CN115028786A - Preparation method of pH and thermal response perfluoropolyether acyl fluoroacrylate copolymer and product thereof - Google Patents

Preparation method of pH and thermal response perfluoropolyether acyl fluoroacrylate copolymer and product thereof Download PDF

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CN115028786A
CN115028786A CN202210527677.5A CN202210527677A CN115028786A CN 115028786 A CN115028786 A CN 115028786A CN 202210527677 A CN202210527677 A CN 202210527677A CN 115028786 A CN115028786 A CN 115028786A
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pfphm
dmaema
pegmea
micelle
perfluoropolyether acyl
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黄方
徐德忠
李翱
肖旺钏
武帅
林伟杰
邹秋霞
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Fujian Agriculture and Forestry University
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Fujian Agriculture and Forestry University
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    • 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
    • C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
    • C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • C08F2438/01—Atom Transfer Radical Polymerization [ATRP] or reverse ATRP

Abstract

The invention provides a preparation method of a pH and thermal response perfluoropolyether acyl fluoride acrylate copolymer and a product thereof, wherein the method comprises the following steps: reacting perfluoropolyether acyl fluoride with hydroxyethyl methacrylate to prepare PFPHM; EBIB (ethyl 2-bromoisobutyrate) as initiator and CuBr 2 Pentamethyldiethylenetriamine (PMDETA) as catalyst system, Sn (OCt) 2 Taking the PPFPHM-Br as a reducing agent to initiate PFPHM self-polymerization, taking the obtained PPFPHM-Br as a macroinitiator, and introducing a pH and thermal response functional monomer DMAEMA to obtain P (PFPHM-b-DMAEMA) -Br; introducing P (PFPHM-b-DMAEMA) -Br as pH and thermal response macroinitiator into hydrophilic chain segment PEGMEA to obtain thermal response amphiphilic triblock polymer P (PFPHM-b-DMAEMA-b-PEGMEA), and making it into blank micelle and carrierA drug micelle.

Description

Preparation method of pH and thermal response perfluoropolyether acyl fluoroacrylate copolymer and product thereof
[ technical field ] A
The invention relates to the technical field of polymer preparation, in particular to a preparation method of a pH and thermal response perfluoropolyether acyl fluoroacrylate copolymer and a product thereof.
[ background ] A method for producing a semiconductor device
Cancer is a global public health problem, and seriously threatens human health due to extremely high morbidity and mortality, and although current cancer treatment has made major progress, thorough cure of cancer remains a troublesome problem. Chemotherapy is one of the non-targeted methods for treating cancer, but in chemotherapy, the non-specific behavior of the drug damages normal tissue cells, thereby causing toxic and side effects to patients. Therefore, it is important to improve the availability and selectivity of drugs for cancer cells.
The nano drug-loaded micelles formed by self-assembling the amphiphilic polymers have great potential in treating cancers, have good biocompatibility and high drug-loading rate, can release drugs under specific conditions, realize targeted release and control of the drugs, reduce drug toxicity and the like. The Critical Micelle Concentration (CMC) is an essential feature of micelles to study the aggregation behavior of micelles. The low CMC micelle has the characteristics of high stability and strong anti-dilution capability. However, the polymeric micelles produced by self-assembly have a high CMC, which limits their use in drug delivery. To overcome this drawback, preventing the drug from being released when the polymeric micelle does not reach the cancer tissue, enhancing the hydrophobicity of the hydrophobic segment of the polymeric micelle has become a direct method for stabilizing the polymeric micelle. In recent years, fluoropolymers have attracted attention because of their extremely strong hydrophobicity, thermal and chemical stability, gas-dissolving ability, high fluidity, low dielectric constant, and low surface energy. Compared with the conventional carbon chain amphiphilic polymer, the fluorine-containing carbon chain amphiphilic polymer has a lower CMC value, so that the fluorine-containing carbon chain amphiphilic polymer has good thermodynamic stability, and the loaded medicine can be slowly and continuously released from polymer micelles, so that the action period of the medicine on cancer cells is prolonged, the dosage required by the medicine is reduced, and the aim of reducing the toxic and side effects of the medicine is fulfilled, which cannot be realized by the non-fluorine-containing amphiphilic polymer. Compared with normal cells, the tumor microenvironment has the physiological characteristics of faintly acid, hypoxia, temperature rise and the like, and the difference enables the nano micelle with the Lowest Critical Solution Temperature (LCST) higher than the physiological body temperature (Tb ≈ 37 ℃) and lower than the tumor tissue temperature (Th ≈ 42 ℃) to be designed, so that the nano micelle has wide application prospect.
Atom Transfer Radical Polymerization (ATRP) is one of the most industrially promising active/controllable radical polymerization methods, and in recent years, extensive research has led to the gradual development of the technology towards 'improving operability' and 'reducing the amount of metal catalysts as much as possible', so that ATRP derivation technologies of different catalytic systems are created, and the defects that the amount of catalysts used in the traditional ATRP reaction is large, the reaction needs to be carried out under the anaerobic condition and the like are overcome by electron transfer activated regenerated catalyst atom transfer radical polymerization (ARGET ATRP) and ARGET ATRP, and the obtained polymer grafted inorganic nanoparticles have the characteristics of enhancement or control on specific applications.
At present, Polymer Micelles (PMs) produced by self-assembly have high CMC, and when the CMC is high, the PMs suddenly release drugs and even burst when reaching tumor tissues, which occurs because the PMs are diluted in the process of delivering drugs to cause the concentration to be lower than the CMC value, and the PMs cannot be formed to cause the PMs to suddenly release drugs and even burst, which limits the application of the PMs in drug delivery.
Compared with the conventional carbon chain amphiphilic polymer, the fluorine-containing carbon chain amphiphilic polymer has lower CMC (carboxy methyl cellulose) due to the super-hydrophobicity of fluorine atoms. According to the preparation method, perfluoropolyether acyl fluoride and hydroxyethyl methacrylate react to generate perfluoropolyether acyl fluoride hydroxyethyl methacrylate (PFPHM) with an olefin structure, 2-bromoethyl isobutyrate (EBIB) is used as an initiator to initiate PFPHM self polymerization and introduce terminal bromine atoms to finally generate PPFPHM-Br, and the PPFPHM-Br is used as a hydrophobic chain segment of an amphiphilic polymer to reduce CMC of the polymer micelle.
[ summary of the invention ]
The invention aims to solve the technical problem of providing a preparation method of a pH and thermal response perfluoropolyether acyl fluoroacrylate copolymer and a product thereof, wherein a polymeric micelle prepared by the preparation method has good thermodynamic stability, can prolong the circulation time in blood, slowly and continuously releases micelle medicines from the polymeric micelle, prolongs the action period of the medicines on cancer cells, and reduces the dosage of the medicines so as to achieve the aim of reducing the toxic and side effects of the medicines.
The invention is realized by the following steps:
a method for preparing a pH and thermal response perfluoropolyether acyl fluoroacrylate copolymer, the method comprising the steps of:
(1) the perfluoropolyether acyl fluoride reacts with hydroxyethyl methacrylate to prepare perfluoropolyether hydroxyethyl methacrylate PFPHM,
(2) EBIB (ethyl 2-bromoisobutyrate) as initiator and CuBr 2 Pentamethyldiethylenetriamine (PMDETA) as catalyst system, Sn (OCt) 2 Taking the PFPHM as a reducing agent to initiate the self-polymerization of the PFPHM generated in the step (1) to obtain a macroinitiator PPFPHM-Br;
(3) taking the PPFPHM-Br generated in the step (2) as a macroinitiator, and introducing a pH and thermal response functional monomer DMAEMA to obtain P (PFPHM-b-DMAEMA) -Br;
(4) introducing P (PFPHM-b-DMAEMA) -Br generated in the step (3) as a pH and thermal response macroinitiator into a hydrophilic chain segment PEGMEA to obtain an amphiphilic triblock polymer P (PFPHM-b-DMAEMA-b-PEGMEA) with thermal response;
(5) preparing P (PFPHM-b-DMAEMA-b-PEGMEA) generated in the step (4) into blank micelles and drug-loaded micelles by using a dialysis method.
Further, the specific steps of the step (1) are as follows:
taking perfluoropolyether acyl fluoride, hydroxyethyl methacrylate, trifluoroethanol and triethylamine in a single-neck flask, reacting for 7-10 h at 20-30 ℃ with the molar ratio of the perfluoropolyether acyl fluoride to the hydroxyethyl methacrylate being 1-2: 1, cooling after the reaction is finished, extracting and washing the reaction solution with dilute hydrochloric acid, taking the lower layer, extracting and washing with deionized water to obtain a light yellow viscous liquid, namely PFPHM.
Further, the specific steps of the step (2) are as follows:
adding Trifluoroethanol (TFEA) and CuBr into a round-bottom flask 2 PMDETA, PFPHM, EBIB and Sn (OCt) 2 Then immediately transferring the flask into a Dewar flask filled with liquid nitrogen for degassing, performing liquid nitrogen freezing-vacuumizing-unfreezing circulation to remove oxygen, filling high-purity nitrogen into the flask, sealing the flask, transferring the flask into an oil bath kettle at 35-45 ℃, and reacting for 8-10 hours; after the reaction is finished, cooling, and adding absolute ethyl alcohol into the flask to dilute the reaction solution; then, using absolute ethyl alcohol as an eluent, enabling the diluted reaction solution to pass through a 200-mesh neutral alumina column for collection, dropwise adding the collected solution into an excessive and rapidly-stirred solution of n (deionized water), wherein n (ethyl alcohol) is 2-3: 1, performing centrifugal separation, and collecting precipitates; and (3) placing the collected precipitate in a vacuum forced air drying oven to be dried for 24 hours at the temperature of 55-65 ℃ to obtain the macroinitiator PPFPHM-Br.
Further, the specific steps of the step (3) are as follows:
a round bottom flask was charged with Trifluoroethanol (TFEA), CuBr2, PMDETA, PPFPHM-Br, DMAEMA, and Sn (OCt) 2 Degassing the round-bottom flask in the same manner as the step (2), transferring the round-bottom flask into an oil bath kettle at the temperature of 35-45 ℃, and reacting for 8-10 h; after the reaction is finished, performing column passing treatment and centrifugal separation treatment on the sample in the same way as the step (2); and (3) placing the collected precipitate in a vacuum forced-air drying oven to be dried for 24 hours at the temperature of 55-65 ℃ to obtain P (PFPHM-b-DMAEMA) -Br.
Further, the specific steps of the step (4) are as follows:
adding Trifluoroethanol (TFEA), CuBr2, PMDETA, P (PFPHM-b-DMAEMA) -Br, DMAEMA and Sn (OCt)2 into a round-bottom flask, degassing the round-bottom flask in the same manner as the step (2), transferring the round-bottom flask into an oil bath kettle at the temperature of 35-45 ℃, and reacting for 8-10 h. After the reaction is finished, cooling, and performing column passing treatment and centrifugal separation treatment on the sample in the same way as the step (2); and (3) drying the collected precipitate in a vacuum forced air drying oven at 55-65 ℃ for 24h to obtain P (PFPHM-b-DMAEMA-b-PEGMEA).
Further, the specific preparation steps of the blank micelle in the step (5) are as follows:
weighing 9-12 mg of P (PFPHM-b-DMAEMA-b-PEGMEA) and dissolving in 3-5 mL of acetone; then, 8-10 mL of deionized water is dripped into a rapidly stirred acetone solution of P (PFPHM-b-DMAEMA-b-PEGMEA) at a concentration of 8-10 muL/s; then, transferring the polymer solution into a dialysis bag with the relative molecular mass of 3500 interception, dialyzing for 20-28 h, completely replacing the deionized water every 2h within the initial 6h, and then completely replacing the deionized water at intervals of 6 h; finally, freeze-drying the dialyzed sample for 70-80 h at-70 to-80 ℃ by using a vacuum freeze-drying oven to obtain a blank micelle;
further, the specific preparation steps of the drug-loaded micelle in the step (5) are as follows:
weighing 3-5 mg of DOX/HCl and dissolving in 1-2 mL of acetone, dissolving 8-10 mg of P (PFPHM-b-DMAEMA-b-PEGMEA) in 3-5 mL of acetone, mixing the two solutions at a speed of 140-150 r/min and stirring for 50-60 min, then dripping 8-10 mL of deionized water into a rapidly-stirred mixed solution of P (PFPHM-b-DMAEMA-b-PEEA), DOX/HCl and acetone at a speed of 8-10 muL/s, then transferring the polymer solution into a dialysis bag with a molecular weight cutoff of 3500, dialyzing for 20-28 h, completely replacing the deionized water every 2h within initial 6h, then completely replacing the deionized water at intervals of 6h, and keeping out of the sun during dialysis; and finally, freeze-drying the dialyzed sample for 70-80 hours at the temperature of-70 to-80 ℃ by using a vacuum freeze-drying box to obtain the drug-loaded micelle.
Further, the perfluoropolyether acyl fluoroacrylate copolymer prepared by the preparation method of the perfluoropolyether acyl fluoroacrylate copolymer with pH and thermal response, and blank micelles and drug-loaded micelles thereof.
The invention has the following advantages:
the method comprises the steps of reacting perfluoropolyether acyl fluoride with hydroxyethyl methacrylate to generate perfluoropolyether acyl fluoride acrylate, carrying out atom transfer radical polymerization for 3 times, using the perfluoropolyether acyl fluoride acrylate, dimethylaminoethyl methacrylate and methoxy polyethylene glycol acrylate as monomers for the first time, preparing the perfluoropolyether acyl fluoride copolymer with good biocompatibility, pH and thermal response, and carrying out self-assembly to form DOX after the formation of the gel.
The block polymer prepared by the method has lower critical micelle concentration, so that the polymeric micelle has good thermodynamic stability, the micelle still keeps stable after being diluted, and under the action of the hydrophilic shell, the polymeric micelle can prolong the circulation time in blood, so that micelle medicines are slowly and continuously released from the polymeric micelle, the action period of the medicines on cancer cells is prolonged, the required dosage of the medicines is reduced, and the aim of reducing the toxic and side effects of the medicines is fulfilled.
[ description of the drawings ]
The invention will be further described with reference to the following examples with reference to the accompanying drawings.
FIG. 1 is a nuclear magnetic resonance spectrum of example 1 of the present invention, wherein (a) is PPFPHM-Br 19 F NMR spectrum; (b) of PPFPHM-Br 1 H NMR spectrum; (c) of P (PFPHM-b-DMAEMA) -Br 1 H NMR spectrum; (d) of P (PFPHM-b-DMAEA-b-PEGMEA) 1 H NMR spectrum.
FIG. 2 is an infrared spectrum of example 2 of the present invention.
FIG. 3 is a graph showing the relationship between the fluorescence intensity and the wavelength of the polymer P (PFPHM-b-DMAEMA-b-PEGMEA) in example 3 of the present invention.
FIG. 4 is a graph showing the logarithmic relationship between the concentration of I344.4.4/I336.2 and P (PFPHM-b-DMAEMA-b-PEGMEA) in example 3 of the present invention.
FIG. 5 is a graph showing the change of transmittance of an aqueous solution of P (PFPHM-b-DMAEMA-b-PEGMEA) according to the invention in example 4 with respect to temperature.
FIG. 6 is a graph showing the effect of pH on the Zeta potential of P (PFPHM-b-DMAEMA-b-PEGMEA) micelles in example 5 of the present invention.
FIG. 7 is a graph showing the particle size distribution and PDI of the blank/drug loaded micelle of example 6 of the present invention.
Fig. 8 is a confocal microscope showing the drug-loaded micelles and blank micelles in example 7 of the present invention, in which a is drug-loaded micelles 488nm, b is drug-loaded micelles 552nm, c is drug-loaded micelles 488 and 552nm, and d is blank micelles 488 and 552 nm.
FIG. 9 is a graph showing the biotoxicity profile of P (PFPHM-b-DMAEMA-b-PEGMEA) in example 8 of the present invention.
FIG. 10 is a graph of the in vitro simulated release rate of drug-loaded micelles of P (PFPHM-b-DMAEMA-b-PEGMEA) drug-loaded micelles of example 10 of the present invention.
[ detailed description ] embodiments
The invention relates to a preparation method of a pH and thermal response perfluoropolyether acyl fluoride acrylate copolymer, which comprises the following steps:
(1) the perfluoropolyether acyl fluoride reacts with hydroxyethyl methacrylate to prepare perfluoropolyether hydroxyethyl methacrylate PFPHM,
(2) EBIB (ethyl 2-bromoisobutyrate) as initiator and CuBr 2 Pentamethyldiethylenetriamine (PMDETA) as catalyst system, Sn (OCt) 2 Taking the PFPHM as a reducing agent to initiate the self-polymerization of the PFPHM generated in the step (1) to obtain a macromolecular initiator PPFPHM-Br;
(3) taking the PPFPHM-Br generated in the step (2) as a macroinitiator, and introducing a pH and thermal response functional monomer DMAEMA to obtain P (PFPHM-b-DMAEMA) -Br;
(4) introducing P (PFPHM-b-DMAEMA) -Br generated in the step (3) as a pH and thermal response macroinitiator into a hydrophilic chain segment PEGMEA to obtain an amphiphilic triblock polymer P (PFPHM-b-DMAEMA-b-PEGMEA) with thermal response;
(5) preparing P (PFPHM-b-DMAEMA-b-PEGMEA) generated in the step (4) into blank micelles and drug-loaded micelles by using a dialysis method.
Preferably, the specific steps of the step (1) are as follows:
taking perfluoropolyether acyl fluoride, hydroxyethyl methacrylate, trifluoroethanol and triethylamine in a single-neck flask, reacting for 7-10 h at 20-30 ℃ with the molar ratio of the perfluoropolyether acyl fluoride to the hydroxyethyl methacrylate being 1-2: 1, cooling after the reaction is finished, extracting and washing the reaction solution with dilute hydrochloric acid, taking the lower layer, extracting and washing with deionized water to obtain a light yellow viscous liquid, namely PFPHM.
Preferably, the specific steps of the step (2) are as follows:
adding Trifluoroethanol (TFEA) and CuBr into a round-bottom flask 2 PMDETA, PFPHM, EBIB and Sn (OCt) 2 Then immediately transferring the flask into a Dewar flask filled with liquid nitrogen for degassing, performing liquid nitrogen freezing-vacuumizing-unfreezing circulation to remove oxygen, filling high-purity nitrogen into the flask, sealing the flask, transferring the flask into an oil bath kettle at 35-45 ℃, and reacting for 8-10 hours; after the reaction is finished, cooling, and adding absolute ethyl alcohol into the flask to dilute the reaction solution; then, using absolute ethyl alcohol as an eluent, collecting the diluted reaction solution after passing through a 200-mesh neutral alumina column, dropwise adding the collected solution into an excessive and rapidly-stirred n (deionized water) solution, namely n (ethyl alcohol) 2-3: 1, performing centrifugal separation, and collecting precipitates; and (3) placing the collected precipitate in a vacuum forced air drying oven to be dried for 24 hours at the temperature of 55-65 ℃ to obtain the macroinitiator PPFPHM-Br.
Preferably, the specific steps of the step (3) are as follows:
a round bottom flask was charged with Trifluoroethanol (TFEA), CuBr2, PMDETA, PPFPHM-Br, DMAEMA, and Sn (OCt) 2 Degassing the round-bottom flask in the same manner as the step (2), transferring the round-bottom flask into an oil bath kettle at the temperature of 35-45 ℃, and reacting for 8-10 h; after the reaction is finished, performing column passing treatment and centrifugal separation treatment on the sample in the same way as the step (2); and (3) placing the collected precipitate in a vacuum forced-air drying oven to be dried for 24 hours at the temperature of 55-65 ℃ to obtain P (PFPHM-b-DMAEMA) -Br.
Preferably, the specific steps of the step (4) are as follows:
adding Trifluoroethanol (TFEA), CuBr2, PMDETA, P (PFPHM-b-DMAEMA) -Br, DMAEMA and Sn (OCt)2 into a round-bottom flask, degassing the round-bottom flask in the same manner as the step (2), transferring the round-bottom flask into an oil bath kettle at the temperature of 35-45 ℃, and reacting for 8-10 h. After the reaction is finished, cooling, and performing column passing treatment and centrifugal separation treatment on the sample in the same way as the step (2); and (3) drying the collected precipitate in a vacuum forced air drying oven at 55-65 ℃ for 24h to obtain P (PFPHM-b-DMAEMA-b-PEGMEA).
Preferably, the specific preparation steps of the blank micelle in the step (5) are as follows:
weighing 9-12 mg of P (PFPHM-b-DMAEMA-b-PEGMEA) and dissolving in 3-5 mL of acetone; then, 8-10 mL of deionized water is dripped into a rapidly stirred acetone solution of P (PFPHM-b-DMAEMA-b-PEGMEA) at a concentration of 8-10 muL/s; then, transferring the polymer solution into a dialysis bag with the relative molecular mass of 3500 interception, dialyzing for 20-28 h, completely replacing the deionized water every 2h within the initial 6h, and then completely replacing the deionized water at intervals of 6 h; finally, freeze-drying the dialyzed sample for 70-80 h at-70 to-80 ℃ by using a vacuum freeze-drying oven to obtain a blank micelle;
preferably, the specific preparation steps of the drug-loaded micelle in the step (5) are as follows:
weighing 3-5 mg of DOX/HCl and dissolving in 1-2 mL of acetone, dissolving 8-10 mg of P (PFPHM-b-DMAEMA-b-PEGMEA) in 3-5 mL of acetone, mixing the two solutions at a speed of 140-150 r/min and stirring for 50-60 min, then dripping 8-10 mL of deionized water into a rapidly-stirred mixed solution of P (PFPHM-b-DMAEMA-b-PEEA), DOX/HCl and acetone at a speed of 8-10 muL/s, then transferring the polymer solution into a dialysis bag with a molecular weight cutoff of 3500, dialyzing for 20-28 h, completely replacing the deionized water every 2h within initial 6h, then completely replacing the deionized water at intervals of 6h, and keeping out of the sun during dialysis; and finally, freeze-drying the dialyzed sample for 70-80 hours at the temperature of-70 to-80 ℃ by using a vacuum freeze-drying box to obtain the drug-loaded micelle.
The invention also relates to the perfluoropolyether acyl fluoroacrylate copolymer prepared by the preparation method of the perfluoropolyether acyl fluoroacrylate copolymer with pH and thermal response, and a blank micelle and a drug-loaded micelle thereof.
The technical solution of the present invention will be clearly and completely described with reference to the accompanying drawings 1-10 and the detailed description. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are not indicated by manufacturers and are commercially available.
Example 1
(1) Testing of PPFPHM-Br Using NMR spectrometer (FIG. 1) 19 Of the F NMR spectra PPFPHM-Br, P (PFPHM-b-DMAEMA) -Br and P (PFPHM-b-DMAEMA-b-PEGMEA) 1 H NMR spectrum, as shown in FIG. 1, (a) is PPFPHM-Br 19 F NMR spectrum; (b) of PPFPHM-Br 1 An H NMR spectrum; (c) of P (PFPHM-b-DMAEMA) -Br 1 An H NMR spectrum; (d) of P (PFPHM-b-DMAEA-b-PEGMEA) 1 H NMR spectrum.
As can be seen from the figure, the method is based on PPFPHM-Br 19 F NMR chart, delta-79.1 to-86.6 is- [ CF (CF) 3 )CF 2 O]-, δ -82.2 is CF 3 -CF 2 -CF 2 -, δ -129.9 and δ -132 are each CF 3 -CF-O-and CF 3 -CF 2 -CF 2 -, at PPFPHM-Br 1 H NMR chart showing that-CH of EIBI appears at. delta. ═ 1.9 3 A proton absorption peak and a proton absorption peak of-CH 2-between delta and 1.8-0.9 are shown, which indicates the successful synthesis of PPFPHM-Br; in P (PFPHM-b-DMAEMA) -Br 1 H NMR spectrum at delta-3.8 and delta-2.3 for DMAEMA-CH 2 Hydrogen proton peak of-N-and-N- (CH) 3 ) 2 The hydrogen proton peak of (a) is-CH of PPFPHM-Br at δ ═ 1.6 and δ ═ 1.4 2 -CH 3 Hydrogen proton peak of (2) and-CH 2 -hydrogen proton peak of DMAEMA at δ ═ 0.9-C-CH 3 Hydrogen proton peak, -N- (CH) 3 ) 2 and-CH 2 The appearance of a hydrogen proton peak of N-, indicating the successful synthesis of P (PFPHM-b-DMAEMA) -Br; in P (PFPHM-b-DMAEA-b-PEGMEA) 1 H NMR spectrum shows hydrogen proton peaks of-CH 2-N-of DMAEMA and-N- (CH) at delta-3.8 and delta-2.3 3 ) 2 The hydrogen proton peak of (1.6) is-CH of PFPHM 2 -CH 3 The hydrogen proton peak of (1) shows-O-CH of PEGMEA at a point of. delta. 1.8 3 Proton peak, which indicates the successful synthesis of P (PFPHM-b-DMAEA-b-PEGMEA).
Example 2
(1) FT-IR spectra of PPFPHM-Br, P (PFPHM-b-DMAEMA) -Br and P (PFPHM-b-DMAEMA-b-PEGMEA) were measured using Fourier Infrared Spectroscopy, as shown in FIG. 2.
From the infrared spectrum of PPFPHM-Br, at 3427cm -1 Vibration peak at-CH, 2962cm -1 And 2929cm -1 is-CH 3 And CH 2 The absorption peak of stretching vibration of-CH-in (C-CH) at 1791cm -1 In the form of an ester carbonyl group C ═ O at 1550cm -1 Is C ═ C stretching vibration absorption peak, 1232cm -1 Is in C-O-C asymmetric telescopic vibration at 1149cm -1 The absorption peak of the C-O-C single bond stretching vibration is 989cm -1 the-C-F vibration peak at the perfluoropolyether acyl fluoride structure-CF (CF3), 500-750cm -1 Is treated as CF 3 -CF 2 -an in-plane rocking vibration absorption peak; 1705cm in the IR spectrum of P (PFPHM-b-DMAEMA) -Br -1 And 1161cm -1 The peak appears in the absorption peak of C ═ O stretching vibration and C-O stretching vibration, 1629cm -1 Bending vibration at-C-N-1469 cm -1 A tertiary amino absorption peak appears, which indicates the successful synthesis of P (PFPHM-b-DMAEMA) -Br; in the P (PFPHM-b-DMAEMA-b-PEGMEA) infrared spectrogram, the C ═ O stretching vibration absorption peak, the bending vibration of-C-N-, and the CF3-CF 2-in-plane rocking vibration absorption peak of P (PFPHM-b-DMAEMA) -Br did not disappear, and the absorption peak was 1240cm -1 the-C-O vibration of PEGMEA appears, which indicates that the synthesis of P (PFPHM-b-DMAEMA-b-PEGMEA) is successful.
Example 3
(1) The critical micelle dissolution temperature of the micelle is tested by a pyrene fluorescence probe method, and the configuration is 5 multiplied by 10 -1 ～1×10 - 4 A series of concentrations of P (PFPHM-b-DMAEMA-b-PEGMEA) in acetone was measured at mg/mL.
(2) Configuration 6 x 10 -5 And transferring 0.5mL of methanol solution of mol/L pyrene into a corresponding amount of 10mL sample bottles, and placing the sample bottles in a dark place for 24 hours to volatilize methanol.
(3) Adding 10mL of the polymer solution with the series of concentrations prepared in the step (1) into the sample bottle in the step (2) respectively, and simultaneously enabling the concentration of pyrene in the sample solution to be 6 x 10 -7 mol/L, and balancing for 24h in dark.
(4) And (3) testing the fluorescence excitation spectra of the micelles with different concentrations prepared in the step (3) by using a fluorescence spectrophotometer, setting the emission wavelength to be 373nm, scanning the mixed solution in the wavelength range of 300-350 nm, recording the data of the excitation wavelengths of 344.4nm and 336.2nm, taking the ratio of the two as a vertical coordinate, and the turning point of a concentration log-value plotting curve as the CMC value of the polymer, and calculating to obtain the CMC of 7.5 mu g/mL, which is specifically shown in fig. 3 and 4.
Example 4
(1) The lowest critical solution temperature of the micelles was measured using an ultraviolet-visible spectrophotometer (as shown in FIG. 5), and a 1mg/mL aqueous solution of P (PFPHM-b-DMAEMA-b-PEGMEA) was prepared.
(2) And (2) testing the light transmittance of the solution obtained in the step (1) at 20-50 ℃ by using an ultraviolet visible spectrophotometer at the wavelength of 510nm, setting the heating rate to be 1 ℃/min, and setting the transmittance of the P (PFPHM-b-DMAEMA-b-PEGMEA) solution to be the lowest critical solution temperature of the micelle when the transmittance is 50%, wherein the lowest critical solution temperature is 37.6 ℃.
Example 5
(1) The micelles were tested for Zeta potential at different pH values (as shown in FIG. 6) using dynamic light scattering in 0.1mg/mL aqueous solutions of P (PFPHM-b-DMAEMA-b-PEGMEA).
(2) And (3) testing the Zeta potential of the micelle configured in the step (1) at different pH values by using a Malvern laser particle size analyzer at room temperature by using a Dynamic Light Scattering (DLS) method, wherein each sample is parallelly processed for 3 times, and the result is averaged, and the absolute value of the Zeta potential of the P (PFPHM-b-DMAEMA-b-PEGMEA) micelle is increased along with the increase of the pH value. The Zeta potential of the P (PFPHM-b-DMAEMA-b-PEGMEA) micelle decreased from-2.7 mV at pH 4.5 to-31.2 mV at pH 8 because the surface negative charge in the pH response segment of the P (PFPHM-b-DMAEMA-b-PEGMEA) micelle was higher and an increase in the absolute value of the Zeta potential indicated an increase in the stability of the micelle, hindering release of DOX. Therefore, in an acidic environment, the low surface charge of the P (PFPHM-b-DMAEMA-b-PEGMEA) micelle is beneficial to drug sustained release.
Example 6
(1) A1 mg/mL P (PFPHM-b-DMAEMA-b-PEGMEA) blank/drug loaded micelle solution in a dynamic light scattering test configuration was used.
(2) The size and the size distribution of the polymer blank/drug-loaded micelle prepared in the step (1) are diluted by 10 times within 15d at 25 ℃, three times of repeated tests are carried out on each sample to obtain the average particle diameter, the polydispersity index (PDI) is calculated by Zetasizer software (shown in figure 7), and the result shows that the particle diameter of the P (PFPHM-b-DMAEMA-b-PEGMEA) blank micelle is about 110-120 nm, the particle diameter of the drug-loaded micelle is about 190-210 nm, and the PDI is 0.15-0.20 within 15 days. As can be seen from the data in the figure, the blank micelles slightly increased in size after day 10 due to slight aggregation of the micelles; the particle size of the same drug-loaded micelle begins to increase on day 9, but the particle size of the blank/drug-loaded micelle is always kept in the range of 130-150 nm and 210-240 nm, which shows that the polymer micelle has good dynamic stability and good dispersibility, and the particle size of the micelle is obviously increased by comparing the particle sizes before and after drug loading, and shows that a certain amount of DOX can be wrapped in the micelle cavity.
(3) Respectively mixing 3mL of serum and 2mL of deionized water, adding the mixture into 5mL of 1.0mg/mL of polymer micelle to form fetal bovine serum containing 30%, testing the particle size of the micelle in 7d by using DLS (DLS) (shown in figure 7), wherein the result shows that the particle size of the blank/drug-loaded micelle is increased, because the blank/drug-loaded micelle enters the fetal bovine serum, one or more layers of protein are adsorbed on the surface of the micelle to form a protein crown, the size of the polymer micelle is increased, and the particle sizes of the blank/drug-loaded micelle in 7 days are consistent, which shows that the polymer micelle has good serum stability.
Example 7
(1) The drug loading performance of the micelle is tested by using a laser confocal microscope, and the prepared 1mg/mL P (PFPHM-b-DMAEMA-b-PEGMEA) blank/drug-loaded micelle solution is used.
(2) Taking 10 μ L of blank/drug-loaded micelle solution prepared in the step (1) to drop in the center of a glass slide, enabling one end of a cover glass to contact with the dropping liquid firstly, then slowly putting down the glass slide, and observing the glass slide under a laser confocal microscope, specifically as shown in fig. 7, processing data by using LAS AF Lite software, and respectively emitting green (shown in fig. 7a) and red fluorescence (shown in fig. 7b) by DOX in the drug-loaded micelle under excitation wavelengths of 488 and 552 nm; FIG. 7c shows orange fluorescence when the green and red fluorescence emitted by DOX in FIGS. 7a and 7b coincide; FIG. 7d is a confocal laser micrograph of blank micelles at 488 and 552nm, and no fluorescence is observed. Therefore, the successful loading of DOX is illustrated, and the P (PFPHM-b-DMAEMA-b-PEGMEA) polymer micelle has potential to be used as a nano-carrier in biomedicine.
Example 8
(1) The biotoxicity of the blank micelles was determined using MTT colorimetry (as shown in FIG. 9) at 37 deg.C, 5% CO 2 HepG2 cells were cultured in a saturated humidity incubator with DMEM as the culture medium.
(2) In 96-well plates, 180. mu.L of each well was seeded with 5X 10 3 Cells were then incubated with a range of concentrations of DOX, blank micelles, and drug loaded micelles for 48h at 37 ℃.
(3) The 96-well plate described in step (2) was incubated for 4h by adding 20. mu.L of MTT solution (5 mg/mL).
(4) All the solution described in step (3) was removed and 150 μ L of DMSO was added per well to dissolve the formazan crystals formed in the 96-well plate described in step (3).
(5) After the formazan crystal formed in the step (4) is placed in a constant-temperature water area shaking table and oscillated for 10min (37 ℃, 100rpm), an ultraviolet spectrophotometer is used for measuring the absorbance value at 490nm, and the cell growth inhibition rate is calculated by using a formula (1), the result shows that when the mass concentration of blank micelles is increased from 0.016 mug/mL to 10 mug/mL, the HepG2 cell inhibition rates are lower than 10%, which indicates that P (PFPHM-b-DMAEMA-b-PEEA) micelles have good biocompatibility, and the inhibition rates of the drug-loaded micelles and DOX on HepG2 cells are obviously higher than those of the blank micelles, which indicates that the drug-loaded micelles have the inhibition effect similar to pure DOX on HepG2 cells, are expected to be used for tumor treatment, and can be used as a nano carrier and applied to biomedicine.
Figure BDA0003645216880000131
In the formula, ODc represents the absorbance value at 490nm after HepG2 cell culture, and ODe represents the absorbance value at 490nm after HepG2 cell culture with DOX, P (PFPHM-b-DMAEMA-b-PEGMEA) -DOX, and P (PFPHM-b-DMAEMA-b-PEGMEA), respectively.
Example 9
(1) The prepared drug-loaded micelle of claim 1 is weighed, and the drug Loading (LC) and the Encapsulation Efficiency (EE) of the micelle are calculated according to the following formulas (shown in the following table 1), and the result shows that the drug Loading (LC) of P (PFPHM-b-DMAEMA-b-PEGMEA) is 21.3 percent and the Encapsulation Efficiency (EE) is 90.0 percent, and the result shows that the polymer micelle can effectively wrap the hydrophobic drug.
Figure BDA0003645216880000132
Figure BDA0003645216880000133
In the formula, m1 is the mass of the drug loaded in the polymer micelle, 10 mg; m2 is the total mass of the drug-loaded micelle, mg; m3 represents the mass of the drug, 3 mg.
Table 1: EE and LC analysis of drug-loaded micelles
Figure BDA0003645216880000134
Example 10
(1) Preparing a DOX/ethanol solution with a series of concentrations of 0.01-0.75 mg/mL. The absorbance at 495nm is measured by an ultraviolet spectrophotometer, and a standard curve of adriamycin/ethanol is drawn.
(2) The drug-loaded micelle prepared in claim 1 was dissolved in 10mL of anhydrous ethanol.
(3) The solution prepared in step (2) was transferred to a dialysis bag with a cut-off of 3500, and transferred to four beakers F1, F2, F3, and F4, respectively, and 200mL of a pH 6.5 phosphate buffer solution was added to F1 and F2, and 200mL of a pH 7.4 phosphate buffer solution was added to F3 and F4.
(4) F1 and F3 in the step (3) are dialyzed at 37 ℃, F2 and F4 are dialyzed at 42 ℃, 3mL of fresh medium is sampled at 1, 2, 4, 8, 12, 24, 48 and 72h respectively, 3mL of fresh medium is supplemented, and the absorbance of DOX in different samples is measured by using an ultraviolet spectrophotometer, and the concentration of DOX is calculated by comparing the absorbance of a standard curve of adriamycin/ethanol. The percentage of cumulative drug release (Er) was calculated using equation (4) (fig. 10) and the release rate was significantly faster at pH 6.5 than at pH 7.4 at 42 ℃ and 37 ℃ and 88.9% at 72 hours for the fastest release medium at pH 6.5 and 42 ℃. And the release rate of the drug for 72 hours is 44.5% at the pH value of 7.4 and the temperature of 42 ℃; the release rate of the drug was 43.7% at pH 6.5 and 37 ℃ for 72 hours, and was only 39.5% at pH 7.4 and 37 ℃.
Figure BDA0003645216880000141
In the formula, Er represents the cumulative drug release percentage, and Ve is the volume of the supplement release medium, 3 mL; v0 is the volume of release medium, 200 mL; cn represents the mass concentration of DOX in the nth sample, g/L; mDOX represents the mass of DOX in the micelle, mg.
In conclusion, the invention utilizes 3 times of atom transfer radical polymerization technology to prepare the perfluoropolyether acyl fluoride copolymer with good biocompatibility, pH and thermal response, and can effectively load DOX after self-assembly forming a gel. The prepared block polymer has lower critical micelle concentration, so that the polymeric micelle has good thermodynamic stability, the micelle is still stable after being diluted, and under the action of the hydrophilic shell, the polymeric micelle can prolong the circulation time in blood, so that micelle medicines are slowly and continuously released from the polymeric micelle, the action period of the medicines on cancer cells is prolonged, the dosage required by the medicines is reduced, and the aim of reducing the toxic and side effects of the medicines is fulfilled.
While specific embodiments of the invention have been described, it will be understood by those skilled in the art that the specific embodiments described are illustrative only and are not limiting upon the scope of the invention, as equivalent modifications and variations as will be made by those skilled in the art in light of the spirit of the invention are intended to be included within the scope of the appended claims.

Claims (8)

1. A method for preparing a perfluoropolyether acyl fluoride acrylate copolymer with pH and thermal response is characterized in that: the method comprises the following steps:
(1) perfluoropolyether acyl fluoride reacts with hydroxyethyl methacrylate to prepare perfluoropolyether hydroxyethyl methacrylate PFPHM,
(2) EBIB (ethyl 2-bromoisobutyrate) as initiator and CuBr 2 Pentamethyldiethylenetriamine (PMDETA) as catalyst system, Sn (OCt) 2 Taking the PFPHM as a reducing agent to initiate the self-polymerization of the PFPHM generated in the step (1) to obtain a macromolecular initiator PPFPHM-Br;
(3) taking the PPFPHM-Br generated in the step (2) as a macroinitiator, and introducing a pH and thermal response functional monomer DMAEMA to obtain P (PFPHM-b-DMAEMA) -Br;
(4) introducing P (PFPHM-b-DMAEMA) -Br generated in the step (3) as a pH and thermal response macroinitiator into a hydrophilic chain segment PEGMEA to obtain an amphiphilic triblock polymer P (PFPHM-b-DMAEMA-b-PEGMEA) with thermal response;
(5) preparing P (PFPHM-b-DMAEMA-b-PEGMEA) generated in the step (4) into blank micelles and drug-loaded micelles by using a dialysis method.
2. The process for preparing a pH and thermally responsive perfluoropolyether acyl fluoroacrylate copolymer in accordance with claim 1, wherein: the specific steps of the step (1) are as follows:
taking perfluoropolyether acyl fluoride, hydroxyethyl methacrylate, trifluoroethanol and triethylamine in a single-neck flask, reacting for 7-10 h at 20-30 ℃ with the molar ratio of the perfluoropolyether acyl fluoride to the hydroxyethyl methacrylate being 1-2: 1, cooling after the reaction is finished, extracting and washing the reaction solution with dilute hydrochloric acid, taking the lower layer, extracting and washing with deionized water to obtain a light yellow viscous liquid, namely PFPHM.
3. The process for preparing a pH and thermally responsive perfluoropolyether acyl fluoroacrylate copolymer in accordance with claim 1, wherein: the specific steps of the step (2) are as follows:
adding Trifluoroethanol (TFEA) and CuBr into a round-bottom flask 2 PMDETA, PFPHM, EBIB and Sn (OCt) 2 Then immediately transferring the flask into a Dewar flask filled with liquid nitrogen for degassing, performing liquid nitrogen freezing-vacuumizing-unfreezing circulation to remove oxygen, filling high-purity nitrogen into the flask, sealing the flask, transferring the flask into an oil bath kettle at 35-45 ℃, and reacting for 8-10 hours; after the reaction is finished, cooling, and adding absolute ethyl alcohol into the flask to dilute the reaction solution; then, using absolute ethyl alcohol as an eluent, collecting the diluted reaction solution after passing through a 200-mesh neutral alumina column, dropwise adding the collected solution into an excessive and rapidly-stirred n (deionized water) solution, namely n (ethyl alcohol) 2-3: 1, performing centrifugal separation, and collecting precipitates; and (3) placing the collected precipitate in a vacuum forced air drying oven to be dried for 24 hours at the temperature of 55-65 ℃ to obtain the macroinitiator PPFPHM-Br.
4. A process for preparing a pH and thermally responsive perfluoropolyether acyl fluoroacrylate copolymer in accordance with claim 3, wherein: the specific steps of the step (3) are as follows:
a round bottom flask was charged with Trifluoroethanol (TFEA), CuBr2, PMDETA, PPFPHM-Br, DMAEMA, and Sn (OCt) 2 Degassing the round-bottom flask in the same manner as the step (2), transferring the round-bottom flask into an oil bath kettle at the temperature of 35-45 ℃, and reacting for 8-10 h; after the reaction is finished, performing column passing treatment and centrifugal separation treatment on the sample in the same way as the step (2); and (3) drying the collected precipitate in a vacuum forced air drying oven at 55-65 ℃ for 24h to obtain P (PFPHM-b-DMAEMA) -Br.
5. A process for preparing a pH and thermally responsive perfluoropolyether acyl fluoroacrylate copolymer in accordance with claim 4, wherein: the specific steps of the step (4) are as follows:
adding Trifluoroethanol (TFEA), CuBr2, PMDETA, P (PFPHM-b-DMAEMA) -Br, DMAEMA and Sn (OCt)2 into a round-bottom flask, degassing the round-bottom flask in the same manner as the step (2), transferring the round-bottom flask into an oil bath kettle at the temperature of 35-45 ℃, and reacting for 8-10 h. After the reaction is finished, cooling, and performing column passing treatment and centrifugal separation treatment on the sample in the same way as the step (2); and (3) drying the collected precipitate in a vacuum forced air drying oven at 55-65 ℃ for 24h to obtain P (PFPHM-b-DMAEMA-b-PEGMEA).
6. The process for preparing a pH and thermally responsive perfluoropolyether acyl fluoroacrylate copolymer in accordance with claim 1, wherein: the specific preparation steps of the blank micelle in the step (5) are as follows:
weighing 9-12 mg of P (PFPHM-b-DMAEMA-b-PEGMEA) and dissolving in 3-5 mL of acetone; then, 8-10 mL of deionized water is dripped into a rapidly stirred acetone solution of P (PFPHM-b-DMAEMA-b-PEGMEA) at a rate of 8-10 muL/s; then, transferring the polymer solution into a dialysis bag with the relative molecular mass of 3500 interception, dialyzing for 20-28 h, completely replacing the deionized water every 2h within the initial 6h, and then completely replacing the deionized water every 6 h; and finally, carrying out freeze drying on the dialyzed sample for 70-80 h at the temperature of-70-80 ℃ by using a vacuum freeze drying box to obtain the blank micelle.
7. The process for preparing a pH and thermally responsive perfluoropolyether acyl fluoroacrylate copolymer in accordance with claim 1, wherein: the specific preparation steps of the drug-loaded micelle in the step (5) are as follows:
weighing 3-5 mg of DOX/HCl, dissolving in 1-2 mL of acetone, dissolving 8-10 mg of P (PFPHM-b-DMAEMA-b-PEGMEA) in 3-5 mL of acetone, mixing the two solutions at a speed of 140-150 r/min, stirring for 50-60 min, dripping 8-10 mL of deionized water into a mixed solution of rapidly stirred P (PFPHM-b-DMAEMA-b-PEEA), DOX/HCl and acetone at a speed of 8-10 mu L/s, transferring the polymer solution into a dialysis bag with a relative molecular mass of 3500, dialyzing for 20-28 h, completely replacing the deionized water every 2h within the initial 6h, completely replacing the deionized water at intervals of 6h, and keeping out of the sun during dialysis; and finally, freeze-drying the dialyzed sample for 70-80 hours at the temperature of-70 to-80 ℃ by using a vacuum freeze-drying box to obtain the drug-loaded micelle.
8. The perfluoropolyether acyl fluoroacrylate copolymer prepared by the method for preparing a perfluoropolyether acyl fluoroacrylate copolymer having pH and thermal response according to any one of claims 1 to 7, and blank micelles and drug-loaded micelles thereof.
CN202210527677.5A 2022-05-16 2022-05-16 Preparation method of pH and thermal response perfluoropolyether acyl fluoroacrylate copolymer and product thereof Pending CN115028786A (en)

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CN102212178A (en) * 2011-04-11 2011-10-12 同济大学 Pentablock copolymer with temperature and pH dual sensitivity, and preparation method and application thereof

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