CN106866978B - self-catalytic-destruction block polymer and preparation method thereof - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000000693 micelle Substances 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- OXEZLYIDQPBCBB-UHFFFAOYSA-N 4-(3-piperidin-4-ylpropyl)piperidine Chemical compound C1CNCCC1CCCC1CCNCC1 OXEZLYIDQPBCBB-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000008367 deionised water Substances 0.000 claims description 11
- 229910021641 deionized water Inorganic materials 0.000 claims description 11
- 238000000502 dialysis Methods 0.000 claims description 11
- GODZNYBQGNSJJN-UHFFFAOYSA-N 1-aminoethane-1,2-diol Chemical compound NC(O)CO GODZNYBQGNSJJN-UHFFFAOYSA-N 0.000 claims description 6
- MSKSQCLPULZWNO-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanamine Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN MSKSQCLPULZWNO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- ACBQROXDOHKANW-UHFFFAOYSA-N bis(4-nitrophenyl) carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 ACBQROXDOHKANW-UHFFFAOYSA-N 0.000 claims description 3
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G64/00—Macromolecular compounds obtained by reactions forming a carbonic ester link in the main chain of the macromolecule
- C08G64/20—General preparatory processes
- C08G64/30—General preparatory processes using carbonates
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G64/00—Macromolecular compounds obtained by reactions forming a carbonic ester link in the main chain of the macromolecule
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Abstract
the invention relates to a self-catalytic-destruction block polymer and a preparation method thereof. The structural formula of the triblock polymer PEG-PCN-PEG (as an example, the invention is described in detail) is as follows: the structural formula of the diblock polymer PEG-PCN (the synthesis and characterization method is the same as that of the triblock polymer) is as follows: the preparation method disclosed by the invention has the characteristics of simple process, mild reaction conditions, strong controllability and the like, and can be prepared by a one-pot method; the obtained novel self-destroying segmented polymer can be self-assembled into a spherical micelle with a hydrophilic shell and a hydrophobic core in an aqueous solution; the polymer micelle is completely cracked into small molecular compounds through self-destruction reaction under the stimulation of oxidation and reduction, so that the biodegradability of the material is improved.
Description
Technical Field
the invention relates to a self-destroying block polymer and a preparation method thereof, belonging to the technical field of high molecular chemical synthesis and block polymer self-assembly.
Background
The effective delivery and uptake of chemotherapeutic drugs are the key points for overcoming tumor drug resistance and improving chemotherapeutic effect, and the polymer has potential application prospect as a drug carrier, but necessary chemical modification is needed to realize the multifunction of the polymer. In addition, in order to be applied to in vivo and even clinical research, the stability and effective controllable release of the carrier in vivo are also considered. Redox-responsive polymer nanocarrier delivery systems have been the focus of research in the field of nanocarriers for cancer therapy, but still have some problems, such as incomplete cleavage of the polymer backbone, incomplete release of entrapped drugs, etc. Furthermore, due to the lack of controllability of the degradation process, the insolubility of the degradation intermediates may lead to the formation of irregular aggregates, thereby hindering the efficient release of the drug and the in vivo metabolism of the carrier fragment. Self-destroying polymers can solve this problem. At present, the research on the polymer micelle with self-destroying and degradation characteristics is rare, and the application in the field of drug carrier release is rare and rare.
the invention aims to design a novel self-destructible redox-responsive polymer nano-carrier to make up for the defects of a pure redox nano-carrier. The nano-carrier based on the polymer is expected to respond to redox stimulation in a tumor microenvironment and be completely broken into small molecular compounds, so that the carried drug can be quickly and effectively released, the drug utilization rate is improved, the biodegradability of the nano-carrier is also improved, and the in-vivo metabolism of the nano-carrier is facilitated.
Disclosure of Invention
It is an object of the present invention to provide a block polymer which is self-destructively degradable.
The second object of the present invention is to provide a process for producing the polymer.
For the above purpose, please refer to fig. 1(a) and fig. 1(b) for the polymerization mechanism of the present invention.
according to the reaction mechanism, the invention adopts the following technical scheme:
a self-destructible block polymer characterized by the structural formula:
The structural formula of the triblock polymer PEG-PCN-PEG (as an example, the invention is described in detail) is as follows:
The structural formula of the diblock polymer PEG-PCN (the synthesis and characterization method is the same as that of the triblock polymer) is as follows:
A self-destructible block polymer characterized by the structural formula being one of:
a. the triblock polymer PEG-PCN-PEG has a structural formula as follows:
b. The diblock polymer PEG-PCN has a structural formula as follows:
wherein m is 10 to 340, and n is 12 to 24.
A method for preparing the self-destructible block polymer is characterized by comprising the following steps:
a. under the protection of inert atmosphere, dissolving 2, 2' -dithiodiethanediyldithio (p-nitrophenyl carbonate) DTDE-PNC and methoxypolyethylene glycol amine mPEG-NH2 in a mixed solvent of dichloromethane and methanol, wherein the volume ratio of the dichloromethane to the methanol in the mixed solvent is 9: 1; stirring and reacting for 2-3 hours at room temperature, and then adding 1, 3-bis (4-piperidyl) propane (CN); the molar ratio of mPEG-NH2 to CN and DTDE-PNC is 2:15: 16-2: 31: 32; reacting for 2-3 days at room temperature;
b. B, adding methoxypolyethylene glycol amine or 1, 3-bis (4-piperidyl) propane into the reactant obtained in the step a, wherein the dosage of the methoxypolyethylene glycol amine or the 1, 3-bis (4-piperidyl) propane is 10% of the dosage of the 1, 3-bis (4-piperidyl) propane added in the step a, and reacting for 2-3 days at room temperature;
c. Dropwise adding the reaction liquid obtained in the step b into deionized water, stirring for 2 hours at room temperature, and dialyzing;
d. and c, putting the dialysis product obtained in the step c into an ultralow temperature freezer at-80 ℃ for 2 hours, and then drying to finally obtain the target polymer, namely the triblock polymer PEG-PCN-PEG or the diblock polymer PEG-PCN.
The preparation method of the micelle of the self-destructible block polymer is characterized by comprising the following specific steps: dissolving a triblock polymer PEG-PCN-PEG or a diblock polymer in dimethyl sulfoxide (DMSO) to prepare a dialysate with the concentration of 100mg/mL, stirring overnight at room temperature, dropwise adding the triblock polymer PEG-PCN-PEG or the diblock polymer into deionized water with the volume of 10 times of the volume of the triblock polymer DMSO while stirring, and dialyzing after stirring for 2 hours to remove the DMSO to finally obtain the dialysate containing the triblock polymer micelle PEG-PCN-PEG or the diblock polymer micelle PEG-PCN.
the preparation of the micelle adopts a dialysis method, the obtained block polymer is dissolved in DMSO solution, nitrogen is used for protection, the mixture is stirred overnight at room temperature, then the mixture is dripped into deionized water dropwise while stirring, then the mixture is put into a dialysis bag (the proper molecular weight cut-off is selected according to the molecular weights of different polymers), the mixture is dialyzed in the deionized water for a period of time, and the deionized water is replaced periodically so as to fully remove the DMSO, and finally the dialysate containing the polymer micelle is obtained. The prepared polymer micelle solution can be stored for a long time at room temperature, and can be widely applied to biomedical diagnosis and treatment of medicaments in river-wearing delivery and the like.
The advantages and features of the method of the invention are as follows:
(1) The self-catalytic-destruction block polymer has the characteristics of simple synthetic process, mild reaction condition, strong controllability and the like, and can be prepared by a one-pot method;
(2) the novel self-destructing block polymer can be self-assembled into a spherical micelle with a hydrophilic shell and a hydrophobic core in an aqueous solution;
(3) The polymer micelle is completely cracked into small molecular compounds through self-destruction reaction under the stimulation of oxidation and reduction, so that the biodegradability of the material is improved.
Drawings
FIG. 1(a) is a scheme showing the synthesis of a self-destructing diblock polymer PEG-PCN according to the present invention;
FIG. 1(b) is a synthetic scheme of the self-destructing triblock polymer PEG-PCN-PEG of the present invention;
FIG. 2 is a GPC chart of PEG, PEG-PCN and PEG-PCN-PEG in the present invention;
FIG. 3 is a diagram showing the critical micelle concentration of the self-destruct block polymers PEG-PCN and PEG-PCN-PEG in the present invention;
FIG. 4 is a diagram showing the particle size of a self-destructed triblock polymer micelle PEG-PCN-PEG in the present invention;
FIG. 5 shows the particle size variation of the self-destructed triblock polymer micelle PEG-PCN-PEG in the presence or absence of DTT;
FIG. 6 is a schematic diagram of the self-destructive degradation of the self-destructing triblock polymer PEG-PCN-PEG of the present invention;
FIG. 7 is a HPLC-MS diagram of the self-destructed triblock polymer micelle PEG-CN-PEG after being treated by DTT in the present invention;
Detailed Description
Specific embodiments of the present invention will now be described.
Example (b): the process and steps in this example are as follows:
1. Preparation of self-catalytic-destruction triblock polymer PEG-PCN-PEG
weighing 1.0g of 2, 2' -dithiodiethanediylbis (p-nitrophenyl carbonate) (DTDE-PNC for short) (2.070mmol), putting the weighed materials into a round-bottom flask, adding 2mL of mixed solution of dichloromethane and methanol (volume ratio is 9: 1), adding a rotor under the protection of nitrogen, and stirring until the compound is completely dissolved; 664.9mg of methoxypolyethyleneglycoamine (0.129mmol PEG-NH2) is weighed and dissolved in 2mL of mixed solution of dichloromethane and methanol (volume ratio is 9: 1), the mixed solution is dropwise added into the flask, and the mixture is stirred and reacted for 2 hours at room temperature under the protection of nitrogen; 434.8mg of 1, 3-bis (4-piperidyl) propane (2.005mmol) is weighed and dissolved in 200 microliter of mixed solution (the volume ratio of dichloromethane to methanol is 9: 1), and the mixture reacts for 3 days at room temperature under the protection of nitrogen; finally, 1067.0mg of methoxypolyethyleneglycoamine (0.207mmol) was added to the reaction mixture, and the reaction was carried out at room temperature for 2 days.
The reaction solution was added dropwise to 100mL of deionized water (pH 7.4), stirred at room temperature for 2 hours, and then placed in an MWCO10000 dialysis bag (a dialysis bag was selected depending on the molecular weight, and here, 10000 was used because the molecular weight of the target polymer was 15000), and dialyzed in 5000mL of deionized water (pH 7.4) for 3 days, and water was changed every 8 hours. And (3) putting the dialysis product into an ultralow temperature freezer at minus 80 ℃ for 2 hours, and then putting the dialysis product into a vacuum freeze dryer for drying to obtain the target polymer PEG-PCN-PEG.
2. Preparation of self-catalytic-destruction triblock polymer micelle PEG-PCN-PEG
The preparation of the micelle adopts a dialysis method, 200mg of triblock polymer (PEG-PCN-PEG) is weighed and dissolved in 2.0mL of DMSO solution, the mixture is stirred overnight at room temperature (the rotating speed is 680r/min), then the triblock polymer is dripped into 2.0mL of deionized water (the pH value is 7.4) dropwise, the mixture is stirred while being dripped (the rotating speed is 820r/min), the mixture is stirred for 2 hours and then is filled into a dialysis bag (the proper molecular weight cut-off is selected according to the molecular weight of different polymers, the molecular weight of the PEG-PCN-PEG is 15000, so that the dialysis bag with the molecular weight cut-off of 10000 is used), and when the mixture is dialyzed for 72 hours in 5000mL of deionized water (the pH value is 7.4), water is changed once every 8 hours, so that the DMSO can be fully removed, and the solution containing the PEG-PCN-PEG micelle is obtained.
the preparation method of the triblock polymer PEG-PCN is similar to that of the triblock polymer PEG-PCN-PEG, except that the finally added methoxypolyethyleneglycolamine is changed into 1, 3-di (4-piperidyl) propane.
3. And (4) conclusion:
FIG. 2 is a GPC chart of the polymer PEG before reaction and the block polymers PEG-PCN and PEG-PCN-PEG after reaction. As can be seen from the figure, the polymers are all single peaks, the peaks are symmetrical, the outflow time of the PEG-PCN is shorter than that of the PEG, which indicates that the molecular weight of the PEG-PCN is larger than that of the PEG, and indicates that the PCN is successfully connected to the PEG; in addition, the outflow time of PEG-PCN-PEG is shorter than that of PEG-PCN, which shows that the molecular weight of PEG-PCN-PEG is larger than that of PEG-PCN, because PEG-PCN-PEG has one more block PEG than PEG-PCN, which comprehensively shows that different block polymers can be obtained according to different input encapsulation end groups.
FIG. 3 shows that 2 prepared polymers can form micelles at a relatively low concentration (8.5-30.2. mu.g/mL), and the CMC can be adjusted by changing the mass percentages of the components of the polymers and the hydrophobic Polyurethane (PU) (i.e., the number of blocks of the hydrophobic block). For example: also, the CMC of the triblock polymer PEG-PCN-PEG is higher than that of the corresponding diblock polymer PEG-PCN when the molecular weights of the hydrophobic blocks are the same. We can find that the larger the mass percentage of polyurethane in the hydrophobic part of the polymer, the less hydrophilic the structural group, and the lower the CMC of the polymer, and the more suitable it is as a carrier for drug delivery.
Fig. 4 measures and observes the size and morphology of the micelle using DLS and TEM. Taking PEG-PNN-PEG micelle as an example, triblock polymer particles are in a uniform spherical appearance structure, and have uniform size of about 80-100 nm; while the DLS measurement gave a micelle hydrated particle size diameter (Rh) of 76.1nm, which is more consistent with the TEM data.
FIG. 5 to determine the stability of polymer micelles in various environments, we treated triblock polymer micelle PEG-PCN-PEG with a solution containing 10mM DTT and observed the size change of the micelle with time, and the micelle cultured without the solution of 10mM DTT was used as a blank. As can be seen from FIG. 5(a), in the 10mM DTT solution, the micelle diameter is gradually increased along with the increase of time, DLS shows that at the time of 2 hours, two bulges appear on the DLS curve of the micelle, which indicates that the part of the micelle diameter is changed and is increased from the original 76nm to 450nm, because the polymer is degraded under the redox condition, and the micelle after cracking is swelled, which results in the increase of the particle diameter size. After 6 hours, more micelles are degraded, the original hydrophilic-lipophilic balance is further broken, and the degraded polymer segments are self-assembled and agglomerated again to form micelles with the size of 200 nm; after 12 hours, the micelle formed by the self-assembly is further degraded and swelled, and the particle size of the micelle is about 400 nm. In contrast, as shown in FIG. 5(b), only a small portion of the PEG-PCN-PEG micelles swelled and most of the micelle sizes did not change significantly within 24h, compared with the blank control in PBS.
FIG. 7 to further demonstrate that redox-induced polymer degradation is a self-destructive process, we detected the product by LC-MS separation. As shown in FIG. 7, the degradation products are separated well by HPLC, and the mass spectrometry of the separation product with the largest content is performed, and the molecular weight of the product is determined to be 211, which indicates that the degradation product of the polymer contains monomer CN originally used for polycondensation reaction, thus proving that the degradation process of the PEG-CN-PEG polymer micelle is a self-destruction process (schematic diagram 6).
Claims (3)
1. a self-destructible block polymer characterized by the structural formula being one of:
a. the triblock polymer PEG-PCN-PEG has a structural formula as follows:
b. The diblock polymer PEG-PCN has a structural formula as follows:
Wherein m is 10 to 340, and n is 12 to 24.
2. A process for the preparation of the self-destructible block polymer according to claim 1, comprising the specific steps of:
a. Under the protection of inert atmosphere, dissolving 2, 2' -dithiodiethanediyldithio (p-nitrophenyl carbonate) DTDE-PNC and methoxypolyethylene glycol amine mPEG-NH2 in a mixed solvent of dichloromethane and methanol, wherein the volume ratio of the dichloromethane to the methanol in the mixed solvent is 9: 1; stirring and reacting for 2-3 hours at room temperature, and then adding 1, 3-bis (4-piperidyl) propane (CN); the molar ratio of mPEG-NH2 to CN and DTDE-PNC is 2:15: 16-2: 31: 32; reacting for 2-3 days at room temperature;
b. b, adding methoxypolyethylene glycol amine or 1, 3-bis (4-piperidyl) propane into the reactant obtained in the step a, wherein the dosage of the methoxypolyethylene glycol amine or the 1, 3-bis (4-piperidyl) propane is 10% of the dosage of the 1, 3-bis (4-piperidyl) propane added in the step a, and reacting for 2-3 days at room temperature;
c. Dropwise adding the reaction liquid obtained in the step b into deionized water, stirring for 2 hours at room temperature, and dialyzing;
d. and c, putting the dialysis product obtained in the step c into an ultralow temperature freezer at-80 ℃ for 2 hours, and then drying to finally obtain the target polymer, namely the triblock polymer PEG-PCN-PEG or the diblock polymer PEG-PCN.
3. A method for preparing a micelle of a block polymer, which is characterized by comprising the following steps: dissolving the self-destructible triblock polymer PEG-PCN-PEG or diblock polymer PEG-PCN of claim 1 in Dimethylsulfoxide (DMSO) to prepare a solution with a concentration of 100mg/mL, stirring overnight at room temperature, then dropwise adding the solution into deionized water with a volume of 10 times of the volume of the solution under stirring, stirring for 2 hours, and dialyzing to remove DMSO, thereby obtaining a dialysate containing the triblock polymer micelle PEG-PCN-PEG or diblock polymer micelle PEG-PCN.
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| US8895674B2 (en) * | 2011-05-07 | 2014-11-25 | Chung-Shan Institute of Science and Technology, Armaments, Bureau, Ministry of National Defense | Method for providing a side-chain dendrimer vesicle |
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