CN115252558A - Multi-drug liposome system with phosphatidyl drug as framework and preparation method and application thereof - Google Patents
Multi-drug liposome system with phosphatidyl drug as framework and preparation method and application thereof Download PDFInfo
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- CN115252558A CN115252558A CN202211078734.2A CN202211078734A CN115252558A CN 115252558 A CN115252558 A CN 115252558A CN 202211078734 A CN202211078734 A CN 202211078734A CN 115252558 A CN115252558 A CN 115252558A
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- 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
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- 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
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Abstract
The invention discloses a multi-drug liposome system taking a phosphatidyl drug as a framework, a preparation method and application thereof, wherein the preparation method comprises the following steps: respectively weighing phosphatidyl prodrug, synergistic chemotherapeutic drug, PEG-lipid complex and cholesterol to prepare a lipid composition; preparing a mixed lipid film; re-dissolving under low-power ultrasound, and performing high-power ultrasound to obtain a crude nano preparation solution; preparing the nanometer preparation with uniform particle size. The invention creatively utilizes the structural similarity of the phosphatidyl prodrug and the traditional phospholipid to prepare the liposome-like nano preparation which does not need to be added with phospholipid and has a bilayer structure, the preparation can respond to the hydrolysis triggered by the phospholipase D highly expressed at a tumor part to achieve the aim of specifically releasing two synergistic chemotherapeutic drugs at the tumor part, the treatment complexity caused by the biological distribution of different pharmacokinetics in the combined administration is avoided, and the problems of multi-drug delivery and safe and effective release in the antitumor treatment are solved.
Description
Technical Field
The invention relates to the field of biological medicine, 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 most prominent method of clinical tumor treatment, and generally exerts a cancer-suppressing effect by affecting the cell proliferation of tumor cells. Side effects of chemotherapeutic agents are the most important problem because traditional chemical drugs, such as various small molecule drugs, have non-specific cytotoxicity, including severe systemic toxicity, low levels of cellular uptake, and development of multidrug resistance (MDR). These toxicities are generally determined by the properties of the drug itself, such as poor stability, low solubility, and rapid metabolism. To overcome these drawbacks, various drug delivery systems have been designed for chemotherapeutic drug delivery. Since a single anti-cancer drug or gene may not be sufficient to cope with the tumor cells and their complex microenvironment, the combination of multiple drugs is a common treatment protocol, such as drug-drug, drug-gene, gene-gene co-administration. The challenges present new requirements for Nanoparticles (NPs), and over the past decade, the search for multidrug combination delivery nanocarriers has increased dramatically for the development of liposomes, which can be divided into both single and bilayer types, and which can deliver hydrophilic and hydrophobic drugs due to the simultaneous presence of both aqueous and scaly lipid bilayers.
Liposomes, the most mature nanocarriers, are often used for co-administration. However, it has disadvantages in that: 1) The drug loading capacity in the current liposome is usually lower than 10% (w/w%), and a large amount of carriers are needed to achieve the administration dose, the physical disintegration of the liposome in the human body may cause systemic toxicity and serious anaphylactic reaction, and the traditional liposome encapsulation strategy usually causes side effects and insufficient dose to target cells; 2) Conventional liposomes do not 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 that the liposome in the prior art is low in drug loading capacity, high in side effect and incapable of targeted release when being used as a multi-drug delivery carrier.
In order to solve the problems, the invention adopts the following technical scheme:
according to the first aspect of the present invention, there is provided a method for preparing a multi-drug liposome system using a phosphatidyl drug as a backbone, comprising the steps of: s1, preparing a lipid composition: respectively weighing and mixing the phosphatidyl prodrug, the synergistic chemotherapeutic drug, the PEG-lipid complex and the cholesterol to obtain a lipid composition; s2, preparing a mixed lipid membrane: dissolving the lipid composition in an organic solvent, and removing the organic solvent by decompression or nitrogen blow-drying to obtain a mixed lipid membrane; s3, obtaining a crude nano preparation solution: re-dissolving the mixed lipid membrane by using a buffer solution under low-power ultrasound, and then performing high-power ultrasound to obtain a crude nano preparation solution; s4, preparing a nano preparation by using an extruder: and preparing the coarse nano preparation solution into a nano preparation with uniform particle size through an extruder, namely a multi-drug liposome system taking the phosphatidyl drug as a skeleton.
Preferably, in step S1, the phosphatidyl prodrug is selected from: phosphatidyl mitoxantrone, phosphatidyl doxorubicin, phosphatidyl cytarabine, or phosphatidyl gemcitabine, which may be released in response to the PLD trigger; the co-chemotherapeutic is selected from: hydroxycamptothecin, irinotecan, taxol, vincristine, etoposide or phorbol ester, etc. It is understood that, according to the present invention, the phosphatidyl prodrug and the co-chemotherapeutic may be optionally combined with each other within the above-mentioned ranges according to actual needs.
It should be understood that "phosphatidyl prodrug" in the present invention is formed by bonding a hydrophilic antitumor drug containing primary alcohol and a phospholipid compound through a phosphorus-oxygen bond under the catalytic action of phospholipase D, and the specific preparation process of the phosphatidyl prodrug can be referred to in patent application CN 105963708A.
Preferably, in step S1, the molar ratio of the phosphatidyl prodrug, the co-chemotherapeutic, the PEG-lipid complex, and the cholesterol is (9-11): (0.5 to 3): 1: (2-4).
According to a preferred embodiment of the present invention, in step S1, the lipid mixture material comprises phosphatidyl mitoxantrone, hydroxycamptothecin, PEG-lipid complex, cholesterol, wherein the molar ratio of phosphatidyl mitoxantrone, hydroxycamptothecin, PEG-lipid complex, cholesterol is 10: (0.5 to 3): 1:3.
in step S2, the organic solvent is selected from: tetrahydrofuran, dichloromethane, or ethanol, and the like.
In step S3, the buffer solution is PBS phosphate buffer solution with pH6.5-7.5.
In step S3, the low-power ultrasound conditions are: carrying out 100W continuous ultrasonic treatment for 2-10 minutes; the high-power ultrasonic conditions are as follows: and (3) carrying out 250W ultrasound for 60-120 cycles, wherein each cycle time is 10 seconds, and ultrasound is carried out for 5 seconds, and the rest is carried out for 5 seconds.
Furthermore, the lipid composition not only comprises necessary additive composition materials of a basic structure, but also can select functional modified materials such as RGD, ANG, folic acid, transferrin, targeted monoclonal antibody and the like, 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 backbone, prepared by the above-described preparation method.
According to the third aspect of the invention, the application of the multi-drug liposome system taking the phosphatidyl drug as the skeleton in preparing the drug for treating the tumor is provided.
In the application, the multidrug liposome system taking the phosphatidyl drug as the framework is prepared into the drug for treating the tumor, the multidrug liposome system taking the phosphatidyl drug as the framework is self-assembled into the nano-class liposome in a water phase, and after the nano-class liposome enters the tumor tissue in a targeting manner, the nano-class liposome simultaneously releases two chemotherapeutic drugs with synergistic effect under the catalysis of phospholipase D highly expressed in the tumor tissue, so that the treatment complexity caused by the biological distribution of different pharmacokinetics in the combined administration is avoided, and the problems of multidrug delivery and safe and effective release in the antitumor treatment are solved.
Preferably, the particle size of the nano lipoid is 100-180 nm.
According to a preferred embodiment of the present invention, there is provided a method for preparing a multidrug liposome system with phosphatidylmitoxantrone liposome as a skeleton, comprising the following steps: weighing 44mg of phosphatidyl mitoxantrone, 11.33mg of DSPE-mPEG2000, 1.47mg of hydroxycamptothecin and 4.4mg of cholesterol, adding 12ml of tetrahydrofuran, and performing ultrasonic treatment at normal temperature to dissolve to obtain an oil phase; preparing 20ml of 10mM PBS buffer solution (pH6.5) as an aqueous phase; evaporating and removing tetrahydrofuran in the oil phase under reduced pressure to obtain a dry lipid film, then soaking the film in the water phase, carrying out 100W continuous ultrasonic treatment for 5 minutes to redissolve a lipid film, and after the solution becomes a blue turbid solution, improving the ultrasonic power, carrying out 250W ultrasonic treatment for 90 cycles, wherein the cycle time is 10 seconds, and carrying out ultrasonic treatment for 5 seconds and carrying out 5-second intermission to obtain a coarse nano preparation solution; finally, the coarse nano preparation is changed into a nano preparation with uniform grain diameter through an extruder, and a multi-drug liposome system taking the phosphatidyl mitoxantrone liposome as a framework is obtained.
Further, we found in the research that when the content of the PEG-lipid complex in the phosphatidylmitoxantrone liposome is increased, the more stable the drug form is, the smaller the liposome particle size is, the higher the encapsulation efficiency is, but when the content of the PEG-lipid complex is too high, the long-term storage performance of the liposome is reduced. Thus preferably, the molar ratio of phosphatidyl mitoxantrone, hydroxycamptothecin, PEG-lipid complex, cholesterol is 10: (0.5 to 3): 1:3.
further, the niosome prodrug can be replaced by phosphatidyl adriamycin, phosphatidyl cytarabine, phosphatidyl gemcitabine and the like which can respond to release under PLD triggering.
Furthermore, the hydroxycamptothecin can also be replaced by irinotecan, paclitaxel, vincristine, etoposide, phorbol ester and other anticancer drugs.
The key point of the 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 enzymatically and targetedly released in tumors, has the amphiphilicity and the self-assembly capability of phospholipid, can be used as a nano carrier to load other drugs, and is further assembled into a multi-drug liposome type nano system which is targetedly released in tumors. However, the prior art never discloses a similar technical scheme for carrying a synergistic chemotherapeutic drug by taking a phosphatidyl prodrug as a framework, and therefore the technical scheme of the invention should have non-obvious property.
According to the multi-drug liposome system taking the phosphatidyl drug as the framework, the preparation method and the application thereof, compared with the prior art, the advantages are as follows:
1) According to the multi-drug delivery carrier prepared by the invention, the phosphatidyl prodrug is used as a framework, and hydrolysis triggered by phospholipase D highly expressed at a tumor part can be responded, so that tumor part specific release of two chemotherapeutic drugs with synergistic effect is realized, and the problems of multi-drug delivery and safe and effective release in antitumor treatment are solved;
2) The phosphatidyl prodrug can not be hydrolyzed and released in normal tissues, so that the nonspecific distribution of two chemotherapeutic drugs in vivo is reduced, the two chemotherapeutic drugs can simultaneously act on target cells at the same position, and the complexity of combined treatment caused by the biological distribution of different pharmacokinetics is avoided;
3) Because the carrier phosphatidyl prodrug is also a medicament with anticancer activity, the total loading capacity of the medicament in the multi-medicament liposome system provided by the invention can exceed 50 percent (w/w percent), the side effect related to the excipient is reduced, and the safety of the medicament is improved;
4) The invention realizes the phospholipase D trigger response release of a plurality of medicaments in tumor tissues at the same time, opens up a new idea for the development of tumor treatment medicaments, and has good application prospect in clinical tumor treatment.
In conclusion, the multi-drug liposome system with 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 chemotherapeutic drugs at a tumor part, and solve the problems of multi-drug delivery and safe and effective release in anti-tumor treatment.
Drawings
FIG. 1A and FIG. 1B are the particle size potential diagram and the encapsulation efficiency diagram, respectively;
FIG. 2 shows the lipoid form of hydroxycamptothecin-phosphatidyl mitoxantrone liposome observed by transmission electron microscopy;
FIG. 3 is the result of hydroxycamptothecin-phosphatidyl mitoxantrone liposome release of entrapped drug in response to phospholipase D hydrolysis;
FIG. 4 shows the cytotoxicity results of phosphatidyl mitoxantrone, hydroxycamptothecin-phosphatidyl mitoxantrone liposomes against MCF-7, respectively.
Detailed Description
The present invention is further illustrated by the following examples. It is to be understood that the following examples are illustrative of the present invention only and are not intended to limit the scope of the present invention.
Example 1 preparation of hydroxycamptothecin-Phosphatidylmixantrone liposomes
Weighing 44mg of phosphatidyl mitoxantrone, 11.33mg of DSPE-mPEG2000, 1.47mg of hydroxycamptothecin and 4.4mg of cholesterol, adding 12ml of tetrahydrofuran, and performing ultrasonic treatment at normal temperature to dissolve to obtain an oil phase; preparing 20ml10mM PBS buffer solution (pH6.5) as an aqueous phase; evaporating and removing tetrahydrofuran in the oil phase under reduced pressure to obtain a dry lipid film, then soaking the film in the water phase, carrying out 100W continuous ultrasonic treatment for 5 minutes to redissolve the lipid film, and after the solution becomes a blue turbid solution, increasing the ultrasonic power, carrying out 250W ultrasonic treatment for 90 cycles with the cycle time of 10 seconds each time, wherein the ultrasonic treatment is carried out for 5 seconds, and the intermittent treatment is carried out for 5 seconds to obtain a crude nano preparation solution. Finally, the coarse nano preparation is changed into a nano preparation with uniform particle size through an extruder to obtain HCPT-PMA, and the HCPT-PMA is stored in a refrigerator at 4 ℃ in a dark place.
Example 2 preparation of paclitaxel-Phosphatidylimide liposomes
Weighing 44mg of phosphatidyl mitoxantrone, 11.33mg of DSPE-mPEG2000, 3.65mg of paclitaxel and 4.4mg of cholesterol, adding 12ml of tetrahydrofuran, and performing ultrasonic treatment at normal temperature to dissolve to obtain an oil phase; preparing 20ml of 10mM PBS buffer solution (pH6.5) as an aqueous phase; evaporating and removing tetrahydrofuran in the oil phase under reduced pressure to obtain a dry lipid film, then soaking the film in the water phase, carrying out 100W continuous ultrasonic treatment for 5 minutes to redissolve the lipid film, and after the solution becomes a blue turbid solution, increasing the ultrasonic power, carrying out 250W ultrasonic treatment for 90 cycles with the cycle time of 10 seconds each time, wherein the ultrasonic treatment is carried out for 5 seconds, and the intermittent treatment is carried out for 5 seconds to obtain a crude nano preparation solution. Finally, the crude nano preparation is changed into a nano preparation with uniform particle size through an extruder, and the PTX-PMA is obtained and stored in a refrigerator at 4 ℃ in a dark place.
Example 3 preparation of hydroxycamptothecin-Phosphatidylachrysomycin Liposome
Weighing 40mg of phosphatidyl adriamycin, 11.33mg of DSPE-mPEG, 1.47mg of hydroxycamptothecin and 4.4mg of cholesterol, adding 12ml of dichloromethane, and performing ultrasonic treatment at normal temperature to dissolve to obtain an oil phase; preparing 20ml of 10mM PBS buffer solution (pH6.5) as an aqueous phase; evaporating under reduced pressure to remove dichloromethane in oil phase to obtain dry lipid film, soaking the film in water phase, performing 100W continuous ultrasonic treatment for 5min to redissolve lipid film, and performing 250W ultrasonic treatment for 90 cycles with each cycle time of 10 s after the solution becomes red turbid solution, wherein the ultrasonic treatment is performed for 5 s, and the intermittent treatment is performed for 5 s to obtain coarse nanometer preparation solution. And finally, the crude nano preparation is changed into a nano preparation with uniform particle size through an extruder to obtain the PTX-PX, and the PTX-PX is stored in a refrigerator at 4 ℃ in a dark place.
Example 4 preparation of hydroxycamptothecin-Phosphatidylchytidine liposomes
Weighing 20mg of phosphatidyl cytarabine, 11.33mg of DSPE-mPEG, 1.47mg of hydroxycamptothecin and 4.4mg of cholesterol, adding 12ml of ethanol, and performing ultrasonic treatment at normal temperature to dissolve to obtain an oil phase; preparing 20ml of 10mM PBS buffer solution (pH6.5) as an aqueous phase; evaporating under reduced pressure to remove ethanol in oil phase to obtain dry lipid film, soaking the film in water phase, performing continuous ultrasonic treatment at 100W for 5min to redissolve lipid film, and performing ultrasonic treatment at 250W for 90 cycles with each cycle time of 10 s after the solution becomes white turbid solution, wherein the ultrasonic treatment is performed for 5 s, and the intermittent treatment is performed for 5 s to obtain coarse nanometer preparation solution. And finally, the crude nano preparation is changed into a nano preparation with uniform particle size through an extruder to obtain the PTX-PAra, and the PTX-PAra is stored in a refrigerator at 4 ℃ in a dark place.
Example 5 preparation of RGD-hydroxycamptothecin-phosphatidylmitoxantrone liposomes
Weighing 44mg of phosphatidyl mitoxantrone, 11.33mg of DSPE-mPEG2000, 1.47mg of hydroxycamptothecin and 5.11mg of DSPE-mPEG2000-RGD, adding 12ml of tetrahydrofuran, and performing ultrasonic treatment at normal temperature to dissolve to obtain an oil phase; preparing 20ml of 10mM PBS buffer solution (pH6.5) as an aqueous phase; evaporating and removing tetrahydrofuran in the oil phase under reduced pressure to obtain a dry lipid film, then soaking the film in the water phase, carrying out 100W continuous ultrasonic treatment for 5 minutes to redissolve the lipid film, and after the solution becomes a blue turbid solution, increasing the ultrasonic power, carrying out 250W ultrasonic treatment for 90 cycles with the cycle time of 10 seconds each time, wherein the ultrasonic treatment is carried out for 5 seconds, and the intermittent treatment is carried out for 5 seconds to obtain a crude nano preparation solution. Finally, the crude nano preparation is changed into a nano preparation with uniform particle size through an extruder, and the HCPT-PMA-RGD is obtained and stored in a refrigerator at 4 ℃ in a dark place.
Example 6 characterization of hydroxycamptothecin-Phosphatidylimide liposomes
6.1 the morphology of hydroxycamptothecin-phosphatidyl mitoxantrone liposomes was studied using transmission electron microscopy (JEM-1400). The filter paper is labeled in advance and placed on a plate. The tweezers are cleaned by absolute ethyl alcohol, and the copper mesh is placed at one end of the tweezers. Add 20uL of sample drop-wise onto the copper mesh and wait 15min. Excess sample solution on the edges was gently washed away with filter paper. Adding a drop of phosphotungstic acid dye solution on the copper net. After staining for 20s, the staining solution was gently aspirated off with filter paper. Finally, the copper mesh was gently scratched from the forceps into a prepared petri dish with filter paper, and the plate was placed on a machine for observation.
As shown in figure 2, the hydroxycamptothecin-phosphatidyl mitoxantrone liposome has a distinct bilayer structure, similar to a conventional liposome, and the hollow structure is beneficial to the storage of the drug.
6.2 study the PLD trigger release capacity of the hydroxycamptothecin-phosphatidyl mitoxantrone liposome by dialysis, dilute the hydroxycamptothecin-phosphatidyl mitoxantrone liposome to 1mg/mL, transfer 1mL into a dialysis bag, and clamp both ends with clamps. Subsequently, the dialysis bag was placed in a 37 ℃ water bath, and the external aqueous phase was a buffer solution with pH6.5 as an activator of PLD, caCl 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 at 6h intervals. At each predetermined time point, 10 μ L of the drug solution in the dialysis bag was taken, as shown in FIG. 3, hydroxygenThe dendrimer-phosphatidyl mitoxantrone liposome has good enzymatic release capacity.
6.3 detecting killing effect of hydroxycamptothecin, phosphatidyl mitoxantrone and hydroxycamptothecin-phosphatidyl mitoxantrone liposome on MCF-7 by CCK-8 method, wherein MCF-7 cells are purchased from cell resource center of Shanghai Life sciences research institute of Chinese academy of sciences, experiment setting concentrations are respectively 10, 5, 2.5, 1.25, 0.625 and 0.3125 μ g/ml culture medium, a blank control group without medicine is provided, each medicine concentration is 3 multiple wells, then removing culture medium in 96-well wells, adding medicine-containing culture medium, and culturing for 48h. After 10 mul CCK-8 is added to each well, 4 hours later, the light absorption value of each well is measured at OD450nm of an enzyme linked immunosorbent assay detector, and the inhibition effect of each drug concentration on cells is calculated.
As a result, as shown in FIG. 4, it can be seen that the hydroxycamptothecin-phosphatidylmitoxantrone liposome has enhanced antitumor activity against both hydroxycamptothecin and phosphatidylmitoxantrone.
The above 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 may be made to the above-described embodiment of the present invention. All simple and equivalent changes and modifications made according to the claims and the content of the specification of the present invention are within the scope of the claims of the present invention. The invention has not been described in detail in order to avoid obscuring the invention.
Claims (10)
1. A preparation method of a multi-drug liposome system taking a phosphatidyl drug as a framework is characterized by comprising the following steps:
s1, preparing a lipid composition: respectively weighing and mixing the phosphatidyl prodrug, the synergistic chemotherapeutic drug, the PEG-lipid complex and the cholesterol to obtain a lipid composition;
s2, preparing a mixed lipid membrane: dissolving the lipid composition in an organic solvent, and removing the organic solvent by decompression or nitrogen blow-drying to obtain a mixed lipid film;
s3, obtaining a crude nano preparation solution: re-dissolving the mixed lipid membrane by using a buffer solution under low-power ultrasound, and then performing high-power ultrasound to obtain a crude nano preparation solution;
s4, preparing a nano preparation by using an extruder: and preparing the coarse nano preparation solution into a nano preparation with uniform particle size through an extruder, namely a multi-drug liposome system taking the phosphatidyl drug as a skeleton.
2. The method of claim 1, wherein in step S1, the phosphatidyl prodrug is selected from the group consisting of: phosphatidylmitoxantrone, phosphatidyldoxorubicin, phosphatidylcytarabine or phosphatidylgemcitabine; the co-chemotherapeutic is selected from: hydroxycamptothecin, irinotecan, paclitaxel, vincristine, etoposide or phorbol ester.
3. The method according to claim 1, wherein the molar ratio of the phosphatidyl prodrug, the co-chemotherapeutic agent, the PEG-lipid complex, and the cholesterol in step S1 is (9-11): (0.5 to 3): 1: (2-4).
4. The method according to claim 1, wherein in step S2, the organic solvent is selected from the group consisting of: tetrahydrofuran, dichloromethane or ethanol.
5. The method according to claim 1, wherein the buffer solution in step S3 is PBS phosphate buffer solution with pH of 6.5-7.5.
6. The method according to claim 1, wherein in step S3, the low-power ultrasound conditions are: carrying out 100W continuous ultrasonic treatment for 2-10 minutes; the high-power ultrasonic conditions are as follows: and (3) carrying out 250W ultrasound for 60-120 cycles, wherein each cycle time is 10 seconds, and ultrasound is carried out for 5 seconds, and the rest is carried out for 5 seconds.
7. A multi-drug liposome system having a phosphatidyl drug as a backbone, which is produced by the production method according to any one of claims 1 to 6.
8. Use of the multi-drug lipoid system with phosphatidyl drug as skeleton of claim 7 in preparing drugs for treating tumors.
9. The use of claim 8, wherein the multi-drug liposome system with the phosphatidyl drug as the backbone is self-assembled into nano-liposomes in an aqueous phase, and when the nano-liposomes enter tumor tissues in a targeted manner, the nano-liposomes release two chemotherapeutic drugs with synergistic effects simultaneously under the catalytic action of phospholipase D highly expressed in the tumor tissues.
10. The use according to claim 9, wherein the nanoliposome has a particle size of 100 to 180nm.
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