CN108236603A - A kind of Allercur polyamide liposome and preparation method thereof and application thereof - Google Patents

Abstract

The invention provides a pyrromidazole polyamide liposome and its preparation method and application, and specifically discloses a pyrromidazole polyamide liposome, which consists of a lipid bilayer and is entrapped in a lipid bilayer The pyrrolidazole polyamide in the composition, wherein lipid bilayer comprises phospholipid molecule and cholesterol, wherein, the molar ratio of phospholipid molecule and cholesterol is (3～4):1, and the mol ratio of phospholipid molecule and pyrrolidazole polyamide is ( 20～30):1. The pyrromidazole polyamide liposome of the present invention entraps pyrromidazole polyamide in the inner cavity of the liposome, which can effectively increase the encapsulation capacity compared with other carrier loading methods, thereby significantly improving the efficacy of pyrromidazole polyamide drugs. bioavailability.

Description

A kind of pyrromidazole polyamide liposome and its preparation method and application

technical field

The invention relates to the field of pharmaceutical preparations, in particular to a pyrromidazole polyamide liposome and a preparation method thereof.

Background technique

Gene-targeted cancer therapy is an emerging and efficient treatment method, and it is particularly critical to develop small molecule compound inhibitory drugs for tumor treatment. Pyrrolimidazole polyamide is a class of artificially synthesized five-membered heterocyclic compounds mainly composed of N-methylpyrrole (Py), N-methylimidazole (Im) and N-methyl-3-hydroxypyrrole (Hp) aromatic amino acids. , artificial small molecule ligands linked via amide bonds. Pyrrole-imidazole polyamides recognize DNA sequences by forming the most possible hydrogen bonds with DNA base pairs: antiparallel paired Py/Py recognizes T·A or A·T base pairs; Im/Py is specific Py/Im specifically recognizes C·G base pairs, Hp/Py specifically recognizes T·A base pairs, and Py/Hp specifically recognizes A·T base pairs. By designing a specific pyrrole-imidazole polyamide that specifically binds to the key sequence of the target gene promoter, the binding of the transcriptional regulatory protein to the target gene promoter can be blocked, thereby blocking the expression of the gene from the gene transcription level. Compared with the shRNAi technology widely used in eukaryotic cells, the gene function inhibition mediated by pyrrole-imidazole polyamides not only has high specificity, but also has significant advantages such as high stability and good cell permeability. It has great potential in the development of drugs aimed at inhibiting gene expression. However, such small molecule drugs (such as polyamides) usually have disadvantages such as poor solubility, short blood half-life, and low bioavailability, so it is necessary to improve the metabolism and kinetic parameters of drugs through preparation technology.

Liposomes are ultramicrospheres formed by lipid bilayers, similar to biological membrane structures, with single or several ring-shaped lipid bilayer shells, and contain a water-phase cavity inside, which can simultaneously contain Hydrophilic and hydrophobic drugs. Its basic component, phospholipid, is an inherent component in the living body, which is degraded by biotransformation in the living body, and has no toxicity and immunogenicity. Therefore, liposome is considered to be one of the most promising drug carriers.

At present, the research groups of Dervan, Sugiyama and Fukuda have prepared a series of pyrrole-imidazole polyamides and their derivatives, and have also deeply studied their effects on gene expression in vivo and in vitro, and have achieved remarkable results in recent years. However, if pyrrole-imidazole polyamides can regulate the expression of target genes, whether they can pass through the cell membrane and nuclear membrane and enter the nucleus is a key step. However, there are large differences in the membrane penetration ability of pyrrole-imidazole polyamides in different cells, and the membrane penetration ability is limited in some tissues, especially in solid tumors, it is difficult to penetrate the cell membrane and nuclear membrane of cancer cells to act on the target DNA sequence. In addition, the pyrrolidazole polyamide also has the problems of poor solubility in the body and easy agglomeration and crystallization, resulting in low availability and large biological usage. Peter B.Dervan's group increased the water solubility of pyrrole-imidazole polyamides by adding hydroxypropyl β-cyclodextrin, which can realize intravenous administration to nude mice. However, hydroxypropyl β-cyclodextrin has a cylindrical hydrophobic inner cavity and a hydrophilic outer edge, resulting in a very low loading efficiency of pyrrolidazole polyamide. However, hydroxypropyl β-cyclodextrin itself has limited water solubility and is prone to hemolysis and irritation.

Contents of the invention

Based on the excellent performance of liposome as a carrier, the purpose of the present invention is to use liposome-based nano-drug carriers to effectively entrap pyrrole-imidazole polyamides, utilizing the characteristics of tumor growth, and a large number of defects caused by angiogenesis The nutrient angiogenesis and imperfect lymphatic return system contribute to the passive targeting effect of nanoparticles on tumors through enhanced penetration and retention effects. Nano-drug delivery carriers with long-term circulation ability can eventually overflow from blood vessels, accumulate in tumor tissue, and enter cells to release therapeutic drugs to play a role.

The present invention aims to realize its highly specific DNA binding ability and excellent membrane-penetrating performance through rational design, starting from the chemical synthesis of inhibitors; and to significantly improve the efficacy of polyamide drugs by using nanomaterial packaging and targeted transport mechanisms And toxicological characteristics, in order to improve the prospect of clinical application of drugs. The key to designing a drug delivery system is to realize the efficient accumulation of drugs in tumor tissues. To achieve this goal, encapsulation of pyrromidazole polyamides with liposome materials similar to biological membrane structures can significantly improve the solubility of the drug and change the transport mode of the drug, and use low immunogenicity coating materials (such as long-chain polyethylene Diol) surface modification strategy improves the biocompatibility and colloidal stability of the drug carrier, prolongs its blood circulation time, and helps it to be passively enriched in tumor tissue through the EPR effect.

The invention discloses a preparation of a nano liposome for carrying a pyrromidazole polyamide small molecule polypeptide drug capable of recognizing a Plk1 target gene. The method mainly includes: preparing nanoliposomes with different surface groups and charges by encapsulating pyrrolidazole polyamide that specifically recognizes the Plk1 sequence through different types of phospholipid molecules, and obtaining drug-loaded nanoliposomes by using a thin film dispersion method; Polyethylene glycol chains are added to the molecular terminal functional groups, and the polyethylene glycol is used to improve the blood circulation time of the polyamide liposome after intravenous injection.

The pyrromidazole polyamide of the present invention refers to an artificially synthesized small molecular compound that can specifically target the key sequence of the Plk1 promoter. According to the human Plk1 gene promoter DNA sequence, select the highly specific 20-25bp sequence located around the TATA box and GC box at the 2-3 end as the target sequence. By chemical synthesis method, pyrromidazole polyamide matching the selected sequence is synthesized. Through reasonable structural design, the coupling of benzimidazole-based fluorescent groups and pyrrole-imidazole-based polyamides can not only enhance the membrane-penetrating ability of polyamides, but also produce Fluorescence, therefore, can be used as an intrinsic fluorescent probe to monitor polyamide transmembrane behavior, movement in cells and binding to DNA sequences.

The present invention provides a kind of pyrrolimidazole polyamide liposome, it is made of lipid bilayer and the pyrrolimidazole polyamide contained in lipid bilayer, wherein lipid bilayer comprises phospholipid molecule and cholesterol, Wherein, the molar ratio of phospholipid molecules to cholesterol is (1-10):1, preferably (3-4):1, and the molar ratio of phospholipid molecules to pyrrolidazole polyamide is (20-30):1.

In the technical scheme of the present invention, the phospholipid molecules are selected from the group consisting of phospholipids, carboxylated polyethylene glycol-phospholipids, distearoylphosphatidylcholine, 1,2-dioleoyl-3-trimethylammonium salt propane, carboxyl One or more mixtures of polyethylene glycol-distearoylphosphatidylethanolamine.

Preferably, the polyethylene glycol molecules in the phospholipid molecules are selected from 2000-5000.

In the technical solution of the present invention, the concentration of pyrrolidazole polyamide is 1 μM-50 μM, preferably 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, 10 μM, 20 μM, 30 μM, 40 μM, 50 μM.

In the technical scheme of the present invention, the phospholipid molecule is selected from distearoylphosphatidylcholine, or carboxylated polyethylene glycol-distearoylphosphatidylethanolamine,

Further, the pyrromidazole polyamide liposome is prepared by one of the thin film dispersion method and the reverse evaporation method.

Further, the pyrrolimidazole polyamide is selected from couplings with two or three of N-methylpyrrole (Py), N-methylimidazole (Im) and N-methyl-3-hydroxypyrrole (Hp). substance, or a derivative of Hurst acid modified thereon, preferably a compound of formula I,

The particle diameter of the pyrromidazole polyamide liposome of the present invention is 50-300nm.

Another aspect of the present invention provides the preparation method of the above-mentioned pyrromidazole polyamide liposome, which is prepared by thin film dispersion method and reverse evaporation method.

Further, it is prepared by thin film dispersion method, comprising the following steps:

1) Dissolving phospholipid molecules and cholesterol in an organic solvent to form a membrane material dispersion;

2) Under reduced pressure, remove the organic solvent in the membrane material dispersion, and make the phospholipid molecules and cholesterol form a uniform dispersed film on the container wall;

3) After dissolving the pyrrolidazole polyamide in ultrapure water and dispersing it, add it to the container obtained in step 2), and mechanically disperse it so that the phospholipid molecules and cholesterol self-assemble into liposomes carrying the pyrromidazole polyamide;

Optionally, steps 4) and 5) are also included,

4) passing the liposome obtained in step 3) through a 0.22 μm water filter;

5) Treat the pyrromidazole polyamide liposome ultrafiltration centrifuge tube obtained in step 4) to remove free pyrromidazole polyamide.

Another aspect of the present invention provides the use of the pyrromidazole polyamide liposome or the compound represented by formula I in the preparation of Plk inhibitors, preferably Plk-1 inhibitors.

Another aspect of the present invention provides the use of the pyrromidazole polyamide liposomes of the present invention in the preparation of medicines for the treatment or prevention of diseases associated with Plk1 inhibitors, and the diseases associated with Plk1 inhibitors are selected from proliferative The disease is preferably a tumor, more preferably lung cancer, liver cancer, ovarian cancer, esophagus cancer, cervical cancer, non-small cell lung cancer, skin cancer, leukemia, Hodgkin's lymphoma.

Beneficial effect

1) The pyrromidazole polyamide liposome of the present invention entraps pyrromidazole polyamide in the inner cavity of the liposome, which can effectively increase the loading capacity compared with other carrier loading methods, thereby significantly improving the pyrromidazole polyamide class. The bioavailability of the drug can reduce the effective concentration of inhibiting tumor cells from 10 μM to below 1 μM.

2) The polyamide liposome of pyrrolidazole of the present invention is coupled with a polyethylene glycol chain on the terminal functional group of the phospholipid molecule, and utilizes polyethylene glycol to improve the blood circulation time of the polyamide liposome after intravenous administration, Increase drug accumulation at tumor sites.

Description of drawings

Fig. 1 is the schematic diagram of the preparation process of pyrromidazole polyamide liposome.

Fig. 2 is the transmission electron micrograph of embodiment 1 pyrrolidazole polyamide liposome.

Fig. 3 is the particle diameter diagram of the pyrrolidazole polyamide liposome of embodiment 3.

Figure 4 shows that DSPC pyrrolidazole polyamide carrier, DSPC-PEG-COOH pyrrolidazole polyamide carrier and free pyrrolidazole polyamide inhibit the expression of PlK1 protein.

Fig. 5 is the HRMS spectrogram of the compound of formula I.

Detailed ways

Embodiment 1: the preparation method of pyrrolidazole polyamide liposome

(1) 24 μL of distearoylphosphatidylcholine (DSPC) with a concentration of 0.1M and 15 μL of cholesterol with a concentration of 50 mM were dissolved in a mixed solution of 2 mL of chloroform and 1 mL of methanol;

(2) Under reduced pressure, the mixed solvent is removed by rotary evaporation, and a uniform film is obtained at the bottom of the bottle;

(3) Dissolve 0.1 μmol of pyrrolimidazole polyamide (compound of formula I) in 2 mL of ultrapure water, add it to the above-mentioned glass bottle covered with phospholipid film, and sonicate for 10 to 20 minutes until the solution changes from turbid to clear;

(4) Pass the solution obtained above through a 0.22 μm water filter membrane, repeating 3 times;

(5) Transfer the above mixed aqueous solution of pyrromidazole and polyamide to an ultrafiltration centrifuge tube with a molecular cut-off of 50,000, and wash with ultrapure water for more than 3 times to remove free drugs.

Embodiment 2: the preparation method of pyrrolidazole polyamide liposome

(1) 240 μL of distearoylphosphatidylcholine (DSPC) with a concentration of 0.1M and 150 μL of cholesterol with a concentration of 50 mM were dissolved in a mixed solution of 20 mL of chloroform and 10 mL of methanol;

(2) Under reduced pressure, the mixed solvent is removed by rotary evaporation, and a uniform film is obtained at the bottom of the bottle;

(3) Dissolve 1 μmol of pyrrolimidazole polyamide (compound of formula I) in 20 mL of ultrapure water, add it to the glass bottle covered with phospholipid film, and sonicate for 10 to 20 minutes until the solution changes from turbid to clear;

(4) Pass the solution obtained above through a 0.22 μm water filter membrane, repeating 3 times;

(5) Transfer the above mixed aqueous solution of pyrromidazole and polyamide to an ultrafiltration centrifuge tube with a molecular cut-off of 50,000, and wash with ultrapure water for more than 3 times to remove free drugs.

Embodiment 3: the preparation method of pyrrolidazole polyamide liposome

(1) 24 μL of carboxylated polyethylene glycol-distearoylphosphatidylethanolamine (DSPC-PEG-COOH) with a concentration of 0.1M and 15 μL of cholesterol with a concentration of 50 mM were dissolved in a mixed solution of 2 mL of chloroform and 1 mL of methanol;

(2) Under reduced pressure, the mixed solvent is removed by rotary evaporation, and a uniform film is obtained at the bottom of the bottle;

(3) Dissolve 0.1 μmol of pyrrolimidazole polyamide (compound of formula I) in 2 mL of ultrapure water, add it to the above-mentioned glass bottle covered with phospholipid film, and sonicate for 10 to 20 minutes until the solution changes from turbid to clear;

(4) Pass the solution obtained above through a 0.22 μm water filter membrane, repeating 3 times;

(5) Transfer the above mixed aqueous solution of pyrromidazole and polyamide to an ultrafiltration centrifuge tube with a molecular cut-off of 50,000, and wash with ultrapure water for more than 3 times to remove free drugs.

Embodiment 4: the preparation method of pyrrolidazole polyamide liposome

(1) 240 μL of carboxylated polyethylene glycol-distearoylphosphatidylethanolamine (DSPC-PEG-COOH) with a concentration of 0.1M and 150 μL of cholesterol with a concentration of 50 mM were dissolved in a mixed solution of 20 mL of chloroform and 10 mL of methanol;

(2) Under reduced pressure, the mixed solvent is removed by rotary evaporation, and a uniform film is obtained at the bottom of the bottle;

(3) Dissolve 1 μmol of pyrrolimidazole polyamide (compound of formula I) in 20 mL of ultrapure water, add it to the glass bottle covered with phospholipid film, and sonicate for 10 to 20 minutes until the solution changes from turbid to clear;

(4) Pass the solution obtained above through a 0.22 μm water filter membrane, repeating 3 times;

(5) Transfer the above mixed aqueous solution of pyrromidazole and polyamide to an ultrafiltration centrifuge tube with a molecular cut-off of 50,000, and wash with ultrapure water for more than 3 times to remove free drugs.

The Western blot method used in Example 5 detects the expression of Plk1 protein induced by liposomes of the present invention

The test cells used the human cervical cancer cell line Hela. Hela cells were cultured using complete medium (DMEM, supplemented with 10% FBS and antibiotics 10% P/S). After Hela cells were digested and reselected by trypsin, they were evenly seeded into 60mm culture dishes, and the test drugs were added 24 hours later. The test drugs (Examples 1 and 3 and free drugs) were diluted with complete medium to 1 μM or 10 μM. After 72 hours of drug action, the cells were digested with 0.25% trypsin. Transfer the collected cells to a 1.5ml centrifuge tube, wash once with PBS, add RIPA lysate, and lyse on ice for 1 hour. Centrifuge at 14,000 rpm at 4 degrees for 15 minutes, and collect the supernatant. After measuring the protein concentration by BCA protein quantification method, add protein denaturation solution and dilute to the same protein concentration; incubate in boiling water for 5min to denature the protein. The target protein was then separated and purified by SDS polyacrylamide gel electrophoresis. After the electrophoresis is completed, the protein on the gel is transferred to the PVDF membrane by electrophoresis. Then incubated with 5% skimmed milk powder/PBS blocking solution for 1 hour at room temperature. Then add Plk1 antibody and incubate overnight at 4 degrees. After washing with PBS-T, the secondary antibody diluted in blocking solution was added and incubated at room temperature for 1 hour. After washing with PBS, dry the excess water on the PVDF membrane with filter paper, add a chemiluminescent substrate, and expose for color development.

It can be seen from Figure 4 that the compound of formula I has the effect of inhibiting Plk1, and its 10 μM group shows a strong effect, but the 1 μM group has almost no inhibitory effect. However, the liposomes of Examples 1 and 3 showed a strong inhibitory effect regardless of the 1 μM group or the 10 μM group, and there was almost no difference between the 1 μM group and the 10 μM group. This experiment proves that the liposome formulation effectively improves the bioavailability, and for the compound of formula I, the bioavailability can be increased by 10 times, and an unexpected effect has been achieved.

The preparation method of embodiment 6 formula I compound

1. Synthesis of Precursor 1

Add hydrazine resin (0.61mmol/g, 400mg, 0.244mmol) and CH2Cl2 (3ml) into a 50mL solid phase reactor, and swell the resin for 20min. Remove CH2Cl2, add 20% piperidine/DMF solution (3ml) to the resin, blow air for 5min, remove the solvent, then add 20% piperidine/DMF solution (3ml), blow air for 5min, remove the solvent, and use DMF (4x 3mL) and NMP (2x3mL) to wash the resin and set aside. Simultaneously, Boc-Py-OH ((176mg, 0.732mmol, 3eq.) and BOP-Cl (186mg, 0.732mmol, 3eq.) were dissolved in NMP (2ml), and DIEA (400μL, 2.2mmol, 9eq .), stir until the solution is clear, transfer the reaction solution to the hydrazine resin that removes Fmoc, and transfer the resin to a 50ml EP tube. In a microwave reactor, the heating power is 200w, 75°C, and react for 15min (indene The triketone reagent is detected until the reaction is complete). The reaction liquid is extracted, the resin is washed with DMF (4x3mL), and the resin is washed with anhydrous DMF (3mL). Add pivalic anhydride (186 μ L, 0.96mmol, 4eq.) and DIEA (500μL, 2.88mmol, 12eq.) in DMF (2mL) was reacted for 15min, the resin was transferred to a solid-phase reactor, the reaction solution was removed, the resin was washed with DMF (4x3mL), and finally washed with DCM (2x3mL) resin.

Then according to the following method until the completion of the synthesis of precursor 1

Method A: Boc deprotection

TFA/TIS/H2O solution (95:2.5:2.5, 3ml) was added to the resin, air blown for 2min, and the solvent was removed, then FA/TIS/H2O solution (95:2.5:2.5, 3ml) was added, air blown for 20min, and the solvent was pumped The solvent was removed and the resin was washed first with DCM (2x3 mL), then with DMF (4x3 mL) and finally with NMP (2x3 mL).

Method B: Coupling of Boc-Im-OH

Boc-Im-OH (176mg, 0.732mmol, 3eq.) (or Fmoc-D-Dab(Boc)-OH (322mg, 0.732mmol, 3eq.)), BOP-Cl (186mg, 0.732mmol, 3eq.) . HOAT (100mg, 0.732mmol, 3eq.) was dissolved in NMP (2ml), and DIEA (400μL, 2.2mmol, 9eq.) was added to the solution, and stirred until the solid was completely dissolved. Transfer the reaction solution to the hydrazine resin that removes Boc, and transfer the resin to a 50ml EP tube. In a microwave reactor, the heating power is 200w, 75°C, and react for 15min (ninhydrin reagent detects that the reaction is complete) . Centrifuge the resin at low speed and remove the supernatant. Then add methanol to the resin to wash, centrifuge at low speed, discard the supernatant, and wash with methanol three times. The methanol-washed resin was transferred to a solid-phase reactor, and the resin was washed with methanol (2x3 mL), then with DMF (4x3 mL), and finally with DCM (2x3 mL).

Method C: Coupling of Boc-Py-OH

Boc-Py-OH (176mg, 0.732mmol, 3eq.) and BOP-Cl (186mg, 0.732mmol, 3eq.) were dissolved in NMP (2ml), and DIEA (400μL, 2.2mmol, 9eq.) was added to the solution , and stirred until the solution was clear. Transfer the reaction solution to the hydrazine resin that removes Boc, and transfer the resin to a 50ml EP tube. In a microwave reactor, the heating power is 200w, 75°C, and react for 15min (ninhydrin reagent detects that the reaction is complete) . The reaction solution was aspirated and the resin was washed with DMF (4x3 mL) and then with DCM (2x3 mL).

Method D: Coupling of Im-OH

Dissolve Im-OH (90mg, 0.732mmol, 3eq.) and PyBOP (380mg, 0.732mmol, 3eq.) in anhydrous DMF (2ml), add DIEA (400μL, 2.2mmol, 9eq.) to the solution, stir until the solution is clear. Transfer the reaction solution to the hydrazine resin that removes Boc, and transfer the resin to a 50ml EP tube. In a microwave reactor, the heating power is 200w, 75°C, and react for 15min (ninhydrin reagent detects that the reaction is complete) . The reaction solution was aspirated and the resin was washed with DMF (4x3 mL).

Method E: Ninhydrin Detection

During the coupling reaction, take out a small amount of resin, wash it twice with DMF, add two drops of ninhydrin detection solution (ninhydrin 15g, acetic acid 3ml, n-butanol 100ml), heat at 90°C for 3min, no color change of the resin indicates that the reaction is complete . The resin turns from red to blue indicating the presence of primary ammonia.

2. Preparation of Precursor 2

Precursor 1 used 20% piperidine/DMF solution ((2x3mL, 5min) to remove the Fmoc protecting group, then washed the resin with DMF (4x3mL), and then washed the resin with anhydrous DMF (3mL) for later use. At the same time, Hoechst33258 acid ( (373mg, 0.732mmol, 3eq.) and PyBOP (380mg, 0.732mmol, 3eq.) were dissolved in anhydrous DMF (2ml), and DIEA (400μL, 2.2mmol, 9eq.) was added to the solution and stirred until the solution was clear. The reaction liquid was transferred to the hydrazine resin from which Fmoc was removed, and air was blown at room temperature for 2 h (the reaction was detected by the ninhydrin reagent). The reaction liquid was withdrawn, and the resin was washed with DMF (4x3 mL).

3. Final product Py-Im-Ht

A small amount of DMF, copper acetate, and 3-dimethylaminopropylamine were added to the resin, shaken overnight, and then purified by semi-preparative HPLC. The product was collected, acetonitrile was removed by rotary evaporation, and the resulting solution was freeze-dried to finally obtain Py-Im-Ht. HRMS(ESI) m/z: calcd for C84H95N27O11[M+H]+1258.7783, found 1658.7819; [M+2H]2+829.8930, found 829.8856; [M+3H]3+553.5979, found 553.6090. Figure 5 shows. The preparation process of the compound of formula I is shown below.

Claims (10)

1. a kind of Allercur polyamide liposome by lipid bilayer and is contained in pyrroles's miaow in lipid bilayer Azoles polyamide is formed, and wherein lipid bilayer includes phospholipid molecule and cholesterol, wherein, mole of phospholipid molecule and cholesterol Than for (1~10):1, preferably (3~4):1, the molar ratio of phospholipid molecule and Allercur polyamide is (20~30):1.

2. Allercur polyamide liposome according to claim 1, phospholipid molecule is selected from phosphatide, the poly- second two of carboxylated Alcohol-phosphatide, Distearoyl Phosphatidylcholine, 1,2- dioleoyl -3- leptodactylines propane, carboxyl polyethylene glycol-distearyl One or more mixtures in acyl phosphatidyl-ethanolamine；

Preferably, the peg molecule in phospholipid molecule is selected from 2000-5000.

3. according to claim 1-2 any one of them Allercur polyamide liposomes, Allercur polyamide, which is selected from, to be had N- methylpyrroles (Py), N- methylimidazoles (Im) and two or three of conjugate in N- methyl -3- hydroxypyrroles (Hp) or The derivative of Hirst acid, preferably Formulas I structural compounds have been modified on it,

4. according to claim 1-3 any one of them Allercur polyamide liposomes, the Allercur polyamide lipid The grain size of body is 50-300nm.

5. according to claim 1-4 any one of them Allercur polyamide liposomes, a concentration of the 1 of Allercur polyamide μM-50μM。

6. according to the preparation method of claim 1-5 any one of them Allercur polyamide liposomes, selected from film point Arching pushing or reverse evaporation.

7. preparation method according to claim 6, includes the following steps：

1) phospholipid molecule and cholesterol are dissolved in organic solvent, form membrane material dispersion liquid；

2) organic solvent in membrane material dispersion liquid at reduced pressure conditions, is removed, and makes phospholipid molecule and cholesterol on the wall Form uniform dispersed film；

3) it after Allercur polyamide being dissolved in ultra-pure water dispersion, adds to obtained by step 2) in container, and mechanical dispersion makes phosphatide Molecule and cholesterol are self-assembled into the liposome to contain Allercur polyamide；

Optionally, step 4) and 5) is further included,

4) liposome that step 3) obtains is passed through into 0.22 μm of water system filter membrane；

5) the Allercur polyamide liposome ultra-filtration centrifuge tube for obtaining step 4) is handled, to remove free Allercur polyamides Amine.

8. Plk is being prepared according to compound shown in claim 1-5 any one of them Allercur polyamide liposome or Formulas I Purposes in inhibitor, the preferably drug of Plk-1 inhibitor.

9. it is controlled according to compound shown in claim 1-5 any one of them Allercur polyamide liposome or Formulas I in preparation It treats or prevents the purposes in the drug with the relevant disease of Plk1 inhibitor.

10. purposes according to claim 9, wherein the relevant disease of Plk1 inhibitor is selected from proliferative diseases, Preferably tumour, more preferably lung cancer, liver cancer, oophoroma, cancer of the esophagus, cervical carcinoma, non-small cell lung cancer, cutaneum carcinoma, leukaemia, Hodgkin's lymphomas.