CN103977434A - P-hydroxybenzoic acid mediated polymer micelle drug delivering system with brain targeting function - Google Patents

Abstract

The invention belongs to the technical field of polymer materials and pharmaceutical preparations, and specifically relates to the preparation of a polymer micelle drug delivery system mediated by p-hydroxybenzoic acid with brain-targeting function and its application in the treatment of brain tumors. The brain-targeting polymer micelle drug delivery system of the present invention is prepared by mixing brain-targeting functional materials and amphiphilic polymer materials. The present invention has been evaluated in vivo and in vitro, and the results show that it can cross the blood-brain barrier and Drug delivery to the brain can significantly increase the accumulation of the drug in the brain, and has a significant anti-tumor effect. Compared with the ordinary polymer micelle drug delivery system, it can significantly improve the therapeutic effect of anti-tumor drugs on brain tumors.

Description

A brain-targeted polymer micellar drug delivery system mediated by p-hydroxybenzoic acid

technical field

The invention belongs to the technical field of polymer materials and pharmaceutical preparations, in particular to a p-hydroxybenzoic acid-mediated brain-targeted polymer micelle drug delivery system and a preparation method thereof, and the brain-targeted polymer micelle drug delivery system Application in the treatment of brain tumors.

Background technique

The prior art discloses that brain tumors are common malignant diseases of the central nervous system, including primary brain tumors and metastatic brain tumors. Since the tumor site is close to the patient's central nervous system, it is difficult to completely remove it with general clinical surgery and the tumor is prone to recurrence. In clinical practice, surgical resection of brain tumors combined with chemotherapy is usually used for the prevention and treatment of tumor recurrence.

In the prior art, targeted drug delivery systems for the treatment of brain tumors mostly use brain-targeted or tumor-targeted nano-drug delivery systems. Receptors specifically expressed by endothelial cells or tumor cells in neovascularization of brain tumor tissues and the corresponding ligands on the nano drug delivery system can be specifically recognized and combined to achieve targeted delivery of anti-tumor drugs.

Studies have shown that the blood-brain barrier (BBB) is a regulatory interface between the blood and the neurons of the brain and spinal cord, and it regulates the exchange of substances between the central nervous system (CNS) and peripheral blood. The BBB has a three-layer structure: the inner layer is brain capillary endothelial cells (BCECs) and the tight junctions between them, the middle layer is basement membrane and pericytes, and the outer layer is astrocytes and extracellular matrix, among which BCECs are extremely tight Connectivity is the main factor that makes up the BBB barrier. Due to the existence of BBB and cerebrospinal fluid barrier (BCSFB), almost all macromolecular drugs and 98% of drugs for treating and diagnosing brain diseases cannot enter the brain and central nervous system. Among them, in addition to the fat solubility of the drug itself, the relative molecular mass and the ability to form hydrogen bonds, etc. are the reasons why the drug is difficult to pass through the BBB, the BBB also has an outward flux mechanism, that is, some drugs are transported from the BBB through the P-glycopeptide on the BBB. out of the brain. In addition, the "enzymatic blood-brain barrier" existing on the BBB, that is, highly active neuropeptide degrading enzymes, such as aminopeptidase, endopeptidase, and angiotensin converting enzyme (ACE) combined with capillaries, also makes Drugs coupled with peptides affect the treatment of brain diseases due to unstable metabolism. Therefore, the BBB not only effectively protects brain tissue, but also creates an insurmountable barrier for drug treatment of brain diseases.

At present, the methods for overcoming the BBB to increase drug delivery in the brain are divided into two categories: invasive and non-invasive. Invasive methods of administration include hyperosmotic shock, carotid artery injection of vasoactive substances, and direct intracerebral injection. Although this method is effective, it may cause brain infection, BBB damage, and surgical injury, and the administration method is complicated, and the patient's compliance is poor, so it is not suitable for routine treatment and diagnosis. In contrast, non-invasive drug delivery methods have broader clinical application prospects. Non-invasive drug delivery methods mainly include: drug structure modification, chemical delivery system, carrier-mediated transport, endocytosis transport and nasal administration system; the first three methods all require certain chemical modification of the drug, which has relatively high requirements on the chemical structure and physical and chemical properties of the drug, and has relatively large limitations.

Benzamide compounds are dopamine D2 receptor selective antagonists with high specificity and strong affinity, and their extrapyramidal side effects are very small. According to reports, the structure-activity relationship between this type of drug and the dopamine D2 receptor at the molecular level is: the N atom of the pyrrole ring is one of the sites where this type of compound interacts with the dopamine D2 receptor, and the greater the charge of the N atom, The more favorable it is for the compound to interact with the COOˉ group on the amino acid residue of the receptor, the stronger the affinity with the dopamine D2 receptor is; the benzene ring is another site for the interaction between benzamide compounds and the dopamine D2 receptor. The benzene ring binds to the hydrophobic part of the acceptor molecule. The binding is affected by the charge on the plane of the benzene ring and the space structure of the benzene ring. The smaller the charge distribution value of the plane of the benzene ring, the benzene ring and the amide group remain coplanar. The spatial structure of the compound has a stronger affinity with the dopamine D2 receptor. Therefore, the work done by domestic and foreign researchers is mainly aimed at structural modification and transformation of the group on the N atom of the pyrrole ring and the side chain of the benzene ring of this kind of compound, and a series of derivatives have been synthesized and studied successively.

The present invention intends to use the feature that benzamide compounds have affinity for dopamine D2 receptors to prepare a p-hydroxybenzoic acid-mediated brain-targeted polymer micelle drug delivery system. So far, there is no literature report on the preparation of p-hydroxybenzoic acid-mediated brain-targeted polymer micellar drug delivery system and its application in the treatment of brain tumors.

Contents of the invention

The purpose of the present invention is to provide a new brain-targeted drug delivery system, in particular to a brain-targeted polymer micelle drug delivery system mediated by p-hydroxybenzoic acid. The present invention constructs a p-hydroxybenzoic acid-modified polymer micelle drug delivery system that can penetrate the blood-brain barrier and realize drug delivery in the brain. The drug delivery system can deliver chemotherapy drugs and diagnostic drugs through intravenous administration. To the brain, play a therapeutic and diagnostic effect.

The brain-targeted polymer micelle drug delivery system mediated by p-hydroxybenzoic acid of the present invention includes targeting molecules, carriers and drugs, the targeting molecule is p-hydroxybenzoic acid, and the carrier is amphiphilic The polymer micelles with a core-shell structure spontaneously formed by block copolymers under appropriate conditions can significantly increase the amount of drugs entering the brain through the blood-brain barrier through entrapment or adsorption.

The present invention uses p-hydroxybenzoic acid as the brain targeting molecule.

In the present invention, the carrier material is an amphiphilic polymer material, the hydrophobic segment is phosphatidylethanolamine, and the hydrophilic segment is polyethylene glycol terminated by methoxy at one end, and its molecular weight is 1000-20000 Da, preferably molecular weight 2000-5000 Da.

In the drug delivery system of the present invention, the drug loading method is encapsulation or electrostatic adsorption.

More specifically, the p-hydroxybenzoic acid-mediated brain-targeting polymer micelle drug delivery system of the present invention is characterized in that it consists of a brain-targeting functional material (I), an amphiphilic polymer material (II) and The drugs are jointly constructed into a drug-loaded polymer micelle drug delivery system; the brain-targeted functional material (I) accounts for 2%-20% of the amphiphilic polymer material (II); among them: the brain-targeted functional material (I ) consists of p-hydroxybenzoic acid-modified polyethylene glycol-phosphatidylethanolamine; the amphiphilic polymer material (II) consists of methoxy-terminated polyethylene glycol-phosphatidylethanolamine. In the embodiment of the present invention, the molecular weight of polyethylene glycol in the brain-targeting functional material is between 2000-5000; the molecular weight of polyethylene glycol in the amphiphilic polymer material is between 1000-5000.

In the present invention, the phosphatidylethanolamine in the brain-targeting functional material or the amphiphilic polymer material is saturated fatty acid phosphatidylethanolamine or unsaturated fatty acid phosphatidylethanolamine.

In the present invention, the drug delivered by the drug delivery system is one or more of diagnostic drugs or therapeutic drugs;

Among them, diagnostic drugs include: nuclear medicine diagnostic drugs such as radioisotope technetium or indium, magnetic resonance diagnostic drugs such as metal ion gadolinium; therapeutic drugs include: lipophilic antineoplastic drugs, selected from paclitaxel (PTX), docetaxel (DTX) , Doxorubicin (DOX), camptothecin, hydroxycamptothecin, 9-nitrocamptothecin, levodopa (L-DOPA), etc.

In the present invention, the particle size of the polymer micelle drug delivery system is 7-30nm.

The invention provides a preparation method of the brain-targeted polymer micelle drug delivery system mediated by p-hydroxybenzoic acid and its application in the treatment of brain tumors.

The present invention adopts thin-film hydration method to prepare polymer micelle drug delivery system, wherein: the brain-targeting functional material (I), the amphiphilic polymer material (II) and the drug are co-dissolved in an organic solvent respectively, and after film formation, add The hydration medium (such as: physiological saline, phosphate buffer saline, 5% glucose solution) is hydrated to form polymer micelles; the ratio of the brain-targeted functional material (I) to the amphiphilic polymer material (II) is molar than 5%, 10%, 15% or 20%.

The object of the present invention is achieved through the following technical solutions:

1 , p-hydroxybenzoic acid - Fluorescent labeling of polymeric micelles

react p-hydroxybenzoic acid with amino polyethylene glycol-distearoylphosphatidylethanolamine at room temperature, and purify the product by dialysis;

The molar ratio of brain-targeting functional materials to framework materials was 5:95, and polymer micelles loaded with coumarin-6 (C6) and DiR were prepared by film-forming hydration method, and free fluorescein was removed by gel chromatography;

2 , p-hydroxybenzoic acid - polymer micelles /DTX preparation of

Using the film-forming hydration method to prepare polymer micelles loaded with chemical drugs at a molar ratio of brain-targeting functional materials to skeleton materials of 5:95, in one embodiment of the present invention, the chemical drugs are selected from docetaxel (DTX);

3 , BCECs Cellular uptake assay

Using fluorescence microscopy and flow cytometry, the qualitative and quantitative uptake of brain capillary endothelial cells BCECs to the C6-loaded polymer micelle drug delivery system was determined;

4 , Animal tissue distribution test

Using a small animal in vivo imaging system to observe the distribution of the DiR-labeled drug delivery system in normal mice, and observe the fluorescence distribution in each organ after treating the mice;

5 , p-hydroxybenzoic acid - polymer micelles /DTX efficacy evaluation

Determination of the effect of polymer micelles on glioma cells U87 at the cellular level by MTT assay The growth inhibition test of MG shows that the prepared polymer micelle drug delivery system can significantly improve the inhibitory effect of the drug on the growth of tumor cells; The brain-targeted polymer micellar drug delivery system mediated by hydroxybenzoic acid has a good effect of penetrating the blood-brain barrier and brain aggregation, and can significantly improve the survival time of glioma model animals.

In the present invention, through coumarin-6 and near-infrared dye DiR fluorescent labeling and tracing technology, p-hydroxybenzoic acid-mediated brain-targeted polymer micellar drug delivery system performs in vitro BCECs cell uptake and mouse living and isolated brain targets To characterization test; through p-hydroxybenzoic acid-polymer micelles entrapped insoluble chemical drug docetaxel, anti-glioma pharmacodynamics evaluation in mice in vivo and in vitro, the results showed that the brain-targeted polymer micelles The drug delivery system can achieve the goal of improving the effect of brain tumor targeted therapy and reducing toxic and side effects; the brain-targeted polymer micelle drug delivery system has specific brain targeting, can overcome BBB and specifically deliver anti-inflammatory drugs. Tumor drugs (such as paclitaxel, docetaxel, camptothecin and other lipophilic drugs) reach the brain, so they have the characteristics of high efficiency and low toxicity against brain tumors.

Through in vivo and in vitro tests, the results of the present invention confirm that the brain-targeting polymer micelle drug delivery system also has a brain-targeting function, can carry drugs through the BBB and deliver drugs to the brain, and enhance the fluorescent probe. The distribution in the brain makes the anti-tumor drugs carried have a good anti-glioma therapeutic effect, especially to achieve a specific brain-targeting effect. The polymer micelle drug delivery system has good application prospects for the treatment of diseases such as brain tumors.

The present invention has the following advantages:

1. It provides a new type of brain-targeting functional material, which is conducive to improving the ability of polymer micelles to cross the BBB and enter the brain. It is compatible with the existing technology of monoclonal antibodies with brain-targeting functions, transferrin, lactoferrin, Compared with protein polypeptide brain-targeting molecules such as cationic albumin and RVG, the p-hydroxybenzoic acid used in the present invention has small molecular weight, no immunogenicity, simple preparation method, low price and easy access;

2. Provides the preparation and combination of functional materials for the brain-targeted polymer micelle drug delivery system. The preparation method is simple and easy, and it is convenient for subsequent development and industrialization;

3. The brain-targeted polymer micelle drug delivery system is conducive to improving the concentration of drugs in the brain and improving the therapeutic effect of drugs on diseases such as brain tumors.

Description of drawings:

picture 1 : p-HA-PEG-DSPE of ¹ H-NMR Atlas

It shows that the synthetic product has the characteristic peak of distearoylphosphatidylethanolamine between 0.8-1.5ppm, the characteristic peak of polyethylene glycol appears between 3.2-4.0ppm, and p-hydroxybenzene appears between 6.8-7.8ppm The characteristic peak of formic acid, p-HA-PEG-DSPE was confirmed.

picture 2 : BCECs Cellular Parabens - polymer micelles ( p-HA-micelles ) Qualitative uptake test

Among them, A and B are the bright field and dark field of free C6 group, C and D are the bright field and dark field of mPEG-micelles/C6 group, E and F are the bright field and dark field of p-HA-micelles/C6 group field; 1 h after administration, free C6, mPEG-micelles/C6 and p-HA-micelles/C6 could all enter the cells, but the fluorescence intensity of p-HA-micelles/C6 micelles group was higher than that of free C6 group and In the mPEG-micelles/C6 group, micelles modified by p-HA could increase the uptake of C6 by BCECs cells.

picture 3 : BCECs Cellular Parabens - polymer micelles ( p-HA-micelles ) quantitative uptake test

Among them, A is the free C6 group, B is the mPEG-micelles/C6 group, and C is the p-HA-micelles/C6 group; free C6, mPEG-micelles/C6 and p-HA-micelles/C6 were all can enter cells, and its uptake rates are 75%, 79.42% and 92.88% respectively, and the cell fluorescence intensity of p-HA-micelles/C6 group is significantly higher than that of free C6 group and mPEG-micelles/C6 group ( P <0.05), p -HA micelles can increase the uptake of C6 by BCECs cells, but unmodified micelles have no such advantage.

picture 4 : p-hydroxybenzoic acid - In vivo tissue distribution of polymeric micelles

It shows the intravital fluorescence imaging images of mice injected with mPEG-micelles/DiR and p-HA-micelles/DiR respectively 24 hours after the tail vein was anesthetized with 10% chloral hydrate, and the one on the left is the mouse injected with mPEG-micelles/DiR Mice, the one on the right is a mouse injected with p-HA-micelles/DiR; it can be seen from the fluorescence distribution map that the fluorescence distribution of p-HA-micelles/DiR in the mouse brain is significantly higher than that of mPEG-micelles/DiR , suggesting that p-HA-micelles/DiR can penetrate the BBB into the brain mediated by p-hydroxybenzoic acid targeting.

picture 5 : p-hydroxybenzoic acid - Mouse tissue distribution map of polymeric micelles,

It shows the fluorescence distribution of the isolated organs of the mouse after injection of mPEG-micelles/DiR and p-HA-micelles/DiR into the tail vein of the mouse at different time points, anesthetized with 10% chloral hydrate, and cardiac perfusion with normal saline. Semi-quantitative diagram, from the fluorescence distribution diagrams of 2 hours, 4 hours, 8 hours, and 12 hours, it can be seen that p-HA-micelles/DiR has obvious fluorescence distribution at various time points in the mouse brain, suggesting that p-HA-micelles Can be mediated by p-hydroxybenzoic acid to penetrate the BBB and distribute in the brain.

picture 6 : Median survival time of orthotopic glioma model mice

It shows that the median survival times of p-HA-micelles/DTX group, mPEG-micelles/DTX group, Taxotere ^® group and physiological saline group are 45.8, 32, 27 and 22 days respectively, indicating that p-HA -micelles/DTX can significantly prolong the median survival time of orthotopic glioma model mice, and has a good anti-glioma effect.

Detailed ways

The description of the following examples will help to further understand the present invention, but the present invention is not limited to the scope of the following description.

Example 1 Preparation of p-hydroxybenzoic acid - polymer micelles /DTX ( p-HA-micelles/DTX )

1 ) to prepare p-hydroxybenzoic acid - polyethylene glycol - Distearoylphosphatidylethanolamine ( p-HA-PEG-DSPE )

Weigh an appropriate amount of p-HA, dissolve it in DMF, add a certain amount of NHS and EDC·HCl to activate for 3 h, centrifuge to get the supernatant; weigh an appropriate amount of NH ₂ -PEG-DSPE in DMF, and separate the supernatant Add dropwise, then add 50 μL of DIEA, and stir overnight at room temperature. The above reaction solution was precipitated and centrifuged with glacial ether. After vacuum drying, the dried product was dispersed with double distilled water, purified by dialysis, and freeze-dried to obtain p-HA-PEG-DSPE as a white solid. The structure was verified by ¹ H-NMR (500 MHz, CD ₃ Cl) (as shown in Figure 1), and the results showed that the compound had the characteristic peak of distearoylphosphatidylethanolamine between 0.8-1.5ppm, The characteristic peak of polyethylene glycol appeared between 3.2-4.0ppm, and the characteristic peak of p-hydroxybenzoic acid appeared between 6.8-7.8ppm, confirming that the obtained product was p-HA-PEG-DSPE.

) to prepare entrapped DTX polymeric micelles

Weigh an appropriate amount of docetaxel (DTX) and mPEG-DSPE, dissolve in acetonitrile, and vortex the two. Put the above solution on a rotary evaporator, hydrate under reduced pressure at 37°C to form a film for 2 h, then use 3 mL of hydration medium for hydration, and filter the obtained polymer micelle drug delivery system with a 0.22 μm microporous membrane to obtain Unmodified DTX polymer micelles (mPEG-micelles/DTX);

Using the same preparation process as above, and adding 5% (p-HA-PEG-DSPE/mPEG-DSPE molar ratio) of p-HA-PEG-DSPE to the formulation, DTX-loaded p-hydroxybenzoic acid (p- HA) modified polymer micelles (p-HA-micelles/DTX).

Example 2 p-hydroxybenzoic acid - polymer micelles ( p-HA-micelles )of BCECs Cellular Uptake Assay

1 ) to prepare p-hydroxybenzoic acid - polymer micelles /C6 ( p-HA-micelles/C6 )

The film-forming hydration method was used to prepare coumarin-6 (C6)-labeled mPEG-micelles, including the steps of: mixing mPEG-DSPE with 50 μg of fluorescent dye C6, vortexing for 1 min, and rotating to dryness at 37°C. The membrane was vacuum-dried to remove residual organic solvents, and 200 μL of HEPES (pH 7.4, 10 mmol/L) was added, vortexed for 10 min, shaken in a water bath at 37 °C for 2 h, and gel filtration chromatography was used, with G50 as filler and HEPES as The unloaded C6 was removed from the elution medium, and mPEG-micelles/C6 was obtained after passing through a 0.22 μm microporous membrane; using the same preparation process, the molar ratio of p-HA-PEG-DSPE to mPEG-DSPE was 5:95 , to prepare p-HA-micelles/C6, measure the content of C6 with a fluorescence spectrophotometer, and calculate the content from the standard curve.

2) Parabens - polymer micelles ( p-HA-micelles )of BCECs Cell Qualitative Uptake Assay

Take the BCECs cells in the logarithmic growth phase, digest them with 0.25% trypsin and blow them into single cells, suspend the cells in DMEM culture medium containing 10% FBS and 1% penicillin-streptomycin, count, and count each 20,000 cells per well were seeded in a 24-well plate with a volume of 1 mL per well, cultured in a carbon dioxide incubator for 24 h, and washed twice with PBS of pH 7.4. Add 1 mL each of free C6, mPEG-micelles/C6 and p-HA-micelles/C6, wherein the concentration of C6 is 0.05 μg/mL, incubate in a carbon dioxide box for 1 h and stop, wash 3 times with PBS, and the cells are washed with 10% The paraformaldehyde solution was fixed for 15 min, washed 3 times with PBS, nuclei were stained with DAPI (1 μg/mL) for 10 min, washed 3 times with PBS, and finally sealed with buffered glycerol and observed under a fluorescent microscope. The results showed that, The uptake of p-HA-micelles/C6 by BCECs was significantly higher than that of free C6 and mPEG-micelles/C6 (as shown in Figure 2).

3) Parabens - polymer micelles ( p-HA-micelles/ )of BCECs Quantitative Cell Uptake Assay

Take the BCECs cells in the logarithmic growth phase, digest them with 0.25% trypsin and blow them into single cells, suspend the cells in DMEM culture medium containing 10% FBS and 1% penicillin-streptomycin, count, and count each 20,000 cells were inoculated in a 24-well plate with a volume of 1 mL per well. After culturing in a carbon dioxide incubator for 24 h, they were washed twice with PBS at pH 7.4, and free C6, mPEG-micelles/C6 and p-HA-micelles were added. /C6 each 1 mL, the concentration of C6 is 25 ng/mL, incubate in a carbon dioxide box for 1 h, stop, wash 3 times with PBS, add an appropriate amount of trypsin to digest and centrifuge the cells, discard the supernatant, and use pH 7.4 The cells were washed twice with PBS, and finally the cells were suspended in 0.5 mL of PBS, and the proportion of fluorescence intensity in tumor cells at each time point was detected by flow cytometry. The results showed that the effect of BCECs on p-HA-micelles/C6 The uptake of C6 was significantly higher than that of free C6 and mPEG-micelles/C6 (as shown in Figure 3)

Example 3 p-hydroxybenzoic acid - polymer micelles ( p-HA-micelles ) animal experiments for intracerebral drug delivery

1 ) p-Hydroxybenzoic acid - polymer micelles /DiR Live tissue distribution of mice

p-HA-micelles/DiR and m PEG-micelles/DiR polymer micelles were prepared respectively, and the amount of DiR was 15.6 μg, and 100 μL/mouse was injected into the tail vein of mice. , 12 and 24 hours anesthetized the mice with 10% chloral hydrate, and observed the fluorescence distribution in the mice in the living animal imaging system. It can be seen from the distribution diagram that p-HA-micelles/DiR has obvious fluorescence distribution in the mouse brain, while mPEG-micelles/DiR has no fluorescence distribution in the brain, suggesting that p-HA-micelles/DiR can pass through p-hydroxybenzene Formic acid mediates penetration of the blood-brain barrier into the brain (as shown in Figure 4).

2) Parabens -- polymer micelles /DiR Mouse tissue distribution in vitro

p-HA-micelles/DiR and mPEG-micelles/DiR polymer micelles were prepared respectively, and the amount of DiR was 15.6 μg, and 100 μL/mouse was injected into the tail vein at 2, 4, 8 and 12 hours after administration, respectively. The mice were anesthetized with 10% chloral hydrate, the heart was perfused with 100ml of normal saline, and the heart, lung, liver, spleen, kidney and brain were taken out and placed in a live animal imaging system for observation and semi-quantitative determination. The results of fluorescence distribution in various organs showed that p-HA-micelles/DiR had obvious fluorescence distribution in the mouse brain, suggesting that p-HA-micelles could penetrate the BBB mediated by p-hydroxybenzoic acid and distribute in the brain (Figure 5 shown).

Example 4

Pharmacodynamic evaluation of p-HA-micelles/DTX (p-HA-micelles/DTX) antigenic glioma

Take the U87 MG cells in the logarithmic growth phase, digest and count the cells, suspend them with an appropriate amount of PBS buffer, inoculate 8×10 ⁵ cells (dispersed in 5 μL PBS buffer) for each nude mouse, and divide the nude mice before the experiment After being anesthetized with 7% chloral hydrate, the brain was fixed with a stereotaxic instrument, and the suspension cells were inoculated in the striatum;

The orthotopic brain tumor model nude mice were randomly divided into 5 groups ( n = 9), and 250 μl of physiological saline (physiological saline), mPEG-micelles/DTX, p-HA-micelles were injected on the 6th, 9th, 12th, and 15th days respectively /DTX and Texotere ^® , the single DTX injection dose was 8 mg/kg, and the survival time of model nude mice was recorded. The results showed that p-HA-micelles/DTX can significantly prolong the median survival of orthotopic glioma model mice time (as shown in Figure 6).

Claims (9)

1. the brain target polymer micelle delivery system of a P-hydroxybenzoic acid mediation, comprise targeted molecular, carrier and medicine, it is characterized in that, be jointly built into by thering is brain target function material (I), amphipathic nature polyalcohol material (II) and medicine the polymer micelle delivery system that wraps medicine carrying thing; Brain target function material (I) accounts for the 2%-20% of amphipathic nature polyalcohol material (II); Wherein: brain target function material (I) is made up of the mPEG2000-DSPE of modifying through P-hydroxybenzoic acid; Amphipathic nature polyalcohol material (II) is made up of the mPEG2000-DSPE of methoxyl group end-blocking.

2. by the brain target polymer micelle delivery system of P-hydroxybenzoic acid mediation claimed in claim 1, it is characterized in that, described P-hydroxybenzoic acid is brain targeted molecular.

3. by the brain target polymer micelle delivery system of P-hydroxybenzoic acid mediation claimed in claim 1, it is characterized in that, molecular weight polyethylene glycol in brain target function material is between 2000-5000, and the molecular weight polyethylene glycol in amphipathic nature polyalcohol material is between 1000-5000.

4. by the brain target polymer micelle delivery system of P-hydroxybenzoic acid mediation claimed in claim 1, it is characterized in that, PHOSPHATIDYL ETHANOLAMINE in brain target function material and amphipathic nature polyalcohol material is satisfied fatty acid PHOSPHATIDYL ETHANOLAMINE or unsaturated fatty acid PHOSPHATIDYL ETHANOLAMINE.

5. by the brain target polymer micelle delivery system of P-hydroxybenzoic acid mediation claimed in claim 1, it is characterized in that, in described delivery system, its medicine carrying mode is parcel or Electrostatic Absorption.

6. by the brain target polymer micelle delivery system of P-hydroxybenzoic acid mediation claimed in claim 1, it is characterized in that, the particle diameter of described polymer micelle delivery system is 7-30nm.

7. by the brain target polymer micelle delivery system of P-hydroxybenzoic acid mediation claimed in claim 1, it is characterized in that, the medicine that described delivery system is sent is one or more in diagnostic medicine or medicine;

Wherein, diagnostic medicine is selected from: nuclear medicine diagnostic medicine, MR diagnosis medicine or lipotropy antitumor drug.

8. by the brain target polymer micelle delivery system of P-hydroxybenzoic acid mediation claimed in claim 1, it is characterized in that, described lipotropy antitumor drug is selected from, one or both in paclitaxel, Docetaxel, amycin, camptothecine, hydroxy camptothecin, 9-nitrocamptothecin or levodopa.

9. the preparation method of the brain target polymer micelle delivery system of the P-hydroxybenzoic acid of claim 1 mediation, it is characterized in that, adopt thin film aquation legal system for polymer micelle delivery system, wherein: respectively brain target function material (I), amphipathic nature polyalcohol material (II) and medicine are dissolved in to organic solvent altogether, after film forming, add aquation medium aquation to form polymer micelle; Its midbrain target function material (I) is mol ratio 5%, 10%, 15% or 20% with the ratio of amphipathic nature polyalcohol material (II); Described medicine is one or more in diagnostic medicine or medicine; Wherein, diagnostic medicine is selected from: nuclear medicine diagnostic medicine, MR diagnosis medicine or lipotropy antitumor drug.