CN117603415A - Functionalized block polymer nano-drug carrier and preparation method and application thereof - Google Patents
Functionalized block polymer nano-drug carrier and preparation method and application thereof Download PDFInfo
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- 229920000642 polymer Polymers 0.000 title claims abstract description 81
- 239000003937 drug carrier Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229920002845 Poly(methacrylic acid) Polymers 0.000 claims abstract description 50
- 239000003814 drug Substances 0.000 claims abstract description 41
- 229940079593 drug Drugs 0.000 claims abstract description 37
- 229920002873 Polyethylenimine Polymers 0.000 claims abstract description 32
- 239000000693 micelle Substances 0.000 claims abstract description 25
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 glycol monomethyl ether amine Chemical class 0.000 claims abstract description 10
- MLGMNVSTCSILMV-UHFFFAOYSA-N 2-methylsulfanylethyl 2-methylprop-2-enoate Chemical compound CSCCOC(=O)C(C)=C MLGMNVSTCSILMV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920001577 copolymer Polymers 0.000 claims abstract description 7
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- 238000005886 esterification reaction Methods 0.000 claims abstract description 4
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
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- 238000000502 dialysis Methods 0.000 claims description 17
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- 238000006243 chemical reaction Methods 0.000 claims description 16
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- 238000000034 method Methods 0.000 claims description 11
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
- 229910052786 argon Inorganic materials 0.000 claims description 8
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 8
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- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 3
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- ZNJRONVKWRHYBF-UHFFFAOYSA-N 2-[2-[2-(1-azatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-7-yl)ethenyl]-6-methylpyran-4-ylidene]propanedinitrile Chemical compound O1C(C)=CC(=C(C#N)C#N)C=C1C=CC1=CC(CCCN2CCC3)=C2C3=C1 ZNJRONVKWRHYBF-UHFFFAOYSA-N 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- WVOXLKUUVCCCSU-ZPFDUUQYSA-N Pro-Glu-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WVOXLKUUVCCCSU-ZPFDUUQYSA-N 0.000 claims 1
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- 238000002835 absorbance Methods 0.000 description 2
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- 206010015866 Extravasation Diseases 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
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- 108010067787 Proteoglycans Proteins 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
- C08F8/32—Introducing nitrogen atoms or nitrogen-containing groups by reaction with amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
- C08G65/3348—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing nitrogen in addition to sulfur
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2438/00—Living radical polymerisation
- C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a functionalized block polymer nano-drug carrier, the structural formula of which is shown as follows,the invention also provides a preparation method of the functionalized block polymer nano-drug carrier,comprises a step of preparing a copolymer mPEG-CPA, wherein polyethylene glycol monomethyl ether amine and 4-cyano-4- (phenylcarbonyl sulfide) pentanoic acid are synthesized by esterification reaction; a step of preparing a block polymer PMAA, wherein the copolymer mPEG-CPA is reacted with monomer methacrylic acid and 2- (methylthio) ethyl methacrylate to obtain the polymer PMAA; and a step of preparing amphiphilic block polymer PEI-PMAA, wherein the block polymer PMAA is reacted with polyethyleneimine. The invention forms nano micelle in water through self-assembly, has the advantages of excellent micelle stability, controllable nano shape, low toxicity and side effect, good drug controlled release and the like, and can be simultaneously used for the combined delivery of biological therapeutic macromolecules such as proteins, genes and the like and chemotherapeutic drugs.
Description
Technical Field
The invention belongs to the field of polymer chemistry, and relates to a drug delivery carrier, in particular to a functionalized block polymer nano drug carrier, a preparation method and application thereof.
Background
Nano-biomaterials have become an attractive technique for biomedical applications. In recent years, the combined delivery of nanomaterials with genes, proteins and small molecule chemotherapeutic drugs has been widely developed for disease treatment. Wherein, in designing a multifunctional drug carrier, not only is the requirement for delivering small molecule drugs satisfied, but also the necessary structure for delivering biological macromolecules is required to be designed. For delivery of biological macromolecules such as nucleic acids, various effective non-viral gene delivery methods have been developed, including physical stimulus transfection electroporation and synthetic transfection reagents such as cationic lipids (lipoplexes) and cationic polymers (polyplexes). The carrier is selected based on that DNA with negative charges can be aggregated with specific compounds into compact particles through electrostatic interaction, so that the DNA can be effectively protected from degradation. Positively charged particles thus produced may also promote uptake into cells by electrostatic interactions with anionic cell surface groups (e.g. proteoglycans). For in vivo gene delivery, there is still a need to overcome many problems, such as non-specific interactions of extracellular matrix with non-target cells, etc. More importantly, the size of the particles must be small enough to pass through blood circulation, extravasation and tissue diffusion. Finally, target-specific recognition and internalization into target cells should avoid non-specific gene delivery and toxic side effects. Among the various synthetic vectors, polyethylenimine (PEI) has shown particularly promising results in cell culture transfection and various in vivo applications. While several essential features necessary for efficient transfection, such as DNA aggregation and endosomal release, have been inherent to PEI molecules, it is necessary to introduce additional modifications to increase target specificity and improve biocompatibility for in vivo applications.
PEI is a polymer that has long been known and is widely used for the delivery of nucleic acid drugs. There are two main forms of such polymers including linear and branched. The branched form is produced by acid catalyzed polymerization of the nitrided pyridine monomer, resulting in a random branched polymer. The linear form of PEI can be obtained by a similar process but at a lower temperature. The ethylamine repeating units give these polymers a higher water solubility. The most important feature of these molecules is their high cationic density, since one of every three atoms is likely to be a protonatable amino nitrogen. Polycationic Polyethyleneimine (PEI) has been widely used in recent years for the design of DNA delivery vehicles. Gene delivery using PEI involves condensing DNA into dense particles, uptake into cells, release from endosomal compartments into the cytoplasm, and uptake of DNA into the nucleus. In particular for in vivo gene delivery, DNA complexation protects DNA from nuclease damage. In vivo applications, the DNA complex must pass through a variety of anatomical and physiological disorders, as well as the environment of biological fluids and extracellular matrix, to reach the target. However, PEI itself has a large cytotoxicity, and excessive use causes strong toxic side effects on the human body, and the non-specific interaction of non-target cells seriously hinders the delivery of PEI-targeted genes.
Stimulus-responsive polymer delivery systems have evolved rapidly over the last decades, with polymer nanomedicines based on functionalized designs exhibiting tremendous drug delivery potential due to the great flexibility of polymer carriers in terms of shape, biodegradability, morphology and functional engineering. Therefore, it can be used as an excellent drug carrier in the field of drug delivery. Drug release behavior can be achieved by constructing functional chemical bonds that respond to stimuli to precisely deliver drugs to cells and diseased tissue at the site of disease. More importantly, polymeric nano-drug delivery systems have a ubiquitous class of drug delivery. It can be used not only for the precise delivery of biological macromolecules including small molecule drugs, genes, nucleic acids and proteins to increase their activity in organisms, but also to avoid the normal cytotoxicity caused by the use of PEI alone.
The amphiphilic functionalized polymer-based nano-drug carrier can greatly improve the in-vivo therapeutic effect of the drug. Compared with the traditional delivery carrier, the functionalized polymer has a stimulus response unit, enhances the drug release, and is beneficial to prolonging the blood circulation of the drug. However, functionalized polymer delivery systems remain a great challenge in the combined delivery of small molecule drugs and biomacromolecule drugs such as nucleic acids. Based on the single functionality of drug carriers, the stability faced by biomacromolecule delivery, and the bottlenecks of drug release accuracy, there is an urgent need to develop novel functionalized polymeric drug delivery carriers to address such problems.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention provides a functionalized block polymer nano-drug carrier and a preparation method and application thereof, and the functionalized block polymer nano-drug carrier and the preparation method and application thereof aim to solve the technical problems that a polymer delivery system in the prior art has poor stability in the joint delivery of biological macromolecular drugs such as small molecular drugs and nucleic acid and the like, can not realize drug controlled release and the like.
The invention provides a functionalized block polymer nano-drug carrier, the structural formula of which is shown as follows,
m＝10-20，k＝5-10,n＝3-5。
specifically, k=5, m=10, and n is 5.
The invention also provides a preparation method of the functionalized block polymer nano-drug carrier, which comprises the following steps:
(1) A step of preparing a copolymer mPEG-CPA, wherein polyethylene glycol monomethyl ether amine and 4-cyano-4- (phenylcarbonyl sulfide) valeric acid are synthesized by esterification reaction;
(2) A step of preparing a block polymer PMAA, wherein the copolymer mPEG-CPA obtained in the step 1) is polymerized with monomer methacrylic acid and 2- (methylthio) ethyl methacrylate, wherein the polymerization degree of the monomer methacrylic acid is k=5-10, and the polymerization degree of the 2- (methylthio) ethyl methacrylate is m=10-20;
(3) A step of preparing amphiphilic block polymer PEI-PMAA, which is to react the block polymer PMAA obtained in the step 2) with polyethyleneimine, wherein the molecular weight of the polyethyleneimine is 1800 g.mol -1 Repeating unit n=3-5.
Further, in step 1), mPEG-NH is reacted with 2 And 4-cyano-4- (phenylcarbonyl sulfide) valeric acid is dissolved in anhydrous dichloromethane and fully reacted under the protection of argon; then dissolving dicyclohexylcarbodiimide and 4-dimethylaminopyridine in anhydrous dichloromethane, dropwise adding the anhydrous dichloromethane into the reaction solution, and stirring at room temperature; concentrating the obtained crude product by rotary evaporation, and precipitating and washing with diethyl ether to obtain a final product mPEG-CPA;
further, in the step 2), in an argon atmosphere, respectively dissolving mPEG-CPA, MAA and MTEMA in a mixed solvent of anhydrous dimethyl sulfoxide and anhydrous 1, 4-dioxane, and placing the mixed solvent in a reaction bottle; adding an initiator azodiisobutyronitrile, performing vacuum freeze-thaw cycle on the reaction bottle for 2-5 times, and introducing argon; stirring at 50-80 ℃ for 20-40 hours, dialyzing the product with methanol, wherein the molecular weight cut-off of a dialysis bag is 3500kDa; finally, washing with diethyl ether, and vacuum drying to obtain a product PMAA;
further, in step 3), PMAA and PEI are dissolved with anhydrous dimethylformamide DMF and placed in a reaction flask to react under the catalysis of a 1-ethyl- (3-dimethylaminopropyl) carbodiimide EDC and N-hydroxysuccinimide NHS; stirring for 20-40 hours at 15-35 ℃ under the argon protection atmosphere; dialyzing the obtained crude product with methanol after the reaction, wherein the molecular weight cut-off of a dialysis bag is 3500kDa, and precipitating and washing with diethyl ether; obtaining a final product PEI-PMAA through vacuum drying;
further, in the step (1), mPEG-NH 2 And 4-cyano-4- (phenylcarbonylthio) pentanoic acid in a molar ratio in the range of (1.1 to 1.2): (1.2 to 1.3), mPEG-NH in anhydrous DCM 2 And 4-cyano-4- (phenylcarbonylthio) pentanoic acid in a molar concentration range of 0.11 to 0.12 mol.L, respectively -1 And 0.12 to 0.13 mol.L -1 The molar concentration ranges of dicyclohexylcarbodiimide and 4-dimethylaminopyridine dissolved in anhydrous DMSO are 0.44 to 0.46 mol.L, respectively -1 And 0.22 to 0.25 mol.L -1 。
Further, in the step (2), the mole ratio of mPEG-CPA, methacrylic acid, ethyl 2- (methylthio) methacrylate and azobisisobutyronitrile is 1:10:20:0.02.
Further, in the step (3), the molar ratio of PMAA, polyethyleneimine PEI, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide is 1:10:6:6.
The invention also provides a preparation method of the amphiphilic block polymer drug-loaded nano micelle POP NPs, which comprises the following steps: dissolving the amphiphilic block polymer PEI-PMAA and the selected medicine camptothecine in DMSO, dissolving the delivered ovalbumin in deionized water, slowly dripping the DMSO solution into the deionized water in a vortex state, stirring, and further self-assembling; and then transferring the nano micelle into a dialysis bag with the molecular weight cutoff of 3500kDa for dialysis, and finally obtaining the amphiphilic block polymer drug loaded nano micelle POP NPs.
Specifically, the volume ratio of anhydrous DMSO to deionized water is 1:5, and the concentration of POP NPs is highThe degree is 1-10 mg.mL -1 The concentrations of OVA and CPT are respectively 0.2-1 mg.mL -1 。
The invention also provides application of the vector in preparation of a drug for delivery, which comprises the following steps:
the amphiphilic block polymer drug-loaded nano micelle comprises a 2- (methylthio) ethyl methacrylate block and a polyethyleneimine block, and polyethylene glycol is used as a linear polymer chain. The polymerized 2- (methylthio) ethyl methacrylate is used as a hydrophobic inner core of the nano micelle to promote the uploading of camptothecin CPT drugs, the polyethyleneimine block can promote the combination of delivery protein OVA, and the polyethylene glycol is used as a hydrophilic outer core to effectively reduce the toxicity of polyethyleneimine to normal cells. At the same time, the polyethyleneimine block can promote the combination of delivery protein OVA, and thioether bond of the ethyl 2- (methylthio) methacrylate can trigger hydrophobic-hydrophilic transformation when the disease microenvironment with high active oxygen level exists, so that the specific release of the camptothecin drug is realized.
Aiming at the bottleneck faced by the current polymer nano-drug delivery system, the invention creatively designs and synthesizes a functionalized block polymer nano-drug carrier. Based on the single functionality of the drug carrier, the stability, the drug release accuracy and other problems faced by the delivery of the biological macromolecules, the carrier designed by the method has strong universality, can deliver biological macromolecules and micromolecular drugs, and can realize the controlled release of loaded drugs. The functional block polymer nano-drug carrier prepared by the invention can effectively solve the problem of strong toxic and side effects of polyethyleneimine used for delivering biological macromolecular drugs, has good stability, is not easy to decompose, and realizes specific release in high-level active oxygen.
Compared with the prior art, the invention has the technical effects of being positive and obvious. The amphiphilic block polymer can form nano micelle in water through self-assembly, has the advantages of excellent micelle stability, controllable nano shape, low toxicity, good drug controlled release and the like, and can be simultaneously used for the combined delivery of biological therapeutic macromolecules such as proteins, genes and the like and chemotherapeutic drugs, thereby showing wide prospects in improving the drug delivery efficiency and being used for disease treatment.
Drawings
FIG. 1 is a schematic diagram showing the synthesis of a functional block polymer PEI-PMAA in example 1.
FIG. 2 is a nuclear magnetic resonance spectrum of the intermediate PMAA of the functional block polymer of example 1.
FIG. 3 shows the nuclear magnetic resonance spectrum of PEI-PMAA as a functional block polymer in example 1.
FIG. 4 is a gel permeation chromatogram of the functional block polymer PEI-PMAA of example 1.
FIG. 5 is a ZETA potential diagram of the functional block polymer micelles PMAA and PEI-PMAA in test example 1.
FIG. 6 is a graph showing the activity of PEI-PMAA as a functional block polymer carrier against cells in test example 2.
FIG. 7 is a dynamic light scattering particle size distribution chart DLS of the functional block polymer nano-drug carrier POP NPs in test example 3.
Fig. 8 is a transmission electron microscope image TEM of the functional block polymer nano-drug carrier POP NPs in test example 4.
FIG. 9 is a long-term stable particle size distribution plot DLS of the functional block polymer nano-drug carrier POP NPs in test example 5.
FIG. 10 is a graph showing the drug release profile of the functional block polymer nano-drug carrier POP NPs in test example 6.
Detailed Description
The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Example 1 a general synthetic schematic of a functionalized block polymer nano-drug carrier is shown in fig. 1, comprising the steps of:
(1) The copolymer mPEG-CPA was prepared as shown below, and the synthetic route thereof was as follows: mPEG-CPA is formed from mPEG-NH 2 And 4-cyano-4- (phenylcarbonyl sulfide) pentanoic acid are synthesized by esterification reaction; mPEG-NH 2 (1 g, mn=5000 g/mol,0.2 mmol) and 4-cyano-4- (phenylcarbonylthio) pentanoic acid (132 mg,0.2 mmol) were dissolved in anhydrous dichloromethane DCM and reacted well under an argon atmosphere; dicyclohexylcarbodiimide DCC (170 mg,0.82 mmol) and 4-dimethylaminopyridine DMAP (48.7 mg,0.4 mmol) were dissolved in DCM and slowly added dropwise to the reaction solution and stirred at room temperature for 24 hours; concentrating the obtained crude product by rotary evaporation, and precipitating and washing with diethyl ether for three times to obtain a final product mPEG-CPA;
(2) Preparation of Block copolymer PMAA the mPEG-CPA obtained in step 1) is reacted with monomer methacrylic acid (MAA) and ethyl 2- (methylthio) methacrylate (MTEMA) to obtain block polymer PMAA, the synthetic route of which is shown below, comprising the following steps: the block polymer PMAA is obtained through reversible addition-fragmentation chain transfer polymerization reaction; mPEG-CPA (500 mg,0.1 mmol), MAA (43.5 mg,0.5 mmol), (wherein the degree of polymerization of monomeric methacrylic acid is k=5), and MTEMA (160.23 mg,1 mmol), (the degree of polymerization of ethyl 2- (methylthio) methacrylate is m=10) were dissolved in a mixed solvent of 1mL of anhydrous dimethyl sulfoxide DMSO and 1mL of anhydrous 1, 4-dioxane Dio, respectively, under an argon atmosphere and placed in a reaction flask; initiator azobisisobutyronitrile AIBN (1.64 mg,0.01 mmol) was added and the flask was subjected to a vacuum freeze-thaw cycle for three times, and argon was purged; stirring at 70deg.C for 24 hr, dialyzing the product with methanol, wherein the molecular weight cut-off of the dialysis bag is 3500kDa; finally, diethyl ether is used for washing for three times, and the product PMAA is obtained after vacuum drying; the nuclear magnetic hydrogen spectrum of PMAA is shown in FIG. 2; the polymerization degree of the monomers polymethacrylic acid and ethyl (2- (methylthio) methacrylate shown in FIG. 4 was calculated by GPC detection molecular weight by gel permeation chromatograph, and the ZETA potential diagram of PMAA is shown in FIG. 5.
(3) Preparing an amphiphilic block polymer PEI-PMAA, and reacting the block copolymer PMAA obtained in the step 2) with Polyethyleneimine (PEI) to obtain the amphiphilic block polymer PEI-PMAA, wherein the synthetic route is shown as follows, and the method comprises the following steps: PMAA (500 mg,0.07 mmol) and PEI (126 mg,0.07 mmol) were dissolved in 10mL anhydrous dimethylformamide DMF, wherein the repeat unit of PEI n=5, placed in a reaction flask and reacted under a catalytic system of 1-ethyl- (3-dimethylaminopropyl) carbodiimide EDC (10.85 mg,0.07 mmol) and N-hydroxysuccinimide NHS (8.05 mg,0.07 mmol); stirring for 24 hours at 23 ℃ under the argon protection atmosphere; after the reaction, the crude product obtained is dialyzed for 24 hours with methanol, water is changed for three times in the middle, wherein the molecular weight cut-off of a dialysis bag is 3500kDa, and the crude product is washed three times with diethyl ether precipitation; obtaining a final product PEI-PMAA through vacuum drying; the nuclear magnetic hydrogen spectrum of PEI-PMAA is shown in FIG. 3.
(4) The preparation method of the amphiphilic block polymer drug-loaded nano micelle POP NPs comprises the following steps: the preparation method comprises the steps of (1) dissolving amphiphilic block polymer PEI-PMAA (10 mg) and selected medicament 1mg Camptothecine (CPT) in 1mL of DMSO, dissolving delivered 1mg Ovalbumin (OVA) in 5mL of deionized water, slowly dripping the DMSO solution into the deionized water in a vortex state, stirring for 30min, and further self-assembling; and then transferring the nano micelle into a dialysis bag with the molecular weight cutoff of 3500kDa for dialysis for 48 hours, changing water for three times in the middle, and finally obtaining the amphiphilic block polymer drug-loaded nano micelle POP NPs.
Example 2 Zeta potential studies of block copolymer PMAA and amphiphilic block polymer PEI-PMAA.
The polymer of PMAA and PEI-PMAA obtained in example 1 was prepared at 1 mg/mL -1 The zeta potential of the aqueous solution, pH 7.4, was measured at 25℃using dynamic light scattering instrument DLS and changed from-16.4 mv to 27.3mv after grafting PEI onto PMAA as shown in FIG. 5.
Example 3 biosafety study of amphiphilic block polymer PEI-PMAA.
The amphiphilic block polymer PEI-PMAA obtained in example 1 was prepared into solutions of different concentrations, and diluted with the cell culture medium DMEM to concentrations of 0, 0.1, 0.2, 0.5, 1, 2 mg. ML, respectively -1 PEI-PMAA with different concentrations is added into the cultured L929 cells, after 24 hours of action, the activity of the cells is measured by adopting an MTT living cell staining method, the absorbance OD value is measured by using an enzyme-labeled instrument at the wavelength of 490nm, and the percentage calculation is carried out on the cells and the control group to determine the activity of the cells. As shown in fig. 6, the cell activity diagram shows that the amphiphilic block polymer PEI-PMAA has good biological safety and is nontoxic to normal cells.
Example 4 particle size and morphology studies of amphiphilic block polymer drug loaded nanomicelle POP NPs.
The amphiphilic block polymer drug-loaded nano-micelle POP NPs prepared in example 1 was diluted 5 times with phosphate buffer PBS, and the hydrated particle size thereof was measured by DLS, as shown in fig. 7, and the hydrated particle size of the nano-micelle POP NPs was 84.08nm.
The morphological size of the polymer drug loaded nano-micelle POP NPs was studied by transmission electron microscopy, TEM, as shown in fig. 8, the nano-micelle exhibited a complete spherical morphology.
Example 5 stability study of amphiphilic block polymer drug loaded nanomicelle POP NPs.
The particle size stability of the amphiphilic block polymer drug-loaded nano-micelle POP NPs prepared in example 1 was measured for one week, and the particle size of the amphiphilic block polymer drug-loaded nano-micelle POP NPs on days 1, 2, 3, 4, 5, 6 and 7 was measured by DLS, as shown in FIG. 9, the nano-micelle POP NPs exhibited good particle size stability, and was beneficial to in vivo transportation.
Example 6 study of in vitro response drug release of amphiphilic block polymer drug loaded nanomicelles POP NPs.
The nano-micelle POP NPs prepared in example 1 was diluted to a concentration of 200. Mu.g.mL -1 Taking 3mL of nano micelle POP NPs water solution into a dialysis bag, sealing the dialysis bag with the molecular weight cut-off of 3500kDa, respectively placing the dialysis bag in PBS solution with pH of 7.4 or PBS containing 1mM hydrogen peroxide, placing the dialysis bag in a shaking table at 37 ℃ in the dark, taking out 1mL of the solution from the dialysis bag at a fixed time point at the rotating speed of 120 revolutions per minute, simultaneously adding an equal amount of fresh medium solution, detecting the ultraviolet absorbance by using an enzyme-labeled instrument, calculating the release amount, and the drug release curve is shown in figure 10.
Finally, it is noted that the above-mentioned preferred embodiments are only intended to illustrate rather than limit the invention, and that, although the invention has been described in detail by means of the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (10)
1. A functionalized block polymer nano-drug carrier is characterized in that the structural formula is shown as follows,
2. a functionalized block polymer nano-drug carrier according to claim 1, wherein k=5,
m=10, n is 5.
3. The method for preparing the functionalized block polymer nano-drug carrier according to claim 1, which is characterized in that,
the method comprises the following steps:
(1) A step of preparing a copolymer mPEG-CPA, wherein polyethylene glycol monomethyl ether amine and 4-cyano-4- (phenylcarbonyl sulfide) valeric acid are synthesized by esterification reaction;
(2) A step of preparing a block polymer PMAA, wherein the copolymer mPEG-CPA obtained in the step 1) is polymerized with monomer methacrylic acid and 2- (methylthio) ethyl methacrylate, wherein the polymerization degree of the methacrylic acid is k=5-10, and the polymerization degree of the 2- (methylthio) ethyl methacrylate is m=10-20;
(3) A step of preparing amphiphilic block polymer PEI-PMAA, which is to react the block polymer PMAA obtained in the step 2) with polyethyleneimine, wherein the molecular weight of the polyethyleneimine is 1800 g.mol -1 The repeating unit n is 3 to 5.
4. The method for preparing a functionalized block polymer nano-drug carrier according to claim 3, wherein in the step 1), polyethylene glycol monomethyl ether amine mPEG-NH 2 And 4-cyano-4- (phenylcarbonyl sulfide) valeric acid is dissolved in anhydrous dichloromethane and fully reacted under the protection of argon; then dissolving dicyclohexylcarbodiimide DCC and 4-dimethylaminopyridine DMAP in anhydrous dichloromethane, dripping the anhydrous dichloromethane into the reaction solution, and stirring at room temperature; concentrating the obtained crude product by rotary evaporation, and precipitating and washing with diethyl ether to obtain a final product mPEG-CPA;
5. the method for preparing the functionalized block polymer nano-drug carrier according to claim 3, wherein in the step 2), mPEG-CPA, monomeric methacrylic acid MAA, and 2- (methylthio) ethyl methacrylate MTEMA are respectively dissolved in a mixed solvent of anhydrous dimethyl sulfoxide and anhydrous 1, 4-dioxane and placed in a reaction bottle under an argon atmosphere; adding an initiator azodiisobutyronitrile, performing vacuum freeze-thaw cycle on the reaction bottle for 2-5 times, and introducing argon; stirring at 50-80 deg.C for 20-40 hr, dialyzing the product with methanol, wherein
The molecular weight cut-off of the dialysis bag is 3500kDa; finally, washing with diethyl ether, and vacuum drying to obtain a product PMAA;
6. the method for preparing a functionalized block polymer nano-drug carrier according to claim 3, wherein in the step 3), PMAA and polyethyleneimine PEI are dissolved by anhydrous dimethylformamide DMF and placed in a reaction bottle, and the reaction is carried out under the catalysis system of 1-ethyl- (3-dimethylaminopropyl) carbodiimide EDC and N-hydroxysuccinimide NHS; stirring for 20-40 hours at 15-35 ℃ under the argon protection atmosphere; dialyzing the obtained crude product with methanol after the reaction, wherein the molecular weight cut-off of a dialysis bag is 3500kDa, and precipitating and washing with diethyl ether; obtaining a final product PEI-PMAA through vacuum drying;
7. according to claim 4The preparation method of the functionalized block polymer nano-drug carrier is characterized in that the step (1) is carried out by mPEG-NH 2 And 4-cyano-4- (phenylcarbonylthio) pentanoic acid in a molar ratio in the range of (1.1 to 1.2): (1.2 to 1.3), mPEG-NH in anhydrous DCM 2 And 4-cyano-4- (phenylcarbonylthio) pentanoic acid in a molar concentration range of 0.11 to 0.12 mol.L, respectively -1 And 0.12 to 0.13 mol.L -1 The molar concentration ranges of dicyclohexylcarbodiimide and 4-dimethylaminopyridine dissolved in anhydrous DMSO are 0.44 to 0.46 mol.L, respectively -1 And 0.22 to 0.25 mol.L -1 。
8. The method for preparing a functionalized block polymer nano-drug carrier according to claim 5 or 6, wherein the molar ratio of mPEG-CPA, methacrylic acid, ethyl 2- (methylthio) methacrylate and azobisisobutyronitrile in step (2) is 1:10:20:0.02; in the step (3), the molar ratio of PMAA, polyethyleneimine PEI, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide is 1:10:6:6.
9. The preparation method of the amphiphilic block polymer drug-loaded nano micelle POP NPs is characterized by comprising the following steps: dissolving the amphiphilic block polymer PEI-PMAA and the selected medicine camptothecine in DMSO (dimethyl sulfoxide), dissolving the delivered ovalbumin in deionized water, dripping the dimethyl sulfoxide DMSO solution into the deionized water in a vortex state, stirring, and further self-assembling; and then transferring the nano micelle into a dialysis bag with the molecular weight cutoff of 3500kDa for dialysis, and finally obtaining the amphiphilic block polymer drug loaded nano micelle POP NPs.
10. Use of the vector of claim 1 for the preparation of a delivery medicament.
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