CN112876837A - Photoreduction degradation composition and preparation method and application thereof - Google Patents

Abstract

Translated fromChinese

本发明涉及智能材料技术领域，具体涉及一种光还原降解组合物及其制备方法和应用。本发明提供一种光还原降解组合物，其特征在于，所述光还原降解组合物包括还原敏感高分子和改性还原剂，所述改性还原剂为还原剂与含光敏感基团的物质反应得到的物质；所述光还原降解组合物在外部光刺激的作用下由于光敏感基团的脱除原位产生还原剂，该还原剂进一步与还原敏感高分子发生反应使得所述还原敏感高分子实现了还原降解。所得光还原降解组合物在正常还原性生理环境中能够响应细胞内水平的GSH实现还原敏感高分子的还原降解；而在缺乏还原剂的情况下，该光还原降解组合物可以在光照条件原位产生还原剂分子，同样能够实现还原敏感高分子的还原降解。

The invention relates to the technical field of smart materials, in particular to a photoreductive degradation composition and a preparation method and application thereof. The present invention provides a photoreduction degradation composition, characterized in that the photoreduction degradation composition comprises a reduction-sensitive polymer and a modified reducing agent, and the modified reducing agent is a reducing agent and a substance containing a photosensitive group The substance obtained by the reaction; the photoreduction degradation composition generates a reducing agent in situ due to the removal of the photosensitive group under the action of external light stimulation, and the reducing agent further reacts with the reduction-sensitive macromolecule to make the reduction-sensitive high Molecules achieve reductive degradation. The obtained photoreductive degradation composition can realize reductive degradation of reduction-sensitive macromolecules in response to intracellular levels of GSH in a normal reducing physiological environment; and in the absence of a reducing agent, the photoreductive degradation composition can be in situ under light conditions. The production of reducing agent molecules can also achieve the reduction and degradation of reduction-sensitive polymers.

Description

Photoreduction degradation composition and preparation method and application thereof

Technical Field

The invention relates to the technical field of intelligent materials, in particular to a photoreduction degradation composition and a preparation method and application thereof.

Background

The stimulus-responsive polymer materials have attracted great attention in the last decades, and they can receive stimulus signals from the external environment, and make their physical state or chemical structure change greatly, thereby affecting their physicochemical properties and functions, and thus having functions of sensing, processing, executing, etc. The nano self-assembly (micelle, microsphere, vesicle and the like) or hydrogel material prepared from the stimulus-response type high polymer material has wide application prospect in various fields of biosensing, drug release, bioengineering, chemical catalysis and the like.

The polymer nano system with the response capability to physiological endogenous stimuli such as pH, redox and enzyme has higher application value in the aspects of drug and gene delivery and the like, and becomes a research hotspot in the fields of materials science, biomedicine and pharmacy in recent years. However, the use effect of these bio-responsive polymeric materials in vivo faces a number of challenges. First, endogenous stimuli are distributed heterogeneously among different individuals, tissues and organs, and change continuously with the progress of the disease, resulting in an unsatisfactory specificity of the stimulus response. Secondly, due to the complexity of the organism, the levels of stimulatory factors in different cells and organelles are not balanced and are always in a dynamically changing state. In addition, the sustained reaction of the bioresponse material system with the body may further deplete the stimulus, leading to a decrease in response efficiency. More importantly, most of the sensitive bonds of the stimulus response polymer nano material are positioned in the hydrophobic inner core or shielded by the protective shell, so that steric hindrance is brought to the attack of water molecules, Glutathione (GSH), enzymes and other biomacromolecules. Therefore, it is of great interest to design novel smart materials to overcome the spatiotemporal barriers to stimulus response.

The illumination is used as a common exogenous environmental stimulus, can avoid the influence caused by the change of the physiological environment in vivo, has the characteristics of accurately controlling time, position and dosage, high efficiency and the like, and has certain advantages compared with other types of environmental stimuli. However, the existing photosensitive materials change the hydrophilicity and hydrophobicity of macromolecules and the interaction between molecules mainly through the shedding or isomerization of photoresponsive groups, thereby causing the structural change of self-assemblies, and causing the drug release efficiency to be low. The main chain photodegradable polymer can realize the complete degradation of the main chain only by introducing a large amount of photosensitive groups into the main chain of the polymer, thereby having great influence on the physicochemical property and biocompatibility of the matrix and limiting the types of the photosensitive polymers. On the other hand, the existing photosensitive polymer material mainly depends on exogenous stimulation, and cannot make adjustment and cooperative response according to the stimulation level in a living body, so that the intelligence and the response efficiency are to be improved.

Disclosure of Invention

The invention aims to solve the problems in the prior art and provides a photoreduction degradation composition which comprises a reduction sensitive polymer and a reducing agent molecule shielded by a photosensitive group. The photoreduction degradation composition can respond to intracellular GSH to realize the reduction degradation of the reduction sensitive macromolecules in a normal reducing physiological environment; in the absence of a reducing agent, the photoreduction degradation composition can generate reducing agent molecules in situ under the illumination condition, and can also realize the reductive degradation of the reduction sensitive macromolecules.

The technical scheme of the invention is as follows:

the first technical problem to be solved by the invention is to provide a photoreduction degradation composition, which comprises a reduction sensitive polymer and a modified reducing agent, wherein the modified reducing agent is a substance obtained by the reaction of the reducing agent and a substance containing a photosensitive group; the photoreduction degradation composition generates a reducing agent in situ due to the removal of photosensitive groups under the action of external light stimulation, and the reducing agent further reacts with the reduction sensitive polymer to realize the reduction degradation of the reduction sensitive polymer.

Further, the reducing agent is one of dithiothreitol, glutathione, dithioerythritol or beta-mercaptoethanol.

Further, the photosensitive group-containing substance is selected from one of the following compounds:

wherein X is a halogen atom, R₁Is a hydrogen atom or an optional substituent, R₂And R₃Is a hydrogen atom or an alkoxy group, wherein R₂And R₃May be the same or different.

Preferably, the modified reducing agent is selected from one of the following compounds:

in the formula, R is a photosensitive group.

Further, the structural formula of R is as follows:

in the formula, R₁Is a hydrogen atom or an optional substituent, R₂And R₃Is a hydrogen atom or an alkoxy group, wherein R₂And R₃May be the same or different; the dotted line indicates the position of attachment to the reducing agent.

Further, the reduction-sensitive polymer is a polymer compound containing a disulfide group or a diselenide group.

Preferably, the reduction-sensitive polymer is selected from: polyurethanes, polyesters, polyamino acids, polycarbonates, polyureas, polyethers containing disulfide groups or diselenide groups or copolymers of the above-mentioned macromolecules.

The second technical problem to be solved by the present invention is to provide a method for preparing the above-mentioned photo-reductive degradation composition, wherein the preparation method comprises: preparing a self-assembly body by a reduction sensitive polymer and a modified reducing agent through a dialysis method, a solvent volatilization method or an extraction method, and then dialyzing, centrifuging and filtering to obtain the photoreduction degradation composition; the modified reducing agent is a substance obtained by reacting a reducing agent with a substance containing photosensitive groups.

Further, the reducing agent is one of dithiothreitol, glutathione, dithioerythritol or beta-mercaptoethanol.

Further, the photosensitive group-containing substance is selected from one of the following compounds:

wherein X is a halogen atom, R₁Is a hydrogen atomOr an optional substituent, R₂And R₃Is a hydrogen atom or an alkoxy group, wherein R₂And R₃May be the same or different.

Further, the reduction-sensitive polymer is a polymer compound containing a disulfide group or a diselenide group.

Preferably, the reduction-sensitive polymer is selected from: polyurethanes, polyesters, polyamino acids, polycarbonates, polyureas, polyethers containing disulfide groups or diselenide groups or copolymers of the above-mentioned macromolecules.

Further, the modified reducing agent is selected from one of the following compounds:

in the formula, R is a photosensitive group.

Further, the structural formula of R is as follows:

in the formula, R₁Is a hydrogen atom or an optional substituent, R₂And R₃Is a hydrogen atom or an alkoxy group, wherein R₂And R₃May be the same or different; the dotted line indicates the position of attachment to the reducing agent.

Furthermore, in the above method, an auxiliary substance may be further added to the reduction-sensitive polymer and the modified reducing agent, wherein the auxiliary substance is selected from: an up-conversion material or a photo-thermal material.

The third technical problem to be solved by the present invention is to provide the use of the above-mentioned photoreductive degradation composition for biosensing or controlled drug release.

The fourth technical problem to be solved by the present invention is to provide a method for improving the response efficiency of a reduction-sensitive polymer self-assembly, wherein the method comprises: preparing a photoreduction degradation composition by coating a modified reducing agent in a core of a reduction sensitive high-molecular self-assembly, wherein the modified reducing agent is a substance obtained by reacting the reducing agent with a substance containing a photosensitive group; the obtained photoreduction degradation composition generates a reducing agent in situ due to the removal of the photosensitive group under the action of external light stimulation, and the reducing agent further reacts with the reduction sensitive polymer to realize the reduction degradation of the reduction sensitive polymer.

Further, the method for improving the response efficiency of the reduction-sensitive polymer self-assembly body specifically comprises the following steps: preparing the reduction sensitive polymer and the modified reducing agent into a self-assembly body by a dialysis method, a solvent volatilization method or an extraction method, and then preparing the photoreduction degradation composition by dialysis, centrifugation and filtration.

The fifth technical problem to be solved by the invention is to provide a method for realizing photodegradation of a non-photosensitive polymer, which comprises the following steps: preparing a self-assembly body by a non-photosensitive reduction sensitive polymer and a modified reducing agent through a dialysis method, a solvent volatilization method or an extraction method, and then dialyzing, centrifuging and filtering to obtain a photoreduction degradation composition, wherein the modified reducing agent is a substance obtained by reacting the reducing agent with a substance containing a photosensitive group; the photoreduction degradation composition generates a reducing agent in situ due to the removal of photosensitive groups under the action of external light stimulation, and the reducing agent further reacts with the reduction sensitive polymer to realize the reduction degradation of the non-photosensitive reduction sensitive polymer.

The invention has the beneficial effects that:

compared with the prior art, the invention has the following advantages:

(1) the invention provides a photoreduction degradation composition, which comprises a reduction sensitive polymer and a modified reducing agent (a reducing agent molecule shielded by a photosensitive group). The photoreduction degradation composition can respond to intracellular GSH to realize the reduction degradation of the reduction sensitive macromolecules in a normal reducing physiological environment; in the absence of reducing agents, the photoreduction degradation composition can release reducing agent molecules in situ under the illumination condition, and can also realize the reductive degradation of the reduction sensitive macromolecules. Therefore, the composition of the invention solves the problems of timing fixed point and response as required, overcomes the problems of steric hindrance, permeability obstacle, concentration obstacle and the like of stimulus response, obtains higher response efficiency than the traditional reduction sensitive and photosensitive material, and requires far lower stimulus source concentration than an external reducing agent.

(2) The photoreduction degradation composition comprises macromolecules without photosensitive groups, but can realize the reductive degradation under the stimulation of illumination, thereby realizing the photodegradation of non-photosensitive macromolecules. The method avoids the need of introducing complex photodegradation groups into the polymer structure of the traditional photoresponse macromolecules, thereby having simpler preparation method and better biocompatibility, and being convenient for popularization and application.

(3) The photoreduction degradation composition can realize the near infrared light triggered reduction degradation by compounding with an up-conversion material or a photo-thermal material, or further improve the reduction response rate through the photo-thermal effect.

(4) The photoreduction degradation composition can controllably release reducing agent in situ in physiological environment (such as focus parts or inflammatory parts), thereby changing local physiological microenvironment and playing roles in resisting oxidation, assisting in treating diseases and the like.

(5) The photoreduction degradation composition provided by the invention can be photoreduction degraded into small molecular substances, has higher biocompatibility and is easy to be eliminated and metabolized by organisms.

(6) The photoreduction degradation composition provided by the invention can be widely applied to the biomedical fields and industrial fields of biosensing, drug controlled release, disease treatment and the like.

Drawings

FIG. 1 is an FTIR spectrum of the photo-reductive degradation composition 1 prepared in example 1 under UV illumination for different time periods: a-0min, b-15min, c-30min, d-60min and e-120 min.

FIG. 2 is a graph of the UV absorption spectra of the tetrahydrofuran solution of the photoreductive self-degradingcomposition 1 prepared in example 1 at various time points of illumination.

FIG. 3 is a graph of fluorescence spectra of the photo-reductive degradation composition 1 prepared in example 1 after loading with Nile Red under UV light for various periods of time.

FIG. 4 is a graph of fluorescence spectra of the photo-reductive degradation composition 1 prepared in example 1 loaded with Nile Red at various times after addition of 0.01mM reducing agent DTT.

FIG. 5 is a plot of the release rate of nile red versus time (a for light and b for added DTT) after nile red was encapsulated in the photo-reductive degradation composition 1 prepared in example 1.

Detailed Description

The mechanism of the invention is as follows:

takingembodiment 1 as an example, the present invention provides a photoreduction degradation composition, which comprises a light-sensitive o-nitrobenzene (ONB) group modified Dithiothreitol (DTT) reducing agent and a reduction-sensitive polyurethane comprising disulfide bonds; the photoreductive degradation composition is capable of effecting cleavage of the backbone in response to intracellular levels of GSH (10mM) in a normal reducing physiological environment; under the condition of lacking the reducing agent, the polymer can be subjected to ONB removal under the illumination condition, the reducing agent molecule DTT is generated in situ and attacks the reduction-sensitive polyurethane containing the disulfide bond, and the reduction degradation of the reduction-sensitive polyurethane can be further realized.

The photoreductive degradation composition provided in example 1 can generate a reducing agent DTT under the stimulation of external light; because DTT is generated in situ near disulfide groups of the hydrophobic core of the self-assembly, steric hindrance and permeability barriers can be effectively overcome, the stimulation response efficiency is greatly improved, and the reduction degradation efficiency higher than that of an external reducing agent (10mM DTT) is obtained. Furthermore, the concentration of in situ generated DTT (0.1mM) required to achieve reductive degradation is much lower than the concentration of the added DTT reducing agent (10mM), overcoming the concentration limitation of the stimulus response.

In addition, the photoreduction degradation composition provided inembodiment 1 of the present invention does not need to introduce an ONB group into a molecular chain of the reduction-sensitive polyurethane, but can achieve the main chain light-triggered degradation of the reduction-sensitive polyurethane, and avoid the need of introducing a complex photodegradation group into a molecular chain of a conventional photodegradation polymer.

The following examples are given to illustrate the present invention, but it should be understood that the following examples are only for illustrative purposes and are not to be construed as limiting the scope of the present invention, and that the present invention may be modified and modified by those skilled in the art in a manner that is not essential to the invention as described above.

Example 1

This example preparedphotoreductive degradation composition 1.

Dissolving dithiothreitol (3.08g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; dropwise adding an ethanol solution (40mL) of 2-nitrobenzyl bromide (10.3g), naturally returning to room temperature for reaction for 6 hours, filtering the generated precipitate, freeze-drying, and storing in the dark to obtain the modified reducingagent 1.

Dissolving a modified reducing agent 1(3mg) and polyurethane (10mg) containing disulfide bonds into N, N-dimethylformamide (1mL), slowly dropwise adding the modified reducing agent and the polyurethane into rapidly stirred deionized water (9mL) at the speed of 30s/d, and continuously stirring for half an hour after dropwise adding; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; then, the liquid was centrifuged (3500r/min), filtered (0.45 μm), and the volume was determined to obtain aphotoreduction degradation composition 1.

Example 2

This example prepared photoreductive degradation composition 2.

Dissolving dithioerythritol (3.08g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; dropwise adding an ethanol solution (40mL) of 2- (1-bromobutyl) -1, 3-dinitrobenzene (13.9g), naturally returning to room temperature for reaction for 6 hours, filtering the generated precipitate, freeze-drying, and storing in the dark to obtain the modified reducing agent 2.

Dissolving a modified reducing agent 2(5mg) and polyurethane (10mg) containing diselenide bonds into tetrahydrofuran (1mL) together, slowly dropwise adding the modified reducing agent into rapidly-stirred deionized water (9mL) at the speed of 30s/d, and continuously stirring overnight after dropwise adding is finished, so that the tetrahydrofuran is completely volatilized; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; then the liquid was centrifuged (3500r/min), filtered (0.45 μm), and the volume was determined to obtain a photoreduction degradation composition 2.

Example 3

This example prepared photoreductive degradation composition 3.

Dissolving glutathione (6.14g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; an ethanol solution (40mL) of N-dodecyl-2-iodo-2- (6-nitro-3, 4-methylenedioxybenzene) -acetamide (9.1g) was added dropwise, the mixture was naturally returned to room temperature for reaction for 6 hours, and the product was concentrated, precipitated with diethyl ether, purified by column chromatography, and stored away from light to obtain a modified reducing agent 3.

Dissolving a modified reducing agent 3(10mg) in acetone, adding the solution into a small bottle, and drying the small bottle by using nitrogen; then adding polyester-polyethylene glycol copolymer micelle (10mL) containing disulfide bonds, and carrying out ultrasonic treatment for 4 hours; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; then, the liquid was centrifuged (3500r/min), filtered (0.45 μm), and the volume was determined to obtain a photoreduction degradation composition 3.

Example 4

This example prepared photoreductive degradation composition 4.

Dissolving beta-mercaptoethanol (1.56g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; dropwise adding an ethanol solution (40mL) of 2-decaethoxymethoxy chloromethyl-3-nitronaphthalene (16.6g), naturally returning to room temperature for reaction for 12 hours, concentrating the product, purifying by using column chromatography, and storing in dark place to obtain the modified reducing agent 4.

Dissolving a modified reducing agent 4(12mg) and polyurethane (10mg) containing disulfide bonds into N, N-dimethylacetamide (1mL), slowly dropwise adding the modified reducing agent 4 and the polyurethane at a speed of 30s/d into rapidly-stirred deionized water (9mL), and continuously stirring for half an hour after dropwise adding; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; then the liquid was centrifuged (3500r/min), filtered (0.45 μm), and the volume was determined to obtain a photoreduction degradation composition 4.

Example 5

This example prepared photoreductive degradation composition 5.

Dissolving dithiothreitol (3.08g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; and (3) dropwise adding an ethanol solution (40mL) of 1-bromomethylpyrene (14.3g), naturally returning to room temperature for reaction for 12 hours, carrying out suction filtration on the generated precipitate, freeze-drying, and storing in a dark place to obtain the modified reducing agent 5.

Dissolving a modified reducing agent 5(8mg) and polyamino acid (10mg) containing disulfide bonds into dioxane (1mL), slowly dropwise adding the modified reducing agent into rapidly stirred deionized water (9mL) at the speed of 30s/d, and continuously stirring for half an hour after dropwise adding; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; then, the liquid was centrifuged (3500r/min), filtered (0.45 μm), and the volume was determined to obtain a photoreduction degradation composition 5.

Example 6

This example prepared a photoreductive degradation composition 6.

Dissolving dithiothreitol (3.08g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; dropwise adding an ethanol solution (40mL) of 4-bromomethylcoumarin (11.5g), naturally returning to room temperature for reaction for 6 hours, carrying out suction filtration on the generated precipitate, freeze-drying, and storing in the dark to obtain the modified reducing agent 6.

Dissolving a modified reducing agent 6(4mg) and polycarbonate (10mg) containing disulfide bonds into N, N-dimethylformamide (1mL), slowly dropwise adding the modified reducing agent into rapidly stirred deionized water (9mL) at the speed of 30s/d, and continuously stirring for half an hour after dropwise adding; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; then the liquid was centrifuged (3500r/min), filtered (0.45 μm), and the volume was determined to obtain a photoreduction degradation composition 6.

Example 7

This example prepared a photoreductive degradation composition 7.

Dissolving dithiothreitol (3.08g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; dropwise adding an ethanol solution (40mL) of 2-bromo-1- (4-methoxyphenyl) ethanone (10.9g), naturally returning to room temperature for reaction for 6 hours, carrying out suction filtration on the generated precipitate, purifying by using column chromatography, and storing in the dark to obtain the modified reducing agent 7.

Dissolving a modified reducing agent 7(1mg) and polyurea (10mg) containing disulfide bonds into N, N-dimethylformamide (1mL), slowly dropwise adding the modified reducing agent and the polyurea into rapidly stirred deionized water (9mL) at the speed of 30s/d, and continuously stirring for half an hour after dropwise adding; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; then the liquid is centrifuged (3500r/min), filtered (0.45 μm) and the volume is determined to obtain the photoreduction degradation composition 7.

Example 8

This example prepared a photoreductive degradation composition 8.

Dissolving dithiothreitol (3.08g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; dropwise adding an ethanol solution (40mL) of 1-bromomethyl-2-nitro-4-decaethoxymethoxy-5-tetradecyloxybenzene (43.08g), naturally returning to room temperature for reaction for 6 hours, concentrating the product, purifying by using column chromatography, and storing in dark place to obtain the modified reducing agent 8.

Dissolving a modified reducing agent 8(8mg) and polyamino ester (10mg) containing disulfide bonds into N, N-dimethylformamide (1mL), slowly dropwise adding the modified reducing agent into rapidly stirred deionized water (9mL) at the speed of 30s/d, and continuously stirring for half an hour after dropwise adding; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; then the liquid was centrifuged (3500r/min), filtered (0.45 μm), and the volume was determined to obtain a photoreduction degradation composition 8.

Example 9

This example prepared a photoreductively degradable composition 9.

Dissolving dithiothreitol (3.08g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; dropwise adding an ethanol solution (40mL) of 2-bromomethyl-4-methoxy-5-tetradecyloxy-1, 3-dinitrobenzene (20.1g), naturally returning to room temperature for reaction for 6 hours, filtering the generated precipitate, freeze-drying, and storing in the dark to obtain the modified reducing agent 9.

Dissolving a modified reducing agent 9(6mg) and polyurethane (10mg) containing disulfide bonds into N, N-dimethylformamide (1mL), slowly dropwise adding the modified reducing agent into rapidly stirred deionized water (9mL) at the speed of 30s/d, and continuously stirring for half an hour after dropwise adding; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; then, the liquid was centrifuged (3500r/min), filtered (0.45 μm), and the volume was determined to obtain a photoreduction degradation composition 9.

Example 10

This example prepared a photoreductive degradation composition 10.

Dissolving dithiothreitol (3.08g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; dropwise adding an ethanol solution (40mL) of 2-nitro-3-iodomethyl-6-methoxynaphthalene (16.5g), naturally returning to room temperature for reaction for 6 hours, and carrying out suction filtration, freeze-drying and light-shielding storage on the generated precipitate to obtain the modified reducing agent 10.

Dissolving a modified reducing agent 10(3mg) and polyurethane (10mg) containing disulfide bonds into N, N-dimethylformamide (1mL), slowly dropwise adding the modified reducing agent into rapidly stirred deionized water (9mL) at the speed of 30s/d, and continuously stirring for half an hour after dropwise adding; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; then the liquid is centrifuged (3500r/min), filtered (0.45 μm) and subjected to constant volume to obtain the photoreduction degradation composition 10.

Example 11

This example prepared a photoreductively degradable composition 11.

Dissolving dithiothreitol (3.08g) in an ethanol solution (40mL) of NaOH, and cooling in an ice bath; dropwise adding an ethanol solution (40mL) of 2-nitrobenzyl bromide (10.3g), naturally returning to room temperature for reaction for 6 hours, filtering the generated precipitate, freeze-drying, and storing in the dark to obtain the modified reducing agent 11.

Dispersing n-hexane dispersion (0.2mL, 5mg/mL) of a modified reducing agent 11(3mg), oil-soluble core-shell type up-conversion nanoparticles (material components: NaYF4, Yb, Tm @ NaYF4) and polyurethane (10mg) containing disulfide bonds in tetrahydrofuran (2mL) together, slowly dropwise adding the mixture into rapidly stirred deionized water (9mL) at the speed of 30s/d, and continuously stirring for half an hour after dropwise adding; then transferring the liquid into a dialysis bag with the molecular weight cutoff of 3500, dialyzing in deionized water for 3 days, and changing water every 3 hours; the liquid was then centrifuged (3500r/min), filtered (0.45 μm), and the volume was determined to obtain the photoreduction degradation composition 11.

Application example 1

This application example was conducted to investigate the stimulus response properties of thephotoreduction degradation composition 1 prepared in example 1.

Coating thephotoreduction degradation composition 1 prepared in example 1 on a potassium bromide salt tablet; carrying out ultraviolet illumination on the salt film, and carrying out Fourier transform infrared spectroscopy (FTIR) test at different illumination time points; the results are shown in FIG. 1; from the FTIR spectrum of FIG. 1, 1700cm^-1The characteristic peak of the carbonyl group is gradually enhanced along with the illumination, which indicates that the aldehyde carbonyl group is generated by the shedding of the photosensitive group. In order to study the dynamic process of the photo-degradation, the tetrahydrofuran solution of the photo-reductive self-degradation composition 1 is subjected to ultraviolet irradiation, and an ultraviolet-visible spectrophotometer is used for testing, and the result is shown in fig. 2, the absorbance of the solution of the photo-reductive self-degradation composition 1 in fig. 2 shows a new peak at 307nm along with the irradiation, and the intensity of the absorption peak does not increase along with the irradiation time and reaches the highest point in about 120 minutes, which indicates that the photo-reductive degradation composition 1 has good photo-responsiveness.

Application example 2

This application example was conducted to investigate the controlled release properties of the stimulus responsive drug of thephotoreduction degradation composition 1 prepared in example 1.

Nile red drug model was entrapped using thephotoreduction degradation composition 1 prepared in example 1; carrying out ultraviolet illumination or external DTT treatment on the drug-loaded self-assembly body, and measuring the change of the Nile red fluorescence intensity along with time by using a fluorescence spectrophotometer; FIG. 3 is a graph of the fluorescence spectra of a photo-reductive degradation composition 1 loaded with Nile Red under UV illumination for different periods of time; FIG. 4 is a graph of fluorescence spectra of a photo-reductive degradation composition 1 loaded with Nile Red at various times after addition of a reducing agent DTT at 0.01 mM; FIG. 5 is a plot of nile red release rate versus time (a for light and b for added DTT).

As can be seen from fig. 3 and fig. 5, under the condition of extremely low concentration (0.01mM) of the reducing agent molecule shielded by the photosensitive group, nile red fluorescence still shows a significant decrease, and still shows good controlled release performance; while with the addition of 0.01mM reducing agent DTT, the fluorescence intensity was almost unchanged, indicating that no nile red molecule was released (FIGS. 4 and 5). The photoreduction degradation composition can overcome steric hindrance and concentration obstacle, improve the efficiency of stimulus sensitivity and drug controlled release, and has response efficiency higher than that of the traditional reduction sensitive polymer system and required stimulus concentration threshold far lower than that of the traditional reduction response system (10 mM).

Claims (10)

Translated fromChinese

1.一种光还原降解组合物，其特征在于，所述光还原降解组合物包括还原敏感高分子和改性还原剂，所述改性还原剂为还原剂与含光敏感基团的物质反应得到的物质；所述光还原降解组合物在外部光刺激的作用下由于光敏感基团的脱除原位产生还原剂，该还原剂进一步与还原敏感高分子发生反应使得所述还原敏感高分子实现了还原降解。1. A photoreduction degradation composition, characterized in that the photoreduction degradation composition comprises a reduction-sensitive macromolecule and a modified reducing agent, and the modified reducing agent is the reaction of a reducing agent with a substance containing a light-sensitive group The obtained substance; the photoreduction degradation composition generates a reducing agent in situ due to the removal of the photosensitive group under the action of external light stimulation, and the reducing agent further reacts with the reduction-sensitive macromolecule to make the reduction-sensitive macromolecule Reductive degradation was achieved.2.根据权利要求1所述的光还原降解组合物，其特征在于，所述还原剂为二硫苏糖醇、谷胱甘肽、二硫赤藓醇或β-巯基乙醇中的一种；2. The photoreduction degradation composition according to claim 1, wherein the reducing agent is one of dithiothreitol, glutathione, dithioerythritol or β-mercaptoethanol;进一步，所述含光敏感基团的物质选自下述化合物中的一种：Further, the substance containing the photosensitive group is selected from one of the following compounds:

式中X为卤原子，R₁为氢原子或任意取代基，R₂和R₃为氢原子或烷氧基，其中R₂和R₃可以相同，也可以不同；In the formula, X is a halogen atom, R₁ is a hydrogen atom or any substituent, R₂ and R₃ are hydrogen atoms or alkoxy groups, wherein R₂ and R₃ can be the same or different;进一步，所述还原敏感高分子为含二硫基或二硒基的高分子化合物；Further, the reduction-sensitive polymer is a polymer compound containing a disulfide group or a diselenyl group;优选的，所述还原敏感高分子选自：含有二硫基或二硒基的聚氨酯、聚酯、聚氨基酸、聚碳酸酯、聚脲、聚醚或上述高分子的共聚物。Preferably, the reduction-sensitive macromolecule is selected from: polyurethane, polyester, polyamino acid, polycarbonate, polyurea, polyether or copolymers of the above macromolecules containing a disulfide group or a diselenide group.3.根据权利要求1所述的光还原降解组合物，其特征在于，所述改性还原剂选自下述化合中的一种：3. The photoreduction degradation composition according to claim 1, wherein the modified reducing agent is selected from one of the following compounds:

式中，R为光敏感基团；In the formula, R is a photosensitive group;进一步，所述R的结构式为：Further, the structural formula of the R is:

式中，R₁为氢原子或任意取代基，R₂和R₃为氢原子或烷氧基，其中R₂和R₃可以相同，也可以不同；虚线表示和还原剂的连接位置。In the formula, R₁ is a hydrogen atom or any substituent, R₂ and R₃ are hydrogen atoms or alkoxy groups, wherein R₂ and R₃ can be the same or different; the dotted line represents the connection position with the reducing agent.4.权利要求1～3任一项所述的光还原降解组合物的制备方法，其特征在于，所述制备方法为：将还原敏感高分子和改性还原剂通过透析法、溶剂挥发法或萃取法制备成自组装体，然后经透析、离心和过滤，得到所述光还原降解组合物；其中，所述改性还原剂为还原剂与含光敏感基团的物质反应得到的物质。4. The preparation method of the photoreductive degradable composition according to any one of claims 1 to 3, wherein the preparation method is: passing the reduction-sensitive polymer and the modified reducing agent through a dialysis method, a solvent volatilization method or a The self-assembly is prepared by an extraction method, and then the photoreduction degradation composition is obtained by dialysis, centrifugation and filtration; wherein, the modified reducing agent is a material obtained by reacting a reducing agent with a substance containing a photosensitive group.5.根据权利要求4所述的光还原降解组合物的制备方法，其特征在于，所述还原剂为二硫苏糖醇、谷胱甘肽、二硫赤藓醇或β-巯基乙醇中的一种；5. The preparation method of photoreduction degradation composition according to claim 4, wherein the reducing agent is dithiothreitol, glutathione, dithioerythritol or β-mercaptoethanol. A sort of;所述含光敏感基团的物质选自下述化合物中的一种：The substance containing the photosensitive group is selected from one of the following compounds:

式中X为卤原子，R₁为氢原子或任意取代基，R₂和R₃为氢原子或烷氧基，其中R₂和R₃可以相同，也可以不同；In the formula, X is a halogen atom, R₁ is a hydrogen atom or any substituent, R₂ and R₃ are hydrogen atoms or alkoxy groups, wherein R₂ and R₃ can be the same or different;进一步，所述还原敏感高分子为含二硫基或二硒基的高分子化合物；优选的，所述还原敏感高分子选自：含有二硫基或二硒基的聚氨酯、聚酯、聚氨基酸、聚碳酸酯、聚脲、聚醚或上述高分子的共聚物；Further, the reduction-sensitive macromolecule is a polymer compound containing a disulfide group or a diselenide group; preferably, the reduction-sensitive macromolecule is selected from: polyurethane, polyester, polyamino acid containing a disulfide group or a diselenide group , Polycarbonate, polyurea, polyether or copolymers of the above polymers;进一步，所述改性还原剂选自下述化合中的一种：Further, the modified reducing agent is selected from one of the following compounds:

式中，R为光敏感基团；In the formula, R is a photosensitive group;进一步，所述R的结构式为：Further, the structural formula of the R is:

式中，R₁为氢原子或任意取代基，R₂和R₃为氢原子或烷氧基，其中R₂和R₃可以相同，也可以不同；虚线表示和还原剂的连接位置。In the formula, R₁ is a hydrogen atom or any substituent, R₂ and R₃ are hydrogen atoms or alkoxy groups, wherein R₂ and R₃ can be the same or different; the dotted line represents the connection position with the reducing agent.6.根据权利要求4或5所述的光还原降解组合物的制备方法，其特征在于，所述还原敏感高分子和改性还原剂中还可以加入辅助物质，所述辅助物质选自：上转换材料或光热材料。6. The preparation method of the photoreduction degradation composition according to claim 4 or 5, characterized in that, auxiliary substances can also be added to the reduction-sensitive polymer and the modified reducing agent, and the auxiliary substances are selected from: Conversion materials or photothermal materials.7.光还原降解组合物用于生物传感或药物控释中，其中，所述光还原降解组合物为权利要求1～3任一项所述的光还原降解组合物，或为采用权利要求4～6任一项所述的方法制得的光还原降解组合物。7. The photoreductive degradation composition is used in biosensing or controlled drug release, wherein the photoreductive degradation composition is the photoreductive degradation composition of any one of claims 1 to 3, or the photoreductive degradation composition according to claim 1. The photoreduction degradable composition prepared by the method of any one of 4 to 6.8.一种提高还原敏感高分子自组装体响应效率的方法，其特征在于，所述方法为：通过在还原敏感高分子自组装体内核包载改性还原剂制得一种光还原降解组合物，所述改性还原剂为还原剂与含光敏感基团的物质反应得到的物质；所得光还原降解组合物在外部光刺激的作用下由于光敏感基团的脱除原位产生还原剂，该还原剂进一步与还原敏感高分子发生反应使得所述还原敏感高分子实现了还原降解。8. A method for improving the response efficiency of a reduction-sensitive polymer self-assembly, wherein the method is: preparing a photoreduction degradation combination by encapsulating a modified reducing agent in the core of the reduction-sensitive polymer self-assembly The modified reducing agent is a substance obtained by reacting a reducing agent with a substance containing a photosensitive group; the obtained photoreduction and degradation composition generates a reducing agent in situ due to the removal of the photosensitive group under the action of external light stimulation , the reducing agent further reacts with the reduction-sensitive macromolecule, so that the reduction-sensitive macromolecule achieves reductive degradation.9.根据权利要求8所述的提高还原敏感高分子自组装体响应效率的方法，其特征在于，所述提高还原敏感高分子自组装体响应效率的方法为：将还原敏感高分子和改性还原剂通过透析法、溶剂挥发法或萃取法制备成自组装体，然后经透析、离心和过滤制得所述光还原降解组合物。9 . The method for improving the response efficiency of a reduction-sensitive polymer self-assembly according to claim 8 , wherein the method for improving the response efficiency of a reduction-sensitive polymer self-assembly is: combining the reduction-sensitive polymer and modified The reducing agent is prepared into self-assembled body by dialysis method, solvent evaporation method or extraction method, and then the photoreduction degradation composition is prepared by dialysis, centrifugation and filtration.10.一种非光敏感高分子实现光降解的方法，其特征在于，所述方法为：通过将非光敏感的还原敏感高分子和改性还原剂通过透析法、溶剂挥发法或萃取法制备得到自组装体，然后经透析、离心和过滤，进而得到光还原降解组合物，所述改性还原剂为还原剂与含光敏感基团的物质反应得到的物质；该光还原降解组合物在外部光刺激的作用下由于光敏感基团的脱除原位产生还原剂，该还原剂进一步与还原敏感高分子发生反应使得所述非光敏感的还原敏感高分子实现了还原降解。10. A method for realizing photodegradation of a non-photosensitive polymer, characterized in that the method is: preparing a non-photosensitive reduction-sensitive polymer and a modified reducing agent by a dialysis method, a solvent volatilization method or an extraction method The self-assembly is obtained, and then dialysis, centrifugation and filtration are carried out to obtain a photoreduction degradation composition, and the modified reducing agent is a substance obtained by reacting a reducing agent with a substance containing a photosensitive group; the photoreduction degradation composition is in Under the action of external light stimulation, a reducing agent is generated in situ due to the removal of the light-sensitive group, and the reducing agent further reacts with the reduction-sensitive polymer, so that the non-light-sensitive reduction-sensitive polymer achieves reduction degradation.

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