CN105273205A - Block polymer with benzeneboronic acid ester as connecting unit, synthesis method and application thereof - Google Patents
Block polymer with benzeneboronic acid ester as connecting unit, synthesis method and application thereof Download PDFInfo
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- CN105273205A CN105273205A CN201510648789.6A CN201510648789A CN105273205A CN 105273205 A CN105273205 A CN 105273205A CN 201510648789 A CN201510648789 A CN 201510648789A CN 105273205 A CN105273205 A CN 105273205A
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Abstract
The invention discloses a diblock polymer with benzeneboronic acid ester as the connecting unit. Benzeneboronic acid catechol ester (BC) is adopted as the connecting unit to synthesize PEG-BC-PBLG diblock polymer so as to construct doxorubicin loaded micelle (PEG-BC@PBLG.Dox). The invention also discloses a preparation method of the diblock polymer, and the method includes: (1) preparing the dopa derivative PEG-3, 4-DA of PEG-NH2; (2) subjecting PEG-3, 4-DA and 3-aminophenylboronic acid to dehydration condensation so as to synthesize the benzeneboronic acid ester derivative PEG-BC of PEG; and (3) using PEG-BC to perform ring opening on 5-benzyl ester-L-glutamic acid-N-carboxyanhydride (BLG-NCA), thus obtaining the diblock polymer PEG-BC-PBLG with benzeneboronic acid ester as the connecting unit. The diblock polymer prepared by the method provided by the invention can be used for construction of a nano-micelle, and has the advantages of good drug release, low cytotoxicity and good cell phagocytosis.
Description
Technical field
The invention belongs to biological medicine technology, nanometer medicine and field of new, be specifically related to synthesis and the assembling thereof of the bi-block copolymer taking borate ester as connector element and be applied to preparation has the intelligent nano-micelle carrier strengthening cell endocytic characteristic purposes to liver cancer cell.
Background technology
Classic chemotherapy medicine obtains very ten-strike in the treatment of tumour, but has a lot of limitation to limit the further raising of its clinical efficacy, as serious toxic side effect, poor selectivity, tumour cell easily produce resistance etc. to it.Nano-medicament carrier is realize the fixed point of chemotherapeutics in tumor tissues and release fast, reduces the damage of normal tissue organ, avoids active drug underdosage to cause tumour cell to produce resistance and provides an effective way.Intelligent nano medicament carrier system mainly based on the environment variations of tumor tissues and human normal tissue, as tumor tissues have weary oxygen, acid ph value, temperature slightly high, have the features such as the raised growth factor and hydrolysising protease.Utilize the Thief zone of solid tumor and long retention effect (EPR effect), nano-drug transporter can be made in tumor tissues enrichment, disintegrate fast under tumor microenvironment effect, discharge rapidly antitumor drug and " kill " tumour cell.
Phenylo boric acid and cis 1,2-or 1,3-dihydroxy compound (as carbohydrate, catechol etc.) can form boric acid ester bond.Boric acid ester bond alkalescence and neutral environment relatively stable, and in sour environment generation cracking, confirm that boric acid ester bond is suitable as the nano-medicament carrier construction unit of acid-sensitive very much.Professor PavelA.Levkin modifies dextran with phenylo boric acid and obtains amphipathic polymer B-Dex.The drug releasing rate of nanoparticle in the acidic medium of pH5.0 that B-Dex self-assembly is formed is 5 times of the drug releasing rate in the medium of pH7.4, show extraordinary acid labile drug release characteristics (Biomaterials, 2013,34,8504-8510).Zhong Zhenlin teach problem group has higher efficiency gene transfection to HepG2 cell after finding phenylo boric acid covalent modification polymine, one of reason is that phenylo boric acid is combined by force with the oligosaccharide (SialylLewisX) of HepG2 surface of cell membrane, achieve receptor-mediated cell endocytic, gene vector system more easily enters cell and transfection (ChemicalCommunication occurs, 2010,46,5888-5890), confirm that phenylo boric acid can be used as the potentiality of the target group of medicament carrier system.
The carrier micelle that traditional block polymer is constructed is usually using polyoxyethylene glycol (PEG) as hydrophilic segment, Thief zone and the long retention effect (EPR effect) of solid tumor can be made full use of, make drug-rich at tumor tissues, but such micella is unfavorable for cell endocytic due to the existence of PEG shell, antitumor drug is difficult to the arrival of sufficient dosage and is positioned at intracellular action target spot, and the target groups such as PEG end folic acid, semi-lactosi or antibody modification are normally realized receptor-mediated cell endocytic by the cell endocytic of this type of micella.
Summary of the invention
In order to overcome above-mentioned defect of the prior art, the present invention proposes a kind of take borate ester as the bi-block copolymer of connector element, the carrier micelle constructed with this bi-block copolymer not only realizes long-acting circulation in vivo, PEG shell can be sloughed after tumor locus accumulation, while avoiding PEG block cell endocytosis, the phenylo boric acid key exposed can strengthen the cell endocytic process of its mediation, therefore, and the new way being configured to realization " long-acting circulation, enhancing cell endocytic " of micella of the present invention.Bi-block copolymer prepared by the present invention may be used for constructing nano-micelle, has good release, lower cytotoxicity and good cytophagy.
The present invention proposes a kind of take borate ester as the bi-block copolymer of connector element, it is characterized in that, the structural formula of described bi-block copolymer such as formula shown in (I),
In formula (I):
x＝40-120
m＝5-20。
Wherein, the structural formula of PEG is such as formula shown in (1):
Wherein, the structural formula of BC is such as formula shown in (2):
Wherein, the structural formula of PBLG is such as formula shown in (3):
The invention allows for a kind of take borate ester as the synthetic method of the bi-block copolymer of connector element: it is characterized in that, said method comprising the steps of: (1) synthesis PEG-NH
2dOPA derivative PEG-3,4-DA; (2) PEG-3,4-DA and 3-amino-benzene boric acid dehydrating condensation, obtains the borate ester derivative PEG-BC of PEG; (3) PEG-BC open loop 5-benzyl ester-Pidolidone-N-carboxyanhydrides BLG-NCA, namely carrying out ring-opening polymerization using PEG-BC as macromole evocating agent to 5-benzyl ester-Pidolidone-N-carboxyanhydrides (BLG-NCA), is the bi-block copolymer PEG-BC-PBLG of connector element with borate ester described in obtaining.
The invention allows for what prepare according to aforesaid method take borate ester as the bi-block copolymer of connector element, and described bi-block copolymer structure is such as formula shown in (I).
Present invention further proposes by described take borate ester as the application of bi-block copolymer for the preparation of pharmaceutical carrier of connector element.
Wherein, described medicine is fat-soluble medicine.Preferably, described fat-soluble medicine comprises Zorubicin, gemcitabine, SN38 and taxol.
Wherein, described carrier is nano-micelle carrier, and preferably, described nano-micelle carrier is acid-sensitive type.
Wherein, described nano-micelle carrier is for strengthening the endocytosis characteristic of tumour cell.
Wherein, described tumour cell is liver cancer cell.
Wherein, the structure of described nano-micelle carrier is as shown in Figure 1B.
The present invention utilizes borate ester to the responsiveness of tumour slightly acidic environment, and the oligosaccharide on phenylo boric acid cell membrane surface has the feature of very strong binding ability, with phenylo boric acid catechu phenolic ester (BC) for connector element synthesizing polyethylene glycol-polyglutamic acid bi-block copolymer (PEG-BC-PBLG), and then build its year Zorubicin micella (PEG-BCPBLGDox).Study this orderly respondent behavior of the active of PEG-BCPBLGDox micella to tumor microenvironment and quick drug release process, evaluate its in vitro toxicity and resisting liver cancer activity.This active in order respondent behavior and quick drug release process specifically can be described as: boric acid ester carrier micella fully realizes being enriched in liver cancer tissue after EPR effect through long-acting circulation; To born of the same parents' outer slightly acidic environment response, PEG shell is sloughed in fracture to boric acid ester bond; Expose phenylo boric acid, phenylo boric acid is combined with the oligosaccharide of surface of cell membrane and realizes phenylo boric acid and mediate the active endocytosis strengthened, and discharges wrapped medicine.
Involved in the present invention take borate ester as the structure of the bi-block copolymer of connector element and carries adriamycin nano micella PEG-BCPBLGDox schematic diagram as shown in Figure 1A, and implementation step is as follows:
The first step: the syntheses and properties of borate ester bi-block copolymer
(1) PEG-NH is synthesized
2dOPA derivative PEG-3,4-DA; (2) PEG-3,4-DA and 3-amino-benzene boric acid dehydrating condensation, obtains the borate ester derivative PEG-BC of PEG; (3) PEG-BC open loop 5-benzyl ester-Pidolidone-N-carboxyanhydrides (BLG-NCA), obtains taking borate ester as connector element bi-block copolymer PEG-BC-PBLG, characterizes its structure; (4) synthesis is used for the bi-block copolymer PEG-PBLG not containing phenylo boric acid ester bond of comparative study, and PEG-BC-PBLG-FITC and PEG-PBLG-FITC that fluorescein isothiocyanate (FITC) marks.
Second step: the constructing and characterizing of borate ester bi-block copolymer nano-micelle system
Prepare PEG-BCPBLG micella with solvent evaporated method and carry Zorubicin micella PEG-BCPBLGDox, measuring its micelle-forming concentration; Observe its pattern with transmission electron microscope (TEM), measure size and distribution with dynamic light scattering (DLS); Encapsulation rate and the drug loading of carrier micelle is measured with ultraviolet absorption method.
The structure of described PEG-BCPBLG micella as shown in Figure 1B.
When bi-block copolymer PEG-BC-PBLG self-assembly forms PEG-BCPBLG micella, PEG end forms hydrophilic outer layer, and PBLG forms hydrophobic spherical kernel (as shown in Figure 1B), is connector element between PEG and PBLG with borate ester.In acid condition during borate ester bond rupture, micella sloughs PEG skin, exposes phenylo boric acid end, as shown in Figure 1 C;
Its chemical structure is as shown in the formula shown in (4):
3rd step: the degraded of block polymer and nano-micelle PEG-BCPBLG and Release Performance
With
1the method of HNMR carries out dynamic monitoring to the degraded situation of block polymer PEG-BC-PBLG in simulation tumor microenvironment pH value (pH6.5, pH6.0, pH5.0) and normal blood pH value (pH7.4); Change of size situation after degrading in above-mentioned pH damping fluid with DLS tracking PEG-BCPBLG nano-micelle; Measure the Release Performance of carrier micelle PEG-BCPBLGDox.
4th step: the cytophagy of PEG-BCPBLG nano-micelle
The more HepG2 cell of research cell surface SialylLewisX engulfs behavior to PEG-BCPBLG micella, with the PEGPBLG micella of not boracic ester bond and the less HL7702 cell of cell surface SialylLewisX in contrast.Cultivate 3h under different pH condition after, mark the fluorescent value of micella sample with measured by flow cytometry cytophagy FITC.
5th step: the Study of cytotoxicity of carrying Zorubicin PEG-BCPBLGDox micella
Tetrazolium bromide (MTT) colorimetric determination PEG-BCPBLG micella, without year Zorubicin micella PEGPBLGDox of boric acid ester connector element, take boric acid ester as year Zorubicin micella PEG-BCPBLGDox and Dox HepG2 cytotoxicity under pH7.4 and pH5.0 culture condition of connector element.
6th step: carry the growth activity evaluation that Zorubicin micella PEG-BCPBLGDox suppresses hepatocellular carcinoma in nude mice model
Evaluate PEG-BCPBLGDox to the growth inhibitory effect of hepatocellular carcinoma in nude mice model (HepG2).
Beneficial effect of the present invention is: block polymer prepared by the present invention may be used for constructing nano-micelle, has good release, lower cytotoxicity and good cytophagy.
Accompanying drawing explanation
Figure 1A is the structure of the bi-block copolymer taking borate ester as connector element and carries adriamycin nano micella PEG-BCPBLGDox schematic diagram;
Figure 1B is the structural representation of PEG-BCPBLG micella;
Fig. 1 C be PEG-BCPBLG micella structure in acid condition borate ester bond rupture time, micella sloughs PEG skin, exposes the structural representation after phenylo boric acid end.
Fig. 2 is be that the block polymer PEG-BC-PBLG of connector element degrades in different pH medium with borate ester
1hNMR spectrogram.After boric acid ester bond rupture, PBLG end is insoluble to DMSO-D6, and PEG end is still dissolved in DMSO-D6, and in figure, PBLG holds characteristic peak h, and i, g place peak area reduces along with the reduction of pH, and PEG holds characteristic peak f, and e, d peak area is substantially constant.
Fig. 3 is before and after PEG-BC-PBLG block polymer dialysis purifying
11bNMR spectrogram.A: boron spectrum before dialysis, a is boron ester peak, and b is boric acid peak; B: boron spectrum after dialysis, only has boron ester peak a.
Fig. 4 is size distribution (DLS figure) and the shape appearance figure (TEM figure) of PEG-BCPBLG micella.
Fig. 5 is the change of size figure of PEG-BCPBLG micella in different pH buffered soln.In pH7.4, micella particle diameter is at about 100nm, relatively stable, reduces with medium pH, and the particle diameter of micella, in the trend obviously increased, reaches 400,950,2100nm respectively.
Fig. 6 is the drug release behavior of PEG-BCPBLGDox carrier micelle in different pH buffered soln.In pH7.4 medium, drug releasing rate is comparatively slow, 9h cumulative release amount only about 10%.Obviously increase along with medium pH reduces release amount, in pH5.0 medium, 4hDox release up to 85%, and contrasts carrier micelle PEGPBLGDox release amount under pH5.0 condition and is only 4.8%.A:PEG-BCPBLG·Dox(pH7.4)；BPEG-BCPBLG·Dox(pH6.5)；CPEG-BCPBLG·Dox(pH6.0)；DPEG-BCPBLG·Dox(pH5.0)；EPEGPBLG·Dox(pH5.0)。
Fig. 7 is HepG2 or HL7702 cell cytophagy behavior fluorescence intensity statistical graph to the PEG-BCPBLG micella of FITC mark under condition of different pH.A) PEGPBLG-FITC acts on HepG2 cell, B) PEG-BCPBLG-FITC acts on HepG2 cell, C) PEG-BCPBLG-FITC acts on HL7702 cell.
Fig. 8 is PEG-BCPBLG micellar carrier and carries after Zorubicin (Dox) at A:pH7.4; Cytotoxicity in B:pH5.0 substratum.PEGPBLGDox and PEG-BCPBLGDox demonstrates hypotoxicity under pH7.4 condition, but PEG-BCPBLGDox cytotoxicity obviously increases and presents concentration-dependent relation under pH5.0 condition.
Fig. 9 is the growth inhibitory effect of PEG-BCPBLGDox to tumor bearing nude mice tumour (HepG2 cell), A) physiological saline, B) DoxHCl, C) PEG-BCPBLG carrier, D) PEG-BCPBLGDox.
Figure 10 is body weight change after tumor bearing nude mice administration.
Embodiment
In conjunction with following specific embodiments and the drawings, the present invention is described in further detail.Implement process of the present invention, condition, experimental technique etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The synthesis of embodiment one, PEG-3,4-DA
Take 3,4-dihydroxyphenyl acetic acid (0.126g, 0.750mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.154g, 0.800mmol) is added, I-hydroxybenzotriazole (0.108g, 0.800mmol), DIPEA (0.260ml, 1.500mmol), PEG-NH
2(1.000g, 0.500mmol) and 30ml anhydrous methylene chloride in reaction flask, nitrogen protection; room temperature reaction 12h; add ultrapure water after concentrated to dissolve, dichloromethane extraction for several times, mix sample and cross column purification (methylene dichloride: methyl alcohol=30:1) by concentrated solution.Be added drop-wise in 50ml ice ether after product after purifying is concentrated, filtration washing for several times rear drying obtains white powder PEG-3,4-DA0.840g, productive rate 78%.
The structural formula of described PEG-3,4-DA is as shown in such as formula (5);
The synthesis of embodiment two, PEG-BC
Take PEG-3,4-DA (0.430g, 0.200mmol), 3-amino-benzene boric acid (0.137g, 1.000mmol), and 100ml heavily steam after toluene be placed in Dean-Stark de-watering apparatus, 120 DEG C of heating 8h, add 10ml anhydrous tetrahydro furan after concentrated to dissolve, being transferred to molecular weight cut-off is dialyse in the dialysis tubing of 2000 after 24h to be added drop-wise in 50ml ice ether in anhydrous tetrahydro furan solvent, filtration washing for several times rear drying obtains pale yellow powder PEG-BC0.360g, productive rate 80%.
The structural formula of described PEG-BC is such as formula shown in (6);
The synthesis of embodiment three, PEG-BC-PBLG
Take PEG-BC (0.897g; 0.400mmol); 5-benzyl ester-Pidolidone-N-carboxyanhydrides (BLG-NCA) (0.500g; 2.000mmol); and 30ml anhydrous tetrahydro furan is in reaction flask; nitrogen protection; room temperature reaction 12h; transferring to molecular weight cut-off after concentrated is in the dialysis tubing of 3500; dialysis 12h; be added drop-wise in 50ml ice ether after dialyzate is concentrated, filtration washing for several times rear drying obtains end product PEG-BC-PBLG1.244g, productive rate 95%.
The structural formula of described PEG-BC-PBLG is as shown in the formula shown in (I);
Embodiment four, FITC mark the synthesis of PEG-BC-PBLG and comparison polymer PEG-PBLG
After PEG-BC-PBLG and FITC room temperature reaction 12h, ether washes away excessive FITC can obtain PEG-BC-PBLG-FITC.Same method, available PEG-NH
2open loop BLG-NCA obtains PEG-PBLG and PEG-PBLG-FITC.
The structural formula of described PEG-BC-PBLG is as shown in the formula shown in (I);
The structural formula of described PEG-PBLG is as shown in the formula shown in (7):
The assembling of embodiment five, PEG-BCPBLG micella
2mgPEG-BC-PBLG is dissolved in 0.5mL methylene dichloride, being added dropwise to stirring velocity is in the 10mL ultrapure water of 500r/min, filter by the syringe filter of 0.45 μm, load dialysis tubing dialysis 48h (every 6h changes a ultrapure water), lyophilize, obtained described PEG-BCPBLG micelle freeze-drying powder.Tem observation its be spherical morphology, dynamic light scattering records its median size and is about 80nm, with DLS result coincide.
The preparation of embodiment six, year Zorubicin micella PEG-BCPBLGDox
Getting 10mgPEG-BC-PBLG and 2mgDox is dissolved in 1mlDMSO, being added dropwise to stirring velocity is in the 20mL ultrapure water of 500r/min, filters by the syringe filter of 0.45 μm, loads dialysis tubing dialysis 48h (every 6h changes a ultrapure water), lyophilize, obtained PEG-BCPBLGDox.
Fluorescence probe method measures its micelle-forming concentration (CMC), takes a certain amount of pyrene and is dissolved in ethanol, allow ethanol volatilize under room temperature, configures above-mentioned micellar concentration scope from 1 × 10
-5to 5 × 10
-1mg/mL, add in the vial containing pyrene respectively, the concentration of pyrene is fixed on 6 × 10
-7mg/mL, record fluorescent value under each concentration with fluorophotometer, calculating micelle-forming concentration is 3.5 × 10
-2mg/mL.
Its drug loading (DLC) and encapsulation rate (DLE) is measured with ultraviolet absorption method, the Zorubicin micella PEG-BCPBLGDox powder that carries of preparation is dissolved in DMSO, measure its ultraviolet absorption value at 480nm place, contrast with the standard working curve of Dox, calculate drug loading and encapsulation rate is respectively 8.5% and 42.5%.
Drug loading (the DLC%)=quality of the quality/polymkeric substance of Dox (in the micella) × 100%
Encapsulation rate (DLE%)=(quality that in micella, the quality/Dox of Dox feeds intake) × 100%.
The schematic diagram of described year adriamycin nano micella PEG-BCPBLGDox as shown in Figure 1A.
The acid degradation performance of embodiment seven, PEG-BC-PBLG block polymer and PEG-BCPBLG micella
With
1hNMR have studied the degraded situation of block polymer PEG-BC-PBLG, and wherein with the pH of pH7.4 medium simulation normal blood, pH6.5, pH6.0, pH5.0 medium simulates tumor tissues, endosome, lysosomal pH respectively.Use D
2o configures the Na that pH is respectively 7.4,6.5,6.0,5.0
2hPO
4/ NaH
2pO
4damping fluid, gets 10mgPEG-BC-PBLG respectively and is dissolved in 1mLDMSO-D6, adds each pH damping fluid of 100 μ L, and mixing is per hour afterwards sweeps once
1hNMR.
The degraded situation of PEG-BCPBLG micella can be reacted with the change of DLS mensuration micella particle diameter in pH damping fluid.Getting 1mgPEG-BCPBLG freeze-drying micella is dissolved in each pH damping fluid of 5mL, monitoring change of size situation.After 30min in pH6.5, pH6.0, pH5.0 medium its change of size.
Embodiment eight, the drug release behavior of PEG-BCPBLGDox micella in different pH medium
The Release Performance of PEG-BCPBLGDox micella at pH damping fluid is measured with ultraviolet spectrophotometer.Get 25mLPEG-BCPBLGDox (0.2mg/mL) and be placed in pH7.4 respectively, 6.5,6.0, dialyse in 5.0 damping fluids 24h (MWCO2000), the absorbancy of ultraviolet spectrophotometer each group after recording dialysis respectively, with the standard curve control recording Dox, calculate each group of release amount.
The cytophagy behavior of embodiment nine, PEG-BCPBLG nano-micelle
The preculture 24h (10 × 10 on four lattice culture dish (Greiner) by HepG2 cell and HL7702 cell
4cells/ hole) after, adding 3mLpH is respectively 7.4,6.5, the substratum of 6.0,5.0, wherein often organizes respectively containing PEG-BCPBLG-FITC and PEGPBLG-FITC (0.4mg/mL), after continuing to cultivate 3h, PBS (pH7.4) cleans for several times, and collected by centrifugation after digestion, measures each group of cell fluorescence intensity with flow cytometer.
The Study of cytotoxicity of embodiment ten, year Zorubicin PEG-BCPBLGDox micella
For studying the vitro cytotoxicity of PEG-BCPBLGDox, the carrier micelle PEGPBLGDox without boric acid ester bond is produced the control experiment for toxicity research.To PEG-BCPBLG micella, without the carrier micelle PEGPBLGDox of boric acid ester bond, carry Zorubicin micella PEG-BCPBLGDox and under pH7.4 and pH5.0 condition, do not carried out hepatocellular carcinoma H22 toxotest by the Dox that micella wraps up.Cell culture processes is: the HepG2 cell being in logarithmic phase is inoculated in every hole 180 μ L on 96 orifice plates, after in constant incubator, culturing cell number reaches 80%, often organize the PEG-BCPBLG adding 20 μ L respectively and contain a series of concentration gradient, PEGPBLGDox, PEG-BCPBLGDox and Dox, concentration all with Dox content for standard is respectively 3.25,7.5,15,30,60 and 120 μ g/mL, cultivate 24h; Add 10 μ LMTT solution (5mg/mL) to continue afterwards to cultivate 4h, suck substratum and add 100 μ LDMSO dissolving first a ceremonial jade-ladle, used in libation crystal, measure absorbancy by microplate reader in 570nm wavelength place.Cell survival rate is calculated as follows:
Cell survival rate (%)=(OD
experimental group-OD
blank group/ OD
control group-OD
blank group) × 100%
Embodiment 11, PEG-BCPBLGDox micella suppress liver cancer growth activity rating
Choose the BALB/c-nu nude mice (mouse 6 weeks ages, body weight 18-20g) of bouncing, in inoculation mouse source, oxter, left side hepatocellular carcinoma H22, inoculating cell density for every only 100 μ L cell count be 5 × 10
7(wherein BD-Martrigel matrigel and cell volume are than being 1:1).(be set as the 0th day) when tumour grows to about about 5mm, tumor bearing nude mice is divided into 4 groups (between group, mouse is heavy roughly the same) at random, often organizes 6.By physiological saline, PEG-BCPBLG, PEG-BCPBLGDox and Dox by 5mg/kg (Dox content is standard) tail vein injection, once, injection 5 times continuously, by the size of vernier caliper measurement tumour, and is calculated as follows gross tumor volume V in injection in every three days:
V(mm
3)＝(a·b
2·π)/6
Wherein a, b are respectively the minimum and maximum size of tumour.
Protection content of the present invention is not limited to above embodiment.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.
Claims (9)
1. be a bi-block copolymer for connector element with borate ester, it is characterized in that, the structural formula of described bi-block copolymer such as formula shown in (I),
In formula (I):
x＝40-120
m＝5-20。
2. one kind take borate ester as the synthetic method of the bi-block copolymer of connector element: it is characterized in that, said method comprising the steps of: (1) synthesis PEG-NH
2dOPA derivative PEG-3,4-DA; (2) PEG-3,4-DA and 3-amino-benzene boric acid dehydrating condensation, obtains the borate ester derivative PEG-BC of PEG; (3) carrying out ring-opening polymerization using PEG-BC as macromole evocating agent to 5-benzyl ester-Pidolidone-N-carboxyanhydrides (BLG-NCA), is the bi-block copolymer PEG-BC-PBLG of connector element with borate ester described in obtaining.
3. what according to claim 2 prepared by method take borate ester as the bi-block copolymer of connector element, and it is characterized in that, described bi-block copolymer structure is such as formula shown in (I).
4. by according to claim 1 take borate ester as the application of bi-block copolymer for the preparation of pharmaceutical carrier of connector element.
5. application according to claim 4, is characterized in that, described medicine is fat-soluble medicine.
6. application according to claim 5, is characterized in that, described fat-soluble medicine is Zorubicin, gemcitabine, SN38, taxol.
7. application according to claim 4, is characterized in that, described pharmaceutical carrier is nano-micelle carrier.
8. apply as claimed in claim 7, it is characterized in that, described nano-micelle carrier is acid-sensitive type.
9. apply as claimed in claim 7 or 8, it is characterized in that, described nano-micelle carrier is for strengthening the endocytosis characteristic of tumour cell.
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| CN108815552A (en) * | 2018-07-05 | 2018-11-16 | 四川大学 | A kind of drug controllably loads and the bio-medical coating material of long-acting slow-release and preparation method thereof |
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| JP2019123805A (en) * | 2018-01-16 | 2019-07-25 | 公益財団法人川崎市産業振興財団 | Block copolymer, micelle composition, and pharmaceutical composition |
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| CN106243343A (en) * | 2016-08-11 | 2016-12-21 | 江苏大学 | The synthesis of a kind of phenylboric acid functionalization block polymer and application |
| CN108727581A (en) * | 2017-04-18 | 2018-11-02 | 华东师范大学 | Using borate ester as amphipathic camptothecine Macromolecule Prodrug of connection unit and its preparation method and application |
| JP2019123805A (en) * | 2018-01-16 | 2019-07-25 | 公益財団法人川崎市産業振興財団 | Block copolymer, micelle composition, and pharmaceutical composition |
| WO2019142823A1 (en) * | 2018-01-16 | 2019-07-25 | 公益財団法人川崎市産業振興財団 | Block copolymer, micelle composition and pharmaceutical composition |
| JP7100457B2 (en) | 2018-01-16 | 2022-07-13 | 公益財団法人川崎市産業振興財団 | Block copolymers, micelle compositions, and pharmaceutical compositions |
| CN108815552A (en) * | 2018-07-05 | 2018-11-16 | 四川大学 | A kind of drug controllably loads and the bio-medical coating material of long-acting slow-release and preparation method thereof |
| CN109985007A (en) * | 2019-03-15 | 2019-07-09 | 华东师范大学 | Using borate ester as two block sensitive camptothecin polymeric object prodrugs of connection unit and preparation method thereof |
| CN112807443A (en) * | 2021-01-20 | 2021-05-18 | 广州医科大学 | Multiple synergistic antibacterial nano prodrug |
| CN112807443B (en) * | 2021-01-20 | 2022-12-23 | 广州医科大学 | Multiple synergistic antibacterial nano prodrug |
| CN115433354A (en) * | 2022-08-17 | 2022-12-06 | 浙江怡辉生物科技有限公司 | Amphiphilic block polymer, self-assembled nanoparticle, drug-encapsulated complex prepared from amphiphilic block polymer and self-assembled nanoparticle, and application of drug-encapsulated complex |
| CN115433354B (en) * | 2022-08-17 | 2023-09-12 | 浙江怡辉生物科技有限公司 | Amphiphilic block polymer, self-assembled nanoparticle, drug-entrapped complex prepared from amphiphilic block polymer and application of drug-entrapped complex |
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