CN113440612B - Photodynamic enhanced polymer nanogel, preparation method and application thereof - Google Patents

Photodynamic enhanced polymer nanogel, preparation method and application thereof Download PDF

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CN113440612B
CN113440612B CN202110684381.XA CN202110684381A CN113440612B CN 113440612 B CN113440612 B CN 113440612B CN 202110684381 A CN202110684381 A CN 202110684381A CN 113440612 B CN113440612 B CN 113440612B
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CN113440612A (en
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陈莉
刘文长
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Northeast Normal University
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    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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Abstract

The invention discloses a photodynamic enhanced polymer nanogel, a preparation method and application thereof, belonging to the technical field of biomedical high molecular materials, wherein the polymer nanogel is prepared from a water-soluble polyethylene glycol monomethyl ether derivative, a porphyrin derivative and oxalyl chloride by a one-step method; under the tumor microenvironment with high expression of hydrogen peroxide, the carbonyl group of the cross-linking agent in the polymer nanogel is subjected to H 2 O 2 The intermediate is decomposed to promote energy to be transferred to the receptor photosensitizer through chemiluminescence resonance energy transfer, the photodynamic efficiency of the photosensitizer is improved, and the tumor growth is better inhibited. The polymer nanogel has the advantages of simple synthetic route and capability of enabling the polymer to participate in the process of photodynamic energy conversion to improve the photodynamic treatment effect of the unit photosensitizer. The invention avoids the construction process of the biological nano particle assembly and has great advantages in the aspect of subsequent production and application.

Description

Photodynamic enhanced polymer nanogel, preparation method and application thereof
Technical Field
The invention relates to the technical field of biomedical high polymer materials, in particular to a photodynamic enhanced polymer nanogel, a preparation method and application thereof.
Background
With the advent of advanced polymerization methods such as living/controlled radical polymerization and click chemistry, the synthesis of porphyrin-containing polymers via covalent bonding has greatly evolved. The functional polymer containing porphyrin has definite macromolecular structure, unique self-assembly shape and special photochemical and photophysical properties, and has important application in the fields of catalysis, solar cells, biomedicine, environmental science and the like. In particular, the use of porphyrin-based photosensitizers or porphyrin-conjugated polymers in the field of photodynamic therapy (PDT). (Angew. Chem. Int. Ed.2018,57
Although FDA has approved porphyrin and derivatives as the second generation photosensitizer for clinical photodynamic therapy, there are still problems of shallow treatment depth, hypoxic tumor microenvironment, photosensitive side effects, etc. To solve these problems, researchers have designed porphyrin-based polymer nano-phototherapy systems, but the synthetic routes and processes of these systems are relatively complex, limiting their wide spread and increasing the cost of treatment. How to design a functional polymer containing porphyrin, which is simple in synthesis and can solve the problems is the central importance of the development of the second-generation photosensitizer. On the other hand, the polymer framework of the current porphyrin-based functional polymer often exists only as a load, and the polymer itself has very limited functions, and often only has the functions of assembling, encapsulating or conjugating small-molecule functional groups to improve the water solubility and arrangement mode of the photosensitizer. How to make the polymer participate in the process of photodynamic energy conversion and improve the photodynamic treatment effect of the unit photosensitizer is a few questions which are very worthy of being researched at present.
Chemiluminescence is a reaction process that converts chemical reaction energy into light energy at room temperature. The peroxyoxalate ester chemiluminescence systems mainly comprising oxalate, hydrogen peroxide and fluorescent agent are considered to be one of the most effective chemical (non-biological) luminescence systems due to the characteristics of high luminous efficiency, high intensity and the like. At present, although peroxyoxalate chemiluminescence systems are reported to enhance fluorescent molecular in vivo imaging (ACS Nano 2020,14, 3696-3702), no polymeric gel containing oxalate, porphyrin and other fluorescent molecules, which provides photodynamic additional activation energy transfer sites by using hydrogen peroxide or other peroxides highly expressed in tumor microenvironment, is reported.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a photodynamic enhancement type polymer nanogel, a preparation method and application thereof.
The invention is realized by the following technical scheme:
a photodynamic enhanced polymer nanogel has a structure shown in a formula (I) or a formula (II), and is prepared from a water-soluble polyethylene glycol monomethyl ether derivative, a porphyrin derivative and oxalyl chloride through a one-step method;
Figure BDA0003123879180000021
wherein m is an integer, and m is more than or equal to 20 and less than or equal to 200;
the structural formula of the porphyrin derivative is as follows:
Figure BDA0003123879180000031
preferably, the porphyrin derivative is tetrahydroxyhexyl ether phenyl porphyrin or tetraaminophenyl porphyrin.
Preferably, the polyethylene glycol monomethyl ether derivative is polyethylene glycol monomethyl ether or aminated polyethylene glycol monomethyl ether.
The invention also provides a preparation method of the photodynamic reinforced polymer nanogel, which comprises the following steps:
in the presence of a catalyst, an acid-binding agent and a solvent, performing nucleophilic substitution reaction on the porphyrin derivative, the polyethylene glycol monomethyl ether derivative and oxalyl chloride, and preparing the polymer nanogel by a one-step method.
The mol ratio of the porphyrin derivative to the polyethylene glycol monomethyl ether derivative to the oxalyl chloride is a: n: 20-25 (n + a), wherein n = 1-4 a.
Preferably, the porphyrin derivative is tetrahydroxyhexyl ether phenyl porphyrin or tetraaminophenyl porphyrin; the catalyst is 4-dimethylamino pyridine; the polyethylene glycol monomethyl ether derivative is polyethylene glycol monomethyl ether or aminated polyethylene glycol monomethyl ether; the acid-binding agent is potassium carbonate or triethylamine; the solvent is anhydrous dichloromethane, anhydrous dimethyl sulfoxide or anhydrous N, N-dimethylformamide; the reaction temperature is 0-10 ℃, and the reaction time is 12-72 h.
Preferably, the tetrahydroxyhexyl ether phenyl porphyrin is prepared by the following method:
under the condition that a solvent and a catalyst exist, mixing tetrahydroxyphenyl porphyrin and 6-chloro-1-hexanol according to a certain proportion, washing the obtained reaction product with a sodium hydroxide solution and deionized water in sequence, adjusting the pH value to 7-8, performing suction filtration on the washed reaction product with a Buchner funnel to obtain a dark purple solid, and performing suction drying in a vacuum drier to obtain tetrahydroxyhexyl ether phenyl porphyrin, wherein the reaction equation is as follows:
Figure BDA0003123879180000041
preferably, the catalyst is sodium iodide, and the solvent is one or more of anhydrous tetrahydrofuran, anhydrous N, N-dimethylformamide or N-methylpyrrolidone. The reaction temperature is 120-160 ℃; the reaction time is 12-36 h.
Preferably, the molar ratio of the tetrahydroxyphenylporphyrin to 6-chloro-1-hexanol is 1:1 to 10.
The structural formula of the tetrahydroxyphenyl porphyrin is shown as a formula VII;
Figure BDA0003123879180000042
the invention also provides application of the photodynamic enhanced polymer nanogel in preparation of antitumor drugs.
The preparation principle of the photodynamic reinforced polymer nanogel is as follows:
the method is characterized in that a perexalate bond or a pereoxamide bond is required to exist in the nanogel as a linker to meet the experimental design concept, so that both porphyrin derivatives and polyethylene glycol monomethyl ether derivatives carry hydroxyl groups as characteristic reaction groups, and the acid chloride group of oxalyl chloride are subjected to nucleophilic substitution condensation reaction to remove hydrogen chloride to generate the polymer nanogel which is crosslinked by the perexalate bond and has the structure shown in the formula (I); the porphyrin derivative and the polyethylene glycol monomethyl ether derivative are designed by the same concept, both have amino as characteristic reactive groups, and the acyl chloride group of oxalyl chloride and the amino carry out nucleophilic substitution condensation reaction to remove hydrogen chloride to generate the polymer nanogel with the structure of the formula (II) and crosslinked by the oxamide bond. Together forming a series of photodynamically enhanced polymer nanogels with crosslinking sites that can respond to strong oxidants. The reaction equation is as follows:
Figure BDA0003123879180000051
compared with the prior art, the invention has the following beneficial effects:
the invention provides a photodynamic enhanced polymer nanogel which can be prepared in H 2 O 2 In a high-expression tumor microenvironment, the carbonyl group of oxalate or oxamide in the structure of formula (I) or formula (II) is subjected to H 2 O 2 The intermediate is decomposed to promote energy to be transferred to acceptor fluorescent molecules through Chemiluminescence Resonance Energy Transfer (CRET), so that the photodynamic efficiency of the unit photosensitizer is improved, and the tumor growth is better inhibited. Such beneficial effects can be verified by combining the MTT cytotoxicity assay for cytotoxicity between different concentration gradients of each group with or without light application, while the present invention verifies via flow cytometry that the nanogels have higher intracellular ROS production relative to the original photosensitizer group and the control group under the same conditions. On the other hand, the synthesis method provided by the invention is simple and rapid in synthesis process, the construction process of the biological nanoparticle assembly is avoided by utilizing the one-step method to prepare the nanoparticles, and the method has great advantages in the aspect of subsequent production and application.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a long alkyl chain-containing four-arm phenyl porphyrin derivative TOPP-C6OH4 prepared in example 1 of the present invention;
FIG. 2 is the NMR spectrum of TAPP-NGT polymer nanogel prepared in example 11 of the invention in heavy water;
FIG. 3 shows that polymer nanogel TAPP-NGT prepared in example 11 of the invention is in DMSO-d 6 Medium nuclear magnetic resonance hydrogen spectrum;
FIG. 4 is the NMR chart of the polymer nanogel TOPPNPS prepared in example 3 of the invention in heavy water;
FIG. 5 shows the polymer nanogel TOPPNPS prepared in example 3 of the invention in DMSO-d 6 Nuclear magnetic resonance hydrogen spectrum;
FIG. 6 is an infrared spectrum of TOPPNPS, a polymer nanogel prepared in example 3 of the invention;
FIG. 7 is a dynamic light scattering diagram of TOPPNPS polymer nanogel prepared in example 3 of the invention;
FIG. 8 is a transmission electron microscope image of TOPPNPS polymer nanogel prepared in example 3 of the invention;
FIG. 9 is an in vitro ROS UV-spectrum of the polymer nanogel TOPPNPS prepared in example 3 of the invention cultured in PBS for seven points taken for 30 min;
FIG. 10 is the survival rate of B16-F10 murine melanoma cells according to example 11 with increasing concentration of photosensitizer in TAPP-NGT;
FIG. 11 is the survival rate of B16-F10 murine melanoma cells from example 3 with increasing concentration of the photosensitizer in TOPPNPS;
FIG. 12 is a flow cytometric map of the intracellular internalization of murine melanoma from B16-F10 for 4 hours in example 11, reflecting the intracellular ROS production of different materials.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. 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.
A photodynamic enhancement type polymer nanogel has a structure shown in a formula (I) or a formula (II), and is prepared by a one-step method from water-soluble polyethylene glycol monomethyl ether, porphyrin derivatives and oxalyl chloride;
Figure BDA0003123879180000071
wherein m is an integer, and m is more than or equal to 20 and less than or equal to 200;
the porphyrin derivative has the following structure:
Figure BDA0003123879180000072
the invention also provides a preparation method of the polymer nanogel, which comprises the following steps:
in the presence of a catalyst, an acid-binding agent and a solvent, matching tetrahydroxyhexyl ether phenyl porphyrin or tetraaminophenyl porphyrin with a structure shown in formula (V) or formula (VI) with polyethylene glycol monomethyl ether or aminated polyethylene glycol monomethyl ether in different proportions and oxalyl chloride to obtain the polymer nanogel with the structure shown in formula (I) or formula (II) through a one-step method.
In the structures shown in the formulas (I) to (VI), the bond corresponding to the wave position is a connecting bond of a group, and is connected with the main structure.
In certain embodiments of the present invention, 20 ≦ m ≦ 200.
In certain embodiments of the invention, n is a, 2a, 3a, or 4a; m is 23, 45 or 113.
The polymer nanogel provided by the invention is synthesized by a simple one-step method. The material can be in H 2 O 2 In a high-expression tumor microenvironment, the carbonyl group of oxalate or oxamide is exposed to H 2 O 2 Nucleophilic attack of (3) to generate energyThe high-energy dioxygen cyclic intermediate dioxabutandione is decomposed to promote energy to be transferred to acceptor fluorescent molecules through Chemiluminescence Resonance Energy Transfer (CRET), so that the photodynamic efficiency of a unit photosensitizer is improved, and the tumor growth is better inhibited.
In certain embodiments of the present invention, the sum of the amounts of the porphyrin derivative having the structure of formula (i) or formula (ii) and the polyethylene glycol monomethyl ether derivative, and the amount of oxalyl chloride in the ratio of 1:20 to 25;
in certain embodiments of the invention, the solvent comprises anhydrous dichloromethane, anhydrous dimethyl sulfoxide, or anhydrous N, N-dimethylformamide; the amount of the solvent used is not particularly limited, and the porphyrin derivative, the polyethylene glycol monomethyl ether derivative and the oxalyl chloride can be dissolved.
In certain embodiments of the invention, the catalyst is DMAP; the acid-binding agent is potassium carbonate or triethylamine.
In certain embodiments of the invention, the temperature of the reaction is between 0 and 10 ℃; the reaction time is 12-72 h.
In some embodiments of the present invention, the nucleophilic substitution reaction is performed under ice bath conditions, and the reaction flask needs to be vacuum-dried before the reaction.
In some embodiments of the present invention, after the condensation of the polymer having the structure of formula (i) or formula (ii) in a solvent is completed, the method further comprises: the reaction product was dialyzed and lyophilized. The method of dialysis and lyophilization is not particularly limited in the present invention, and a method of dialysis and lyophilization known to those skilled in the art may be used.
In certain embodiments of the present invention, the long alkyl chain-containing four-arm phenylporphyrin derivative having the structure of formula (v) is prepared by:
under the action of a catalyst, the phenolic hydroxyl of the tetrahydroxyphenyl porphyrin with the structure shown in the formula (VII) is easy to deprotonate so as to react with 6-chloro-1-hexanol in a solvent to obtain the long alkyl chain-containing four-arm phenyl porphyrin derivative with the structure shown in the formula (V); the catalyst is sodium iodide; the solvent is one or more of anhydrous tetrahydrofuran, anhydrous N, N-dimethylformamide and N-methylpyrrolidone;
Figure BDA0003123879180000091
in certain embodiments of the invention, the molar ratio of tetrahydroxyphenyl porphyrin having the structure of formula (VII) to 6-chloro-1-hexanol is 1:1 to 10.
In certain embodiments of the invention, the temperature of the reaction is 120 to 160 ℃; the reaction time is 12-36 h.
In some embodiments of the present invention, after the reaction of the long alkyl chain-containing four-arm phenyl porphyrin derivative in the solvent is completed, the method further comprises: washing the obtained reaction product with sodium hydroxide solution and deionized water in sequence, and adjusting the pH value to 7-8. In certain embodiments of the present invention, the number of washes is 3 or more.
In some embodiments of the present invention, after the washing process is finished, the method further includes: and (3) carrying out suction filtration on the washed reaction product by using a Buchner funnel to obtain a dark purple solid, and carrying out suction drying in a vacuum drier to obtain the porphyrin derivative with the structure shown in the formula (V).
The source of the above-mentioned raw materials is not particularly limited in the present invention, and may be generally commercially available.
The invention also provides application of the polymer nanogel or the polymer nanogel prepared by the preparation method in preparation of antitumor drugs.
The present invention will be described in further detail with reference to examples.
Example 1
Synthesis of a long alkyl chain-containing four-armed phenylporphyrin derivative having the structure of formula (v):
0.678g (0.001 mol) of tetrahydroxyphenylporphyrin was weighed out and dissolved in 100mL of DMF, and 5g of NaI (0.0035 mol) was added thereto under ice bath conditions to activate the resulting mixture. After activation, the reaction was stirred at 25 ℃ for 6h. The reaction was then transferred to an oil bath at 151 ℃ under reflux. 1.4mL (0.01 mol) of 6-chloro-1-hexanol was added dropwise to the closed system using a syringe, and the reaction was continued under reflux for 12 hours. After the reaction was stopped, the reaction solution was poured into chilled deionized water, and sodium hydroxide was slowly added to observe the color change. Washing with deionized water for three times, performing suction filtration with a Buchner funnel to obtain a dark purple solid, and performing suction drying in a vacuum drier to obtain tetrahydroxyhexyl ether phenyl porphyrin TOPP-C6OH4; the reaction equation is as follows:
Figure BDA0003123879180000101
the structural representation of the obtained long alkyl chain-containing four-arm phenyl porphyrin derivative TOPP-C6OH4 is shown in figure 1. FIG. 1 shows the NMR spectrum of TOPP-C6OH4, a four-arm phenyl porphyrin derivative with long alkyl chain, prepared in example 1 of the present invention.
Example 2
Synthesis of long alkyl chain-containing four-arm phenyl porphyrin derivative with structure of formula (v):
0.678g (0.001 mol) of tetrahydroxyphenylporphyrin was weighed out and dissolved in 100mL of DMF, and activated by adding 5g of NaI (0.0035 mol) in an ice bath. After activation, the reaction was stirred at 25 ℃ for 6h. The reaction was then transferred to an oil bath at 151 ℃ and refluxed. 0.7mL (0.005 mol) of 6-chloro-1-hexanol was added dropwise to the closed system using a syringe, and the reaction was continued under reflux for 24 hours. After the reaction was stopped, the reaction solution was poured into chilled deionized water, and sodium hydroxide was slowly added to observe the color change. And washing with deionized water for three times, performing suction filtration by using a Buchner funnel to obtain a dark purple solid, and performing suction drying in a vacuum drier to obtain the tetrahydroxyhexyl ether phenyl porphyrin.
Example 3
Synthesis of a polyoxalate-crosslinked nanogel having the structure of formula (i) wherein n = a:
anhydrous and anaerobic treatment is carried out on a reaction device, 0.5g (0.0001 mol) of methoxypolyethylene glycol (mPEG 5000, molecular weight of 5000) is weighed, and azeotropic reflux is carried out for 4h by taking toluene as a solvent to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature to fully dissolve the toluene solvent, and 0.113g (0.0001 mol) of tetrahexyl-terminated porphyrin derivative with the structure of the formula (V) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in ice bath and protected by nitrogen, 0.5mL (0.005 mol) of oxalyl chloride is added dropwise and slowly by a syringe, after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. And after the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TOPPNPS. The reaction equation is as follows:
Figure BDA0003123879180000111
the polymer nanogel TOPPNPS obtained above was characterized, and the results are shown in fig. 4 and 5. FIG. 4 is the NMR spectrum of the polymer-process nanogel TOPPNPS prepared in example 3 of the invention in heavy water. FIG. 5 shows the NMR spectrum of TOPPNPS polymer nanogel prepared in example 3 of the invention in DMSO-d 6. As can be seen from fig. 4 and 5, polymer nanogel TOPPNPS has been successfully synthesized and has constituted a nanoscale assembly. The analysis of the infrared spectrogram of FIG. 6 assists this argument.
FIG. 7 is a dynamic light scattering diagram of TOPPNPS polymer nanogel prepared in example 3 of the invention; FIG. 8 is a transmission electron microscope image of TOPPNPS polymer nanogel prepared in example 3 of the invention. Both together indicate that the nanoparticles are stable and between 120-200nm in size.
FIG. 9 is an in vitro ROS UV-spectrum of the polymer nanogel TOPPNPS prepared in example 3 of the invention cultured in PBS for seven points taken for 30 min; the polymer rice gel TOPPNPS can continuously generate ROS under illumination and can be used as a photodynamic phototherapy system.
The antitumor activity of polymer nanogel TOPPNPS was examined by cytotoxicity assay:
the polymer nanogel TOPPNPS prepared in the embodiment 3 of the invention is co-cultured with B16-F10 murine melanoma cells, and is evaluated by adopting an MTT (methyl thiazolyl tetrazolium) experiment:
the corresponding cells were first seeded at a density of 7000 cells/well (suspended in 200L DMEM medium) in 96-well plates and incubated for 24h at 37 ℃ in a cell incubator. The next day, the corresponding polymer nanogel TOPPNPS was dissolved in fresh DMEM medium and diluted to different concentrations in a gradient, the medium from the previous day was discarded, DMEM containing different concentrations of polymer nanogel TOPPNPS was added and incubation continued in the cell culture chamber at 37 ℃ for 24h. MTT solution (final concentration 0.5 mg/mL) was then added to each well and incubation at 37 ℃ continued for 4h. The liquid in the well plate was discarded, and 150L of DMSO was added to each well, respectively, to dissolve purple formazan crystals. Finally, the absorbance of each well at 492nm is measured by a microplate reader (Tecan, switzerland), and the cell survival rate can be calculated by comparing the absorbance value of the experimental group with that of the control group.
FIG. 11 is the survival rate of B16-F10 murine melanoma cells from example 3 with increasing concentration of the photosensitizer in TOPPNPS; the non-light group almost does not kill, the tumor killing rate of the light group polymer nanogel TOPPNPS is obviously improved in each concentration gradient compared with that of a pure photosensitizer treatment group, and the polymer nanogel TOPPNPS is proved to cause that the photodynamic efficiency of a unit photosensitizer is comprehensively and obviously improved, so that the idea of better anti-tumor effect is played.
Example 4
Synthesis of a polyoxalate-crosslinked nanogel having the structure of formula (i) wherein n =2a:
anhydrous and anaerobic treatment is carried out on a reaction device, 1.0g (0.0002 mol) of polyethylene glycol monomethyl ether (mPEG 5000, molecular weight of 5000) is weighed, and toluene is used as a solvent to carry out azeotropic reflux for 4h for removing water. The toluene solvent is drained, at room temperature, 20mL of anhydrous dichloromethane is added to fully dissolve the toluene solvent, and under the protection of nitrogen, 0.113g (0.0001 mol) of the tetrahydroxyhexyl terminated porphyrin derivative with the structure of the formula (V) and an acid binding agent are added. The mixture is cooled in an ice bath and protected by nitrogen, 0.7mL (0.0075 mol) of oxalyl chloride is slowly added dropwise by a syringe, and after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. And after the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TOPPNPS.
Example 5
Synthesis of a polyoxalate cross-linked nanogel having the structure of formula (i) wherein n =3a:
anhydrous and anaerobic treatment is carried out on a reaction device, 1.5g (0.0003 mol) of polyethylene glycol monomethyl ether (mPEG 5000, molecular weight 5000) is weighed, and toluene is used as a solvent for azeotropic reflux for 4h to remove water. The toluene solvent is drained, at room temperature, 20mL of anhydrous dichloromethane is added to fully dissolve the toluene solvent, and under the protection of nitrogen, 0.113g (0.0001 mol) of the tetrahydroxyhexyl terminated porphyrin derivative with the structure of the formula (V) and an acid binding agent are added. The mixture is cooled in ice bath and protected by nitrogen, 0.9mL (0.01 mol) of oxalyl chloride is slowly added dropwise by a syringe, after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. And after the reaction is finished, settling with frozen ether, dialyzing, and freeze-drying to obtain the polymer nanogel TOPPNPS.
Example 6
Synthesis of a polyoxalate-crosslinked nanogel having the structure of formula (i) wherein n =4a:
anhydrous and anaerobic treatment is carried out on a reaction device, 1.0g (0.0002 mol) of polyethylene glycol monomethyl ether (mPEG 5000, molecular weight of 5000) is weighed, and toluene is used as a solvent to carry out azeotropic reflux for 4h for removing water. The toluene solvent is drained, at room temperature, 20mL of anhydrous dichloromethane is added to fully dissolve the toluene solvent, and under the protection of nitrogen, 0.113g (0.0001 mol) of the tetrahydroxyhexyl terminated porphyrin derivative with the structure of the formula (V) and an acid binding agent are added. The mixture is cooled in an ice bath and protected by nitrogen, 0.7mL (0.0075 mol) of oxalyl chloride is slowly added dropwise by a syringe, and after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. And after the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TOPPNPS.
Example 7
Synthesis of a polyoxalate cross-linked nanogel having the structure of formula (i) wherein n = a:
the reaction device is subjected to anhydrous and anaerobic treatment, 0.2g (0.0001 mol) of polyethylene glycol monomethyl ether (mPEG 2000, molecular weight of 2000) is weighed, and toluene is used as a solvent for azeotropic reflux for 4h to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature to fully dissolve the toluene solvent, and 0.113g (0.0001 mol) of tetrahexyl-terminated porphyrin derivative with the structure of the formula (V) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in ice bath and protected by nitrogen, 0.5mL (0.005 mol) of oxalyl chloride is slowly added dropwise by a syringe, after 4h of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24h. And after the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TOPPNPS.
Example 8
Synthesis of a polyoxalate cross-linked nanogel having the structure of formula (i) wherein n =2a:
the reaction device is subjected to anhydrous and anaerobic treatment, 0.4g (0.0002 mol) of polyethylene glycol monomethyl ether (mPEG 2000, molecular weight 2000) is weighed, and the mixture is subjected to azeotropic reflux for 4 hours by taking toluene as a solvent to remove water. The toluene solvent is drained, at room temperature, 20mL of anhydrous dichloromethane is added to fully dissolve the toluene solvent, and under the protection of nitrogen, 0.113g (0.0001 mol) of the tetrahydroxyhexyl terminated porphyrin derivative with the structure of the formula (V) and an acid binding agent are added. The mixture is cooled in an ice bath and protected by nitrogen, 0.7mL (0.0075 mol) of oxalyl chloride is slowly added dropwise by a syringe, and after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. And after the reaction is finished, settling with frozen ether, dialyzing, and freeze-drying to obtain the polymer nanogel TOPPNPS.
Example 9
Synthesis of a polyoxalate cross-linked nanogel having the structure of formula (i) wherein n =3a:
the reaction device is subjected to anhydrous and anaerobic treatment, 0.6g (0.0003 mol) of polyethylene glycol monomethyl ether (mPEG 2000, molecular weight 2000) is weighed, and toluene is used as a solvent for azeotropic reflux for 4h to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature to fully dissolve the toluene solvent, and 0.113g (0.0001 mol) of tetrahexyl-terminated porphyrin derivative with the structure of the formula (V) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in ice bath and protected by nitrogen, 0.9mL (0.01 mol) of oxalyl chloride is slowly added dropwise by a syringe, after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. And after the reaction is finished, settling with frozen ether, dialyzing, and freeze-drying to obtain the polymer nanogel TOPPNPS.
Example 10
Synthesis of a polyoxalate cross-linked nanogel having the structure of formula (i) wherein n =4a:
the reaction device is subjected to anhydrous and anaerobic treatment, 0.8g (0.0004 mol) of polyethylene glycol monomethyl ether (mPEG 2000, molecular weight 2000) is weighed, and toluene is used as a solvent for azeotropic reflux for 4h to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature to fully dissolve the toluene solvent, and 0.113g (0.0001 mol) of tetrahexyl-terminated porphyrin derivative with the structure of the formula (V) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in ice bath and protected by nitrogen, 1.1mL (0.0125 mol) of oxalyl chloride is added dropwise and slowly by a syringe, after 4 hours of reaction, the temperature is raised to 25 ℃, and the reaction is stirred and carried out for 24 hours. And after the reaction is finished, settling with frozen ether, dialyzing, and freeze-drying to obtain the polymer nanogel TOPPNPS.
Example 11
Synthesis of a peraoxamide cross-linked nanogel having the structure of formula (ii) wherein n = a:
the reaction device is subjected to anhydrous and anaerobic treatment, 0.5g (0.0001 mol) of polyethylene glycol monomethyl ether (mPEG 5000, molecular weight of 5000) is weighed, and toluene is used as a solvent for azeotropic reflux for 4h to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature to fully dissolve the toluene solvent, and 0.068g (0.0001 mol) of tetraaminophenylporphyrin with the structure of the formula (VI) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in ice bath and protected by nitrogen, 0.5mL (0.005 mol) of oxalyl chloride is added dropwise and slowly by a syringe, after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. After the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TAPP-NGT. The reaction equation is as follows:
Figure BDA0003123879180000141
the polymer nanogel TAPP-NGT obtained in the above way is characterized, and the results are shown in figures 2 and 3. FIG. 2 shows the NMR spectrum of the polymer nanogel TAPP-NGT prepared in example 11 of the invention in heavy water. FIG. 3 is the nuclear magnetic resonance hydrogen spectrum of the polymer nanogel TAPP-NGT prepared in example 11 of the invention in DMSO-d 6. As can be seen from FIGS. 2 and 3, the polymer nanogel TAPP-NGT has been successfully synthesized and has been constructed into nanoscale assemblies.
FIG. 10 is a graph showing the cell survival rate of B16-F10 murine melanoma cells according to example 11 with increasing concentration of photosensitizer contained in TAPP-NGT; the polymer nanogel TAPP-NGT in the non-illumination group is almost not killed, the tumor killing rate of the polymer nanogel TAPP-NGT in the illumination group is obviously improved in each concentration gradient compared with that of a pure photosensitizer treatment group, and the idea that the photodynamic efficiency of a unit photosensitizer caused by the polymer nanogel TAPP-NGT is comprehensively and obviously improved, and a better anti-tumor effect is achieved.
FIG. 12 is a flow cytometric map of the intracellular internalization of murine melanoma from B16-F10 for 4 hours in example 11, reflecting the intracellular ROS production of different materials. The abscissa corresponds to the fluorescence intensity of the DCF-DH probe, the test can reflect the ROS generation amount in cells, the result shows that the ROS generation amount of a pure photosensitizer treatment group is obviously improved compared with the polymer nanogel TAPP-NGT, the photodynamic efficiency of a unit photosensitizer caused by the polymer nanogel TAPP-NGT is comprehensively and obviously improved, and the viewpoint of better antitumor effect is played.
Example 12
Synthesis of a polyoxamide cross-linked nanogel having the structure of formula (ii) wherein n =2a:
a reaction device is subjected to anhydrous and anaerobic treatment, 1g (0.0002 mol) of polyethylene glycol monomethyl ether (mPEG 5000, molecular weight of 5000) is weighed, and toluene is used as a solvent for azeotropic reflux for 4h to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature to fully dissolve the toluene solvent, and 0.068g (0.0001 mol) of tetraaminophenylporphyrin with the structure of the formula (VI) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in an ice bath and protected by nitrogen, 0.7mL (0.0075 mol) of oxalyl chloride is slowly added dropwise by a syringe, and after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. After the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TAPP-NGT.
Example 13
Synthesis of a polyoxamide cross-linked nanogel having the structure of formula (ii) wherein n =3a:
anhydrous and anaerobic treatment is carried out on a reaction device, 1.5g (0.0003 mol) of polyethylene glycol monomethyl ether (mPEG 5000, molecular weight 5000) is weighed, and toluene is used as a solvent for azeotropic reflux for 4h to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature to fully dissolve the toluene solvent, and 0.068g (0.0001 mol) of tetraaminophenylporphyrin with the structure of the formula (VI) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in ice bath and protected by nitrogen, 0.9mL (0.01 mol) of oxalyl chloride is added dropwise and slowly by a syringe, after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. After the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TAPP-NGT.
Example 14
Synthesis of a peraoxamide cross-linked nanogel having the structure of formula (ii) wherein n =4a:
the reaction device is subjected to anhydrous and anaerobic treatment, 2g (0.0004 mol) of polyethylene glycol monomethyl ether (mPEG 5000, molecular weight of 5000) is weighed, and toluene is used as a solvent for azeotropic reflux for 4h to remove water. The toluene solvent is drained, 30mL of anhydrous dichloromethane is added at room temperature to be fully dissolved, and 0.068g (0.0001 mol) of tetraaminophenylporphyrin with the structure of formula (VI) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in ice bath and protected by nitrogen, 1.1mL (0.0125 mol) of oxalyl chloride is slowly added dropwise by a syringe, and after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. After the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TAPP-NGT.
Example 15
Synthesis of a peraoxamide cross-linked nanogel having the structure of formula (ii) wherein n = a:
the reaction device is subjected to anhydrous and anaerobic treatment, 0.2g (0.0001 mol) of polyethylene glycol monomethyl ether (mPEG 2000, molecular weight 2000) is weighed, and the mixture is subjected to azeotropic reflux for 4 hours by taking toluene as a solvent to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature, and after full dissolution, 0.068g (0.0001 mol) of tetraaminophenylporphyrin with the structure of formula (VI) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in ice bath and protected by nitrogen, 0.5mL (0.005 mol) of oxalyl chloride is added dropwise and slowly by a syringe, after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. And after the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TAPP-NGT.
Example 16
Synthesis of a polyoxamide cross-linked nanogel having the structure of formula (ii) wherein n =2a:
the reaction device is subjected to anhydrous and anaerobic treatment, 0.4g (0.0002 mol) of polyethylene glycol monomethyl ether (mPEG 2000, molecular weight 2000) is weighed, and the mixture is subjected to azeotropic reflux for 4 hours by taking toluene as a solvent to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature, and after full dissolution, 0.068g (0.0001 mol) of tetraaminophenylporphyrin with the structure of formula (VI) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in an ice bath and protected by nitrogen, 0.7mL (0.0075 mol) of oxalyl chloride is slowly added dropwise by a syringe, and after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. After the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TAPP-NGT.
Example 17
Synthesis of a polyoxamide cross-linked nanogel having the structure of formula (ii) wherein n =3a:
the reaction device is subjected to anhydrous and anaerobic treatment, 0.6g (0.0003 mol) of polyethylene glycol monomethyl ether (mPEG 2000, molecular weight 2000) is weighed, and toluene is used as a solvent for azeotropic reflux for 4h to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature to fully dissolve the toluene solvent, and 0.068g (0.0001 mol) of tetraaminophenylporphyrin with the structure of the formula (VI) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in ice bath and protected by nitrogen, 0.9mL (0.01 mol) of oxalyl chloride is slowly added dropwise by a syringe, after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. After the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TAPP-NGT.
Example 18
Synthesis of a polyoxamide cross-linked nanogel having the structure of formula (ii) wherein n =4a:
the reaction device is subjected to anhydrous and anaerobic treatment, 0.8g (0.0004 mol) of polyethylene glycol monomethyl ether (mPEG 2000, molecular weight 2000) is weighed, and the mixture is subjected to azeotropic reflux for 4 hours by taking toluene as a solvent to remove water. The toluene solvent is drained, 20mL of anhydrous dichloromethane is added at room temperature to fully dissolve the toluene solvent, and 0.068g (0.0001 mol) of tetraaminophenylporphyrin with the structure of the formula (VI) and an acid-binding agent are added under the protection of nitrogen. The mixture is cooled in ice bath and protected by nitrogen, 1.1mL (0.0125 mol) of oxalyl chloride is slowly added dropwise by a syringe, and after 4 hours of reaction, the temperature is raised to 25 ℃, and the mixture is stirred and reacted for 24 hours. After the reaction is finished, using frozen ether for settling, dialyzing and freeze-drying to obtain the polymer nanogel TAPP-NGT.
From the above embodiments, the present invention provides a polymer nanogel, a preparation method and applications thereof. The nanogel has a structure shown in a formula (I) or a formula (II): wherein m is more than or equal to 20 and less than or equal to 200. The nanogel provided by the invention is synthesized by a simple one-step method. The material can be in H 2 O 2 In a high-expression tumor microenvironment, the carbonyl group of oxalate or oxamide is exposed to H 2 O 2 The intermediate is decomposed to promote energy to be transferred to acceptor fluorescent molecules through Chemiluminescence Resonance Energy Transfer (CRET), so that the photodynamic efficiency of the unit photosensitizer is comprehensively and remarkably improved, and a better anti-tumor effect is achieved.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (9)

1. A photodynamic enhancement type polymer nanogel is characterized by having a structure shown in a formula (I) or a formula (II) and being prepared from a water-soluble polyethylene glycol monomethyl ether derivative, a porphyrin derivative and oxalyl chloride through a one-step method;
Figure FDA0003802450830000011
wherein m is an integer, and m is more than or equal to 20 and less than or equal to 200;
the structural formula of the porphyrin derivative is as follows:
Figure FDA0003802450830000021
2. the photodynamic reinforced polymer nanogel of claim 1, wherein the porphyrin derivative is tetrahydroxyhexyl ether phenyl porphyrin or tetraaminophenyl porphyrin.
3. The photodynamic reinforced polymer nanogel of claim 1, wherein the polyethylene glycol monomethyl ether derivative is polyethylene glycol monomethyl ether or aminated polyethylene glycol monomethyl ether.
4. The method of claim 1, comprising the steps of:
carrying out nucleophilic substitution reaction on porphyrin derivatives, polyethylene glycol monomethyl ether derivatives and oxalyl chloride in the presence of a catalyst, an acid-binding agent and a solvent, and preparing polymer nanogel by a one-step method;
the molar ratio of the porphyrin derivative, the polyethylene glycol monomethyl ether derivative and the oxalyl chloride is a: n:20 to 25 x (n + a), wherein n =1 to 4 x a.
5. The method for preparing the photodynamic reinforced polymer nanogel as recited in claim 4, wherein the porphyrin derivative is tetrahydroxyhexyl ether phenyl porphyrin or tetraaminophenyl porphyrin; the catalyst is 4-dimethylamino pyridine; the polyethylene glycol monomethyl ether derivative is polyethylene glycol monomethyl ether or aminated polyethylene glycol monomethyl ether; the acid-binding agent is potassium carbonate or triethylamine; the solvent is anhydrous dichloromethane, anhydrous dimethyl sulfoxide or anhydrous N, N-dimethylformamide; the reaction temperature is 0-10 ℃, and the reaction time is 12-72 h.
6. The method for preparing the photodynamic reinforced polymer nanogel as recited in claim 5, wherein the tetrahydroxyhexyl ether phenyl porphyrin is prepared by the following steps:
under the condition that a solvent and a catalyst exist, mixing tetrahydroxyphenyl porphyrin and 6-chloro-1-hexanol according to a certain proportion, washing an obtained reaction product with a sodium hydroxide solution and deionized water in sequence, adjusting the pH value to 7-8, performing suction filtration on the washed reaction product with a Buchner funnel to obtain a dark purple solid, and performing suction drying in a vacuum drier to obtain tetrahydroxyhexyl ether phenyl porphyrin, wherein the reaction equation is as follows:
Figure FDA0003802450830000031
7. the method for preparing the photodynamic reinforced polymer nanogel as claimed in claim 6, wherein the catalyst is sodium iodide, and the solvent is one or more of anhydrous tetrahydrofuran, anhydrous N, N-dimethylformamide or N-methylpyrrolidone; the reaction temperature is 120-160 ℃; the reaction time is 12-36 h.
8. The method of claim 6, wherein the molar ratio of tetrahydroxyphenylporphyrin to 6-chloro-1-hexanol is 1:1 to 10; the structural formula of the tetrahydroxyphenyl porphyrin is shown as a formula VII;
Figure FDA0003802450830000041
9. the use of the photodynamic amplification type polymer nanogel as defined in claim 1 in the preparation of an antitumor drug.
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