 5 minutes to redissolve the lipid film at 100W, and after the solution is changed into a blue turbid solution, increasing ultrasonic power, and ultrasonic for 90 cycles at 250W, wherein each cycle time is 10 seconds, and ultrasonic for 5 seconds and intermittent for 5 seconds to obtain a crude nano preparation solution. Finally, changing the crude nano preparation into nano preparation with uniform particle size by an extruder, thus obtaining PTX-PMA, and storing the PTX-PMA in a refrigerator at 4 ℃ in a dark place.
EXAMPLE 3 preparation of hydroxycamptothecin-phosphatidyldoxorubicin liposomes
Weighing 40mg of phosphatidyl doxorubicin, 2000.33 mg of DSPE-mPEG, 1.47mg of hydroxycamptothecin and 4.4mg of cholesterol, and adding 12ml of dichloromethane, and performing ultrasonic treatment at normal temperature until the phosphatidyl doxorubicin, the DSPE-mPEG, the hydroxycamptothecin and the cholesterol are dissolved to obtain an oil phase; 20ml of 10mM PBS buffer solution (pH 6.5) was prepared as an aqueous phase; after removing dichloromethane in the oil phase by reduced pressure evaporation, a dry lipid film is obtained, then the film is soaked in a water phase, the lipid film is redissolved for 5 minutes by 100W continuous ultrasound, after the solution is changed into a red turbid solution, the ultrasonic power is increased by 250W for 90 cycles, and the cycle time is 10 seconds each time, wherein the ultrasonic power is 5 seconds and the ultrasonic power is intermittent for 5 seconds, so that a crude nano preparation solution is obtained. Finally, changing the crude nano preparation into nano preparation with uniform particle size by an extruder, thus obtaining PTX-PX, and storing in a refrigerator at 4 ℃ in a dark place.
EXAMPLE 4 preparation of hydroxycamptothecin-phosphatidyl cytarabine liposomes
Weighing 20mg of phosphatidyl cytarabine, 2000.33 mg of DSPE-mPEG, 1.47mg of hydroxycamptothecin and 4.4mg of cholesterol, adding 12ml of ethanol, and performing ultrasonic treatment at normal temperature until the mixture is dissolved to obtain an oil phase; 20ml of 10mM PBS buffer solution (pH 6.5) was prepared as an aqueous phase; after ethanol in the oil phase is removed by reduced pressure evaporation, a dry lipid film is obtained, then the film is soaked in a water phase, the lipid film is redissolved for 5 minutes by 100W continuous ultrasound, after the solution is changed into a white turbid solution, the ultrasonic power is increased by 250W for 90 cycles, and the cycle time is 10 seconds each time, wherein the ultrasonic power is 5 seconds and the ultrasonic power is intermittent for 5 seconds, so that a crude nano preparation solution is obtained. Finally, changing the crude nano preparation into nano preparation with uniform particle size by an extruder, thus obtaining PTX-PAra, and storing the PTX-PAra in a refrigerator at 4 ℃ in a dark place.
EXAMPLE 5 preparation of RGD-hydroxycamptothecin-phosphatidylmitoxantrone liposomes
Weighing 44mg of phosphatidylmitoxantrone, 2000.33 mg of DSPE-mPEG, 1.47mg of hydroxycamptothecin, 5.11mg of DSPE-mPEG2000-RGD, adding 12ml of tetrahydrofuran, and performing ultrasonic treatment at normal temperature until the mixture is dissolved to obtain an oil phase; 20ml of 10mM PBS buffer solution (pH 6.5) was prepared as an aqueous phase; removing tetrahydrofuran in the oil phase by reduced pressure evaporation to obtain a dry lipid film, then soaking the film in a water phase, continuously ultrasonic for 5 minutes to redissolve the lipid film at 100W, and after the solution is changed into a blue turbid solution, increasing ultrasonic power, and ultrasonic for 90 cycles at 250W, wherein each cycle time is 10 seconds, and ultrasonic for 5 seconds and intermittent for 5 seconds to obtain a crude nano preparation solution. Finally, changing the crude nano preparation into nano preparation with uniform particle size by an extruder, thus obtaining HCPT-PMA-RGD, and storing in a refrigerator at 4 ℃ in a dark place.
EXAMPLE 6 characterization of hydroxycamptothecin-phosphatidylmitoxantrone liposomes
6.1 the morphology of hydroxycamptothecin-phosphatidylmitoxantrone liposomes was studied using transmission electron microscopy (JEM-1400). The filter paper was labeled in advance and placed on a plate. The tweezers are cleaned by absolute ethyl alcohol, and a copper net is placed at one end of the tweezers. 20uL of sample was added dropwise to the copper mesh and the mixture was allowed to stand for 15min. Excess sample solution at the edges was gently washed off with filter paper. And adding a drop of phosphotungstic acid dye liquor on the copper wire. After 20s of staining, the staining solution was gently sucked off with filter paper. Finally, the copper mesh was gently scraped from the tweezers onto a pre-prepared petri dish with filter paper and observed on-machine.
As shown in fig. 2, hydroxycamptothecin-phosphatidylmitoxantrone liposome has obvious bilayer structure, and similar to the conventional liposome, the cavity structure is beneficial to the storage of medicine.
6.2 study of PLD trigger Release ability of hydroxycamptothecin-phosphatidylmitoxantrone Liposome by dialysis, diluting hydroxycamptothecin-phosphatidylmitoxantrone Liposome to 1mg/mL, transferring 1mL into dialysis bag, and clamping both ends with clamps. Then placing the dialysis bag in 37deg.C water bath, wherein the outer water phase is buffer solution with pH of 6.5, and can be used as activator of PLD, caCl 2 The final concentration of (2) was 10mM. 5U of PLD was added to each dialysis bag, reacted in a shaker at 220rpm, and the external aqueous phase was completely replaced once every 6h interval. At each predetermined time point, a drug solution in a 10. Mu.L dialysis bag was taken, and as shown in FIG. 3, hydroxycamptothecin-phosphatidylmitoxantrone liposome had good enzymatic release ability.
6.3, the killing effect of hydroxycamptothecin, phosphatidylmitoxantrone and hydroxycamptothecin-phosphatidylmitoxantrone liposome on MCF-7 is detected by adopting a CCK-8 method, wherein MCF-7 cells are purchased from cell resource centers of Shanghai life science research institute of China academy of sciences, the experimental set concentrations are respectively 10, 5, 2.5, 1.25, 0.625 and 0.3125 mug/ml of culture medium, a blank control group without adding medicine is arranged, the concentration of each medicine is 3 compound holes, then the culture medium in 96-hole plate holes is removed, and the culture medium with medicine is added for culturing for 48 hours. After adding 10 mu l of CCK-8 for 4 hours to each hole, the absorbance of each hole is measured at the OD450nm position of the ELISA, and the inhibition effect of each drug concentration on cells is calculated.
The results are shown in FIG. 4, which shows that hydroxycamptothecin-phosphatidylmitoxantrone liposomes have enhanced antitumor activity relative to both hydroxycamptothecin and phosphatidylmitoxantrone.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and various modifications can be made to the above-described embodiment of the present invention. All simple, equivalent changes and modifications made in accordance with the claims and the specification of this application fall within the scope of the patent claims. The present invention is not described in detail in the conventional art.
Claims (4)
1. The preparation method of the multi-drug liposome system taking the phosphatidyl drug as the framework is characterized by comprising the following steps:
s1, preparing a lipid composition: respectively weighing and mixing a phosphatidyl prodrug, a synergistic chemotherapeutic, a PEG-lipid complex and cholesterol to obtain a lipid composition, wherein the phosphatidyl prodrug is phosphatidyl mitoxantrone; the synergistic chemotherapeutic agent is selected from the group consisting of: hydroxycamptothecin or paclitaxel, wherein the molar ratio of the phosphatidyl prodrug, the synergistic chemotherapeutic, the PEG-lipid complex and the cholesterol is (9-11): (0.5-3): 1: (2-4);
s2, preparing a mixed lipid membrane: the lipid composition is first dissolved in an organic solvent selected from the group consisting of: tetrahydrofuran, dichloromethane or ethanol, and drying the organic solvent by decompression or nitrogen to obtain a mixed lipid membrane;
s3, obtaining a crude nano preparation solution: the mixed lipid membrane is redissolved by using a buffer solution under low-power ultrasound, and then high-power ultrasound is carried out to obtain a crude nano preparation solution, wherein the low-power ultrasound conditions are as follows: continuously performing ultrasonic treatment for 2-10 minutes at 100W; the high-power ultrasonic conditions are as follows: 250W ultrasonic wave is circulated for 60-120 times, the time of each circulation is 10 seconds, wherein the ultrasonic wave is 5 seconds, and the time is intermittent for 5 seconds;
s4, preparing a nano preparation by using an extruder: the crude nano preparation solution is prepared into nano preparation with uniform particle size by an extruder, namely a multi-drug liposome system taking phosphatidyl drugs as frameworks.
2. The method according to claim 1, wherein in step S3, the buffer solution is PBS phosphate buffer solution with pH of 6.5-7.5.
3. A multi-drug liposome system with a phosphatidyl drug as a skeleton, prepared by the preparation method of any one of claims 1-2.
4. Use of a multidrug liposome system having a phosphatidyl drug as a matrix according to claim 3 in the manufacture of a medicament for the treatment of a tumor.
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