CN112250888B

CN112250888B - X-ray development thermotropic hydrogel and preparation method and application thereof

Info

Publication number: CN112250888B
Application number: CN202011011594.8A
Authority: CN
Inventors: 俞麟; 吴晓慧; 王欣; 丁建东
Original assignee: Fudan University; Zhuhai Fudan Innovation Research Institute
Current assignee: Fudan University; Zhuhai Fudan Innovation Research Institute
Priority date: 2020-09-23
Filing date: 2020-09-23
Publication date: 2022-04-01
Anticipated expiration: 2040-09-23
Also published as: CN112250888A

Abstract

The invention belongs to the technical field of biomedical high polymer materials, and discloses an X-ray developing thermotropic hydrogel and a preparation method and application thereof. The invention utilizes the synthesized iodic polycarbonate polymer as a macromolecular developer to be blended with the thermally gelled amphiphilic block polymer, and the iodic polycarbonate macromolecules are uniformly dispersed in a water system through the solubilization of the amphiphilic block polymer, so that the thermally induced hydrogel system with X-ray developing capability is obtained. The system is sol with good fluidity at normal temperature, forms gel in situ at body temperature after being injected into a body, has excellent X-ray developing performance, can obtain parameters such as three-dimensional appearance, volume and the like of the thermally induced hydrogel in vivo by a CT imaging technology and a three-dimensional reconstruction technology, and provides an intuitive technical means for in-situ visual detection and nondestructive tracing of the thermally induced hydrogel in vivo.

Description

X-ray development thermotropic hydrogel and preparation method and application thereof

Technical Field

The invention belongs to the technical field of biomedical high polymer materials, and particularly relates to an X-ray developing thermotropic hydrogel and a preparation method and application thereof.

Background

The thermotropic hydrogel based on the amphiphilic block copolymer is a polymer aqueous system with a three-dimensional network structure and taking water as a main dispersion medium, and the characteristics of the thermotropic hydrogel comprise sol-gel phase transition, biocompatibility and biodegradability. The hydrogel can be injected at low temperature due to the temperature-sensitive characteristic, can be rapidly formed into gel in situ at an implanted part after being injected into a body, has the characteristics of convenient use, minimal invasion and the like, has simple synthesis of a block copolymer and adjustable structure and performance, and is widely used in the biomedical fields such as drug delivery, wound repair, tissue regeneration and the like. In addition, the amphiphilic block copolymer can spontaneously form micelles with a core-shell structure in water, and can solubilize other hydrophobic molecules or drugs.

It is worth noting that the degradation behavior of the thermotropic hydrogel material based on the amphiphilic block copolymer when the thermotropic hydrogel material plays a role in vivo has a close influence on the effects of controlled release of drugs and tissue repair. Therefore, mastering the degradation process in vivo and revealing the degradation mechanism are crucial to better exploit the application of thermotropic hydrogels in the biomedical field. The research methods of the in vivo degradation behavior of the material can be classified into invasive and non-invasive. Invasive research, namely anatomical observation, has the defects of high animal consumption and high cost, and non-invasive observation mainly utilizes in-vivo imaging technical means such as fluorescence imaging, magnetic resonance imaging and CT imaging to carry out nondestructive tracing on materials implanted in animals. Among them, CT imaging is favored because of its deep imaging depth and high resolution. CT imaging shows the structure of an object according to the degree of absorption of X-rays by the object, and a common thermal hydrogel material only contains C, H, O, N elements with relatively low atomic mass, so that the X-rays are absorbed weakly, and the imaging detection under CT is difficult. In order to make the thermal hydrogel have X-ray development performance, the thermal hydrogel material can be modified or modified in the following two ways.

There are two ways to prepare thermotropic hydrogels with X-ray developability-physical and chemical methods. The physical method is that small molecules/polymers with imaging capability are introduced into a system in an encapsulation or blending mode to form a uniform and stable whole, so that the whole material has imaging capability; and the chemical method means that a developing group is introduced into a polymer by a method such as polymerization, grafting, end group modification or surface modification, and the like, so that the polymer has imaging capability. The way of encapsulating or blending small molecule imaging contrast agents in physical methods may allow visualization of the thermal hydrogel material, but the thermal hydrogel material is only visible for a short period of time due to the rapid diffusion of the small molecule imaging contrast agents in vivo, and the rapid leakage of the small molecule imaging contrast agents may also cause potential systemic toxicity. A chemical method, namely a group with the X-ray developing characteristic is introduced into a molecular chain of the amphiphilic block copolymer with the temperature-sensitive characteristic, so that the original temperature-sensitive characteristic of the polymer is possibly damaged, and the difficulty and the cost for directly constructing the amphiphilic block polymer with the X-ray developing performance and the temperature-sensitive characteristic are high.

Currently, a thermal gel system for X-ray development is only reported, and patent CN104645356B discloses a method for preparing an X-ray development thermal hydrogel by modifying a PEG/polyester block copolymer with an iodine-containing small molecular material. However, the iodine content that this method can introduce is still relatively very limited and X-ray visualization of the gel must be achieved by increasing the overall concentration of the polymer.

Therefore, it is an urgent need to develop a macromolecular contrast agent that can be blended with various thermal gelation amphiphilic block polymers so that the iodine-containing macromolecular contrast agent can be uniformly dispersed in an aqueous system by the solubilization of the amphiphilic block polymers, and the iodine content can be increased while the thermal gelation properties of the system are considered.

Disclosure of Invention

In view of the above, the first object of the present invention is to provide an amphiphilic iodine-containing polycarbonate-based polymer with ultra-high iodine content (more than 50 wt%) as a macromolecular imaging contrast agent, and uniformly disperse the iodine-containing polycarbonate macromolecules in the system through the solubilization of the amphiphilic block polymer for thermal gelation, so as to improve the iodine content and simultaneously achieve the thermal gelation properties of the system.

In order to achieve the purpose, the invention adopts the following technical scheme:

an X-ray developing thermotropic hydrogel comprises 5-20% of iodine-containing polycarbonate polymer, 5-40% of amphiphilic block copolymer and the balance of solvent.

Considering that the temperature-sensitive characteristic of a group with X-ray development property is possibly damaged by covalently introducing the group with the X-ray development property into the amphiphilic block copolymer, the water-soluble micromolecule imaging contrast agent is blended/encapsulated into the thermotropic hydrogel system and cannot be seen for a long time, and the potential systemic toxicity is also caused by the quick leakage of the micromolecule imaging contrast agent, the invention selects the blending of the macromolecular imaging contrast agent and the thermotropic gelatinized amphiphilic block polymer, and the iodine-containing polycarbonate macromolecules are uniformly dispersed in a water system by utilizing the solubilization of the amphiphilic block polymer, so that the thermotropic hydrogel system with excellent X-ray development capability is obtained. Therefore, the problem that the small molecule imaging contrast agent cannot be developed for a long time due to rapid diffusion is avoided, and the thermal gelation property of the system can be maintained while the iodine content of the system is effectively ensured.

It is worth to say that the X-ray development thermotropic hydrogel is a system formed by blending an iodine-containing polycarbonate polymer, an amphiphilic block copolymer and a solvent which takes water as a main dispersion medium; the system has temperature-sensitive characteristic, is a flowing liquid when the temperature is lower than the sol-gel phase transition temperature, has good injectability, and is spontaneously transformed into semisolid hydrogel when the temperature is higher than the sol-gel phase transition temperature; meanwhile, the sol-gel phase transition temperature of the system is between 4 and 37 ℃.

Further, the iodine containing polycarbonate polymer has the structure:

wherein, x is 12-45, and y is 2-20.

It is worth to be noted that, the pure iodine-containing polycarbonate polymer is very strong in hydrophobicity, the invention introduces the PEG component with lower molecular weight (550-2000) into the iodine-containing polycarbonate polymer to give certain amphipathy to the macromolecular contrast agent on the premise of not weakening the iodine content of the iodine-containing polycarbonate polymer remarkably, so that the synthesized macromolecular contrast agent can be blended with various thermally-gelled amphiphilic block polymers, and the iodine-containing polycarbonate macromolecules are conveniently and uniformly dispersed in a water system through the solubilization of the amphiphilic block polymers, thereby obtaining various thermally-induced hydrogel systems with X-ray developing capability. The macromolecular imaging contrast agent has good universality in the aspect of constructing an X-ray developing thermal gel system. The X-ray development thermotropic hydrogel system still has good fluidity at normal temperature, can form gel in situ at body temperature after being injected into a body, has excellent X-ray development performance, can obtain parameters such as the three-dimensional appearance, the volume and the like of the thermotropic hydrogel in the body by a CT imaging technology and a three-dimensional reconstruction technology, and provides an intuitive technical means for in-situ visual detection and nondestructive tracing of the thermotropic hydrogel.

Further, the amphiphilic block copolymer comprises a hydrophilic block A and a hydrophobic block B, wherein the hydrophilic block A is a polyethylene glycol PEG block with the average molecular weight of 400-8000g/mol, the hydrophobic block B is a polyester block or a polyamino acid block with the average molecular weight of 500-40000g/mol, the mass of the hydrophilic block A accounts for 10-90% of the mass of the amphiphilic block copolymer, and the mass of the hydrophobic block B accounts for 10-90% of the mass of the amphiphilic block copolymer.

It is understood that the amphiphilic block copolymer of the present invention can be dissolved in a solvent having water as a main dispersion medium at room temperature or low temperature, and can be spontaneously transformed into a gel at human body temperature.

Still further, the polyester block comprises one or more of polyglycolide, polylactide, polyepsilon caprolactone, polyorthoester, polyepsilon alkyl-substituted caprolactone, poly-valerolactone, poly-1, 4, 8-trioxaspiro [4,6] -9-undecanone, poly-p-dioxanone, polyesteramide, polycarbonate, polyacrylate, polyetherester, and copolymers of the foregoing polyesters; and the polyamino acid block comprises one or more of polyalanine, polylysine, polyglutamic acid and polyaspartic acid, and copolymer of the polyamino acid.

Further, the amphiphilic block copolymer is a triblock copolymer of ABA type or BAB type, a diblock copolymer of AB type, a graft copolymer of A-g-B or B-g-A type, (A-B)_nOr (B-A)_nA star block copolymer of (A), (BA)_nOr B (AB)_nOne or more of a multi-block copolymer of configuration, wherein n is an integer from 2 to 10.

Further, the solvent comprises one or more of pure water, water for injection, physiological saline, buffer solution, animal and plant or human body fluid and tissue culture solution.

It should be understood that although the present invention is limited to the kind of the solvent, other aqueous solutions or media not mainly composed of an organic solvent may be suitably used as the solvent of the present invention under appropriate conditions.

Furthermore, the X-ray development thermotropic hydrogel also comprises a regulator with the mass fraction of 0.01-15% of the solvent, wherein the regulator comprises one or more of Tween 20, Tween 40, Tween 80, sodium carboxymethylcellulose, carbomer, simethicone, propylene glycol, mannitol, sorbitol, xylitol, oligosaccharide, chondroitin, chitin, chitosan, gelatin, protein glue, hyaluronic acid and polyethylene glycol.

Further, the temperature of the sol-gel phase transition of the X-ray development thermal hydrogel is between 4 and 37 ℃.

It is a second object of the present invention to provide a method for preparing the above-mentioned X-ray developable thermotropic hydrogel.

firstly, stirring the mixture in an environment lower than the sol-gel phase transition temperature of the amphiphilic block polymer to fully dissolve the amphiphilic block polymer into a solvent, then adding a certain amount of iodine-containing polycarbonate polymer, and continuously stirring the mixture to form a uniform and stable polymer water system, thus obtaining the polymer aqueous solution of the X-ray developing thermotropic hydrogel.

It is a third object of the present invention to provide a use of the thermally induced hydrogel for X-ray imaging as described above.

The X-ray developing thermotropic hydrogel is applied to the field of preparation of drug slow-release carriers, tissue repair scaffolds, tissue markers or vascular embolization agents.

Compared with the prior art, the invention has the advantages that:

1. the invention utilizes the synthesized iodine-containing polycarbonate polymer as a macromolecular developer to be blended with the amphiphilic block polymer, and the solubilization of the amphiphilic block polymer enables the iodine-containing polycarbonate macromolecules to be uniformly dispersed in the system, thereby obtaining the thermal hydrogel system with X-ray developing capability. The iodine-containing polycarbonate polymer in the system can be blended with various thermally gelled amphiphilic block copolymer materials to obtain the thermally induced hydrogel for X-ray development, and has good universality in the aspect of constructing an X-ray developing thermally induced gel system.

2. The X-ray development thermotropic hydrogel system prepared by the invention has good fluidity at normal temperature, forms gel in situ at body temperature after being injected into a body, has good X-ray development performance, can obtain parameters such as the three-dimensional appearance, the volume and the like of the thermotropic hydrogel in the body by a CT imaging technology and a three-dimensional reconstruction technology, and provides an intuitive technical means for the in-situ visual detection and the nondestructive tracing of the thermotropic hydrogel.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.

FIG. 1 is a nuclear magnetic resonance comparison graph (CDCl) of an iodine-containing polycarbonate polymer PI2 and a functional monomer₃)。

Fig. 2 is a gel permeation chromatogram of the iodine-containing polycarbonate polymer PI 2.

FIG. 3 is the polymer PEG (M)_n1000) and iodine containing polycarbonate polymer PI 2.

FIG. 4 is a scanning electron micrograph and an energy spectrum of an iodine-containing polycarbonate PI2(a) and a statistical chart of the distribution of each element.

FIG. 5 is a rheological diagram of aqueous solutions of different polymers: (a)15 wt% P1, 15 wt% wtP2 and 15 wt% P3 aqueous polymer solution; (b)30 wt% P1PI2, 30 wt% P2PI2 and 30 wt% P3PI2 aqueous polymer solution.

FIG. 6 is a CT scan of different gel materials (from left to right: alumina powder, 15 wt% P1, 15 wt% P2, 15 wt% P3, 30 wt% P1, 30 wt% P1PI2, 30 wt% P2PI2, and 30 wt% P3PI2 aqueous polymer solution).

FIG. 7 is a cross-sectional view and a three-dimensional reconstructed image of different gel materials of example 38 injected subcutaneously into mice.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all 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.

The present invention will be further specifically illustrated by the following examples for better understanding, but the present invention is not to be construed as being limited thereto, and certain insubstantial modifications and adaptations of the invention by those skilled in the art based on the foregoing disclosure are intended to be included within the scope of the invention.

Example 1

An iodine-containing functional monomer and a preparation method thereof, comprising the following steps:

in the first step, diiodoneopentyl glycol is synthesized. 45g of NaI (300.22mmol) powder was weighed into a 500mL eggplant-shaped bottle (containing magnetons), and about 200mL of anhydrous acetone was added thereto, followed by stirring to sufficiently dissolve the solid. Then, 30g of dibromoneopentyl glycol (114.53mmol) was added to the eggplant-shaped bottle, and the mixture was condensed and refluxed at 58 ℃ to start the reaction. When the reaction proceeded to day 4, the supernatant was transferred to a new eggplant-shaped bottle and supplemented with about 15g of NaI and 40mL of anhydrous acetone, and the reaction was continued at 58 ℃ for 4 days. After the reaction is finished, filtering out white solid precipitate in the system, and evaporating acetone by using a rotary evaporator to obtain a large amount of light yellow solid. Subsequently, about 400mL of deionized water and 4g of sodium bisulfite were added to the reaction flask, stirred well to reduce the impurity iodine to water-soluble iodide ions, and filtered with suction to give a white solid. And finally, drying in an oven at 85 ℃ for about 12 hours to obtain pure diiodoneopentyl glycol.

And secondly, acylating two hydroxyl groups on the diiodoneopentyl glycol by ethyl chloroformate to close the ring to obtain a functional monomer. 7.12g (20mmol) of diiodoneopentyl glycol was weighed into a 250mL eggplant-shaped bottle, and about 100mL of freshly distilled anhydrous tetrahydrofuran was added thereto and then subjected to ice-bath for 10 min. Next, 4.3mL (44mmol) of ethyl chloroformate solution was injected into the reaction flask and allowed to stand in the ice bath for another 15 min. 6.6mL (48mmol) of anhydrous triethylamine is mixed into 8mL of tetrahydrofuran, the mixture is uniformly mixed and slowly dripped into a reaction system, the ice water bath is ensured for the first two hours, and then the reaction is carried out at room temperature for about 12 hours. After the reaction is finished, solid triethylamine hydrochloride in the system is filtered, and the filtrate is concentrated by rotary evaporation to obtain a crude product. The crude product was hot dissolved in about 2mL of tetrahydrofuran and then tetrahydrofuran was slowly added dropwise until the crude product was completely dissolved. Slowly adding diethyl ether (about 6mL) into the system until the solution is turbid, quickly adding one drop of tetrahydrofuran, standing at room temperature after the turbidity disappears, allowing crystals to appear in the system, and transferring after 3hThe crystals were removed to-20 ℃ in a refrigerator overnight to complete. After being taken out, the supernatant is poured out, and the product is dried in vacuum (35 ℃) for about 24 hours to obtain the functional monomer 5, 5-diiodomethyl-1, 3-dioxane-2-one (ITMC), which is¹The HNMR spectrum is shown in FIG. 1.

Example 2

An iodine-containing polycarbonate polymer and a method for preparing the same, comprising:

0.8g (1mmol) of PEG (M) is weighed_n800) into a 50mL eggplant-shaped bottle, 23mL of anhydrous toluene was added, a water separation apparatus was set up, and after stirring at 125 ℃ for 30min, about 20mL of anhydrous toluene was distilled out of the system. Subsequently, the heating was stopped and argon was introduced, and the system was gradually cooled under argon protection. The water-separating portion was removed, 1.91g (5mmol) of ITMC was added to the flask, and the eggplant-shaped mouth was sealed with a rubber stopper, and the system was purged three times and then was adjusted to an argon-introducing state. 2mL of 386mg Zn (HMDS) was injected into the system by means of a syringe₂The reaction was continued for 24h at 40 ℃ with stirring. After the reaction is finished, the eggplant-shaped bottle is taken down, and a solid product is separated by using a sand core funnel. Further purification, the solid was collected in a 50mL eggplant-shaped bottle, 1.5mL of THF was added to disperse the product uniformly, 18mL of anhydrous ether was added, and then the solution was allowed to settle at-20 ℃ for about 24 h. The reaction flask was taken out, the supernatant was poured off, and purification was repeated once. And (3) drying the purified product in vacuum (at 35 ℃) for about 24 hours to remove residual solvent to obtain the iodine-containing polycarbonate polymer PI 1.

The number average and weight average molecular weights (M) of the triblock copolymer PI1 were determined by Gel Permeation Chromatography (GPC) using tetrahydrofuran as the mobile phase and polystyrene as the standard_n,M_w) 2410 and 3760, respectively, molecular weight distribution coefficient (M)_w/M_n) Is 1.56.

Example 3

1g (1mmol) of PEG (M) are weighed_n1000) into a 50mL eggplant-shaped bottle, 23mL of anhydrous toluene was added, a water separation device was set up, and after stirring at 125 ℃ for 30min, about 15mL of anhydrous toluene was distilled out of the system. Subsequently, the heating is stopped, argon is introduced, and the system is enabled to be protected by argonAnd (5) gradually cooling. The water-separating portion was removed, 3.82g (10mmol) of ITMC was added to the flask, and the eggplant-shaped mouth was sealed with a rubber stopper, and the system was purged three times and then was adjusted to an argon-introducing state. 2mL of 386mg Zn (HMDS) was injected into the system by means of a syringe₂The reaction was continued for 24h at 40 ℃ with stirring. After the reaction is finished, the eggplant-shaped bottle is taken down, and a solid product is separated by using a sand core funnel. Further purification, collecting the solid in a 50mL eggplant-shaped bottle, adding 2.5mL of THF to uniformly disperse the product, adding 30mL of anhydrous ether, and then settling at-20 deg.C for about 24 h. The reaction flask was taken out, the supernatant was poured off, and purification was repeated once. Vacuum drying (35 deg.C) the purified product for about 24h to remove residual solvent to obtain iodine-containing polycarbonate polymer PI2¹The H NMR spectrum is shown in FIG. 1.

The number average and weight average molecular weights (M) of the triblock copolymer PI2 were determined by Gel Permeation Chromatography (GPC) using tetrahydrofuran as the mobile phase and polystyrene as the standard_n,M_w) 3870 and 6350, respectively, molecular weight distribution coefficient (M)_n/M_w) It was 1.64, and its gel permeation chromatogram was shown in FIG. 2. FIG. 3 Polymer PEG (M)_n1000) and iodine-containing polycarbonate polymer PI 2; FIG. 4 is a scanning electron micrograph and a power spectrum of the iodine-containing polycarbonate polymer PI 2.

Example 4

1.5g (1mmol) of PEG (M) are weighed_n1500) into a 50mL eggplant-shaped bottle, 33mL of anhydrous toluene was added, a water separation device was set up, and after stirring at 125 ℃ for 30min, about 15mL of anhydrous toluene was distilled out of the system. Subsequently, the heating was stopped and argon was introduced, and the system was gradually cooled under argon protection. After the water-separating portion was removed, 7.64g (20mmol) of ITMC was added to the flask, and the eggplant-shaped mouth was sealed with a rubber stopper, and the system was purged three times and then was adjusted to an argon-introducing state. 2mL of 386mg Zn (HMDS) was injected into the system by means of a syringe₂The reaction was continued for 24h at 40 ℃ with stirring. After the reaction is finished, the eggplant-shaped bottle is taken down, and a solid product is separated by using a sand core funnel. Further purifying, collecting the solid in 100mL eggplant formIn a bottle, 5.5mL of THF was added to disperse the product uniformly, 66mL of anhydrous ether was added, and then the solution was allowed to settle at-20 ℃ for about 24 hours. The reaction flask was taken out, the supernatant was poured off, and purification was repeated once. And (3) drying the purified product in vacuum (at 35 ℃) for about 24 hours to remove residual solvent to obtain the iodine-containing polycarbonate polymer PI 3.

The number average and weight average molecular weights (M) of the triblock copolymer PI3 were determined by Gel Permeation Chromatography (GPC) using tetrahydrofuran as the mobile phase and polystyrene as the standard_n,M_w) 6490 and 10350, respectively, molecular weight distribution coefficient (M)_w/M_n) It was 1.59.

Example 5

0.55g (1mmol) of monomethoxy-terminated polyethylene glycol (MPEG, M) are weighed out_n550) was put into a 50mL eggplant-shaped bottle, 23mL of anhydrous toluene was added, a water separation apparatus was set up, and after stirring at 125 ℃ for 30min, about 20mL of anhydrous toluene was distilled out of the system. Subsequently, the heating was stopped and argon was introduced, and the system was gradually cooled under argon protection. The water-separating portion was removed, 1.91g (5mmol) of ITMC was added to the flask, and the eggplant-shaped mouth was sealed with a rubber stopper, and the system was purged three times and then was adjusted to an argon-introducing state. 2mL of 386mgZn (HMDS) solution was injected into the system using a syringe₂The reaction was continued for 24h at 40 ℃ with stirring. After the reaction is finished, the eggplant-shaped bottle is taken down, and a solid product is separated by using a sand core funnel. Further purification, the solid was collected in a 50mL eggplant-shaped bottle, 1.5mL of THF was added to disperse the product uniformly, 18mL of anhydrous ether was added, and then the solution was allowed to settle at-20 ℃ for about 24 h. The reaction flask was taken out, the supernatant was poured off, and purification was repeated once. And (3) drying the purified product in vacuum (at 35 ℃) for about 24 hours to remove residual solvent to obtain the iodine-containing polycarbonate polymer PI 4.

The number average and weight average molecular weights (M) of the triblock copolymer PI4 were determined by Gel Permeation Chromatography (GPC) using tetrahydrofuran as the mobile phase and polystyrene as the standard_n,M_w) 2170 and 3280, respectively, molecular weight distribution coefficient (M)_w/M_n) Was 1.51.

Example 6

0.75g (1mmol) of MPEG (M) are weighed out_n750) into a 50mL eggplant-shaped bottle, 23mL of anhydrous toluene was added, a water separation device was set up, and after stirring at 125 ℃ for 30min, about 15mL of anhydrous toluene was distilled out of the system. Subsequently, the heating was stopped and argon was introduced, and the system was gradually cooled under argon protection. The water-separating portion was removed, 3.82g (10mmol) of ITMC was added to the flask, and the eggplant-shaped mouth was sealed with a rubber stopper, and the system was purged three times and then was adjusted to an argon-introducing state. 2mL of 386mg Zn (HMDS) was injected into the system by means of a syringe₂The reaction was continued for 24h at 40 ℃ with stirring. After the reaction is finished, the eggplant-shaped bottle is taken down, and a solid product is separated by using a sand core funnel. Further purification, collecting the solid in a 50mL eggplant-shaped bottle, adding 2.5mL of THF to uniformly disperse the product, adding 30mL of anhydrous ether, and then settling at-20 deg.C for about 24 h. The reaction flask was taken out, the supernatant was poured off, and purification was repeated once. And (3) drying the purified product in vacuum (at 35 ℃) for about 24 hours to remove residual solvent to obtain the iodine-containing polycarbonate polymer PI 5.

The number average and weight average molecular weights (M) of the triblock copolymer PI5 were determined by Gel Permeation Chromatography (GPC) using tetrahydrofuran as the mobile phase and polystyrene as the standard_n,M_w) 3320 and 4950, respectively, molecular weight distribution coefficient (M)_w/M_n) Was 1.49.

Example 7

1g (1mmol) of MPEG (M) are weighed out_n1000) into a 50mL eggplant-shaped bottle, 33mL of anhydrous toluene was added, a water separation device was set up, and after stirring at 125 ℃ for 30min, about 15mL of anhydrous toluene was distilled out of the system. Subsequently, the heating was stopped and argon was introduced, and the system was gradually cooled under argon protection. After the water-separating portion was removed, 7.64g (20mmol) of ITMC was added to the flask, and the eggplant-shaped mouth was sealed with a rubber stopper, and the system was purged three times and then was adjusted to an argon-introducing state. 2mL of 386mg Zn (HMDS) was injected into the system by means of a syringe₂At 40 ℃ in dry tolueneThe reaction was stirred continuously for 24 h. After the reaction is finished, the eggplant-shaped bottle is taken down, and a solid product is separated by using a sand core funnel. Further purification, collecting the solid in 100mL eggplant-shaped bottle, adding 5.5mL of THF to uniformly disperse the product, adding 60mL of anhydrous ether, and then settling at-20 deg.C for about 24 h. The reaction flask was taken out, the supernatant was poured off, and purification was repeated once. And (3) drying the purified product in vacuum (at 35 ℃) for about 24 hours to remove residual solvent to obtain the iodine-containing polycarbonate polymer PI 6.

The number average and weight average molecular weights (M) of the triblock copolymer PI6 were determined by Gel Permeation Chromatography (GPC) using tetrahydrofuran as the mobile phase and polystyrene as the standard_n,M_w) 5990 and 9280, respectively, molecular weight distribution coefficient (M)_w/M_n) Is 1.55.

The characterization results and the related properties of the iodine-containing polycarbonate polymers of the comprehensive examples 2 to 7 are shown in Table 1.

TABLE 1

Example 8

An amphiphilic block copolymer and a method for preparing the same, comprising:

weigh 15g (10mmol) of PEG (M)_n1500) was placed in a dry 250mL three-necked flask, and the system was evacuated and stirred at an oil bath temperature of 120 ℃. After about 2h, the system was cooled to 80 ℃ by introducing argon. Under protection of argon, 28.70g (251.4mmol) Caprolactone (CL) and 7.30g (62.8mmol) Glycolide (GA) were added, and 2mL of a solution containing 144mg stannous octoate (Sn (Oct)₂) The anhydrous toluene solution of (1). Sealing the system, pumping and changing gas for three times, adjusting the system to be in an argon introducing state, and stirring and reacting for 12 hours at 150 ℃. After the reaction is finished, the temperature is reduced to 120 ℃ and vacuum is pumped for 1h to remove the unreacted monomers. Then, about 200mL of 80 ℃ hot water was added to the crude product in the flask, and the mixture was stirred sufficiently and then allowed to stand. After the supernatant liquid became clear, the supernatant solution was poured out while hot. Repeatedly washing with water for three times, freeze drying for about 3 days to remove water, and dryingThen obtaining the triblock copolymer PCGA-PEG-PCGA (P1).

The number average and weight average molecular weights (M) of the triblock copolymer P1 were determined by Gel Permeation Chromatography (GPC) using tetrahydrofuran as the mobile phase and polystyrene as the standard_n,M_w) 5240 and 7070, respectively, molecular weight distribution coefficient (M)_w/M_n) Is 1.35.

Example 9

An amphiphilic block copolymer and a method for preparing the same, comprising:

weigh 15g (10mmol) of PEG (M)_n1500) was placed in a dry 250mL three-necked flask, and the system was evacuated and stirred at an oil bath temperature of 120 ℃. After about 2h, the system was cooled to 80 ℃ by introducing argon. Under the protection of argon, 24.24g (168.2mmol) of Lactide (LA) and 9.76g (84.1mmol) of GA were added, and 2mL of a solution containing 136mg of Sn (Oct)₂The anhydrous toluene solution of (1). Sealing the system, pumping and changing gas for three times, adjusting the system to be in an argon introducing state, and stirring and reacting for 12 hours at 150 ℃. After the reaction is finished, the temperature is reduced to 120 ℃ and vacuum is pumped for 1h to remove the unreacted monomers. Then, about 200mL of 80 ℃ hot water was added to the crude product in the flask, and the mixture was stirred sufficiently and then allowed to stand. After the supernatant liquid became clear, the supernatant liquid was poured out while hot. The water washing operation is repeated for three times, and finally the product is freeze-dried for about 3 days to remove a large amount of water in the product, and the triblock copolymer PLGA-PEG-PLGA (P2) is obtained after drying.

The number average and weight average molecular weights (M) of the triblock copolymers P2 were determined by GPC (using tetrahydrofuran as the mobile phase and polystyrene as the standard)_n,M_w) 4270 and 5290, respectively, molecular weight distribution coefficient (M)_w/M_n) Is 1.24.

Example 10

An amphiphilic block copolymer and a method for preparing the same, comprising:

weigh 15g (10mmol) of PEG (M)_n1500) was placed in a dry 250mL three-necked flask, and the system was evacuated and stirred at an oil bath temperature of 120 ℃. After about 2h, the system was cooled to 80 ℃ by introducing argon. Under the protection of argon, 27.36g (239.7mmol) of CL are addedAnd 8.64g (59.9mmol) of LA, and 2mL of a solution containing 144mg of Sn (Oct)₂The anhydrous toluene solution of (1). Sealing the system, pumping and changing gas for three times, adjusting the system to be in an argon introducing state, and stirring and reacting for 12 hours at 150 ℃. After the reaction is finished, the temperature is reduced to 120 ℃ and vacuum is pumped for 1h to remove the unreacted monomers. Then, about 200mL of 80 ℃ hot water was added to the crude product in the flask, and the mixture was stirred sufficiently and then allowed to stand. After the supernatant liquid became clear, the supernatant liquid was poured out while hot. Repeatedly washing with water for three times, freeze drying for 3 days to remove large amount of water, and drying to obtain the triblock copolymer PCLA-PEG-PCLA (P3).

The number average and weight average molecular weights (M) of the triblock copolymers P3 were determined by GPC (using tetrahydrofuran as the mobile phase and polystyrene as the standard)_n,M_w) 5350 and 7120, respectively, molecular weight distribution coefficient (M)_w/M_n) Is 1.33.

Example 11

An amphiphilic block copolymer and a method for preparing the same, comprising:

15g (20mmol) of MPEG (M) mono-methoxy-terminated are weighed_n750) was dissolved in 80mL of toluene and distilled to 30mL of the system to remove residual water in the polymer. Subsequently, 35g (242.8mmol) of LA and 1mL of a solution containing 60mg of Sn (Oct)₂The anhydrous toluene solution of (1). Sealing the system, pumping and changing gas for three times, adjusting the system to be in an argon introducing state, and stirring and reacting for 12 hours at 150 ℃. After the reaction is finished, the temperature is reduced to 120 ℃ and vacuum is pumped for 1h to remove the unreacted monomers. The crude product was then dissolved thoroughly by adding dichloromethane to the bottle, the solution was added dropwise to cold ether to settle and allowed to stand at-20 ℃ for 24 h. Finally, the upper solution was poured off, and the precipitate was vacuum dried for about 12 hours to remove the residual solvent, and dried to obtain the diblock copolymer MPEG-PLA (P4).

The number average and weight average molecular weights (M) of the diblock copolymer P4 were determined by GPC (using tetrahydrofuran as the mobile phase and polystyrene as the standard)_n,M_w) 2690 and 3740, respectively, molecular weight distribution coefficient (M)_w/M_n) Is 1.39.

Example 12

An amphiphilic block copolymer and a method for preparing the same, comprising:

15g (20mmol) of MPEG (M) mono-methoxy-terminated are weighed_n750) was dissolved in 80mL of toluene and distilled to 30mL of the system to remove residual water in the polymer. Next, 30g (208.3mmol) of LA and 4g (34.5mmol) of GA were added, and 1mL of a solution containing 60mg of Sn (Oct)₂The anhydrous toluene solution of (1). Sealing the system, pumping and changing gas for three times, adjusting the system to be in an argon introducing state, and stirring and reacting for 12 hours at 150 ℃. After the reaction is finished, the temperature is reduced to 120 ℃ and vacuum is pumped for 1h to remove the unreacted monomers. The crude product was then dissolved thoroughly by adding dichloromethane to the bottle, the solution was added dropwise to cold ether to settle and allowed to stand at-20 ℃ for 24 h. And finally pouring the upper layer solution, drying the precipitate in vacuum for about 12 hours to remove residual solvent, and obtaining the two-block copolymer MPEG-PLGA (P5) after drying.

The number average and weight average molecular weights (M) of the diblock copolymer P5 were determined by GPC (using tetrahydrofuran as the mobile phase and polystyrene as the standard)_n,M_w) 3620 and 4740, molecular weight distribution coefficient (M)_w/M_n) Is 1.31.

Example 13

An amphiphilic block copolymer and a method for preparing the same, comprising:

11g (20mmol) of monomethoxy-terminated MPEG (M) were weighed_n550) was dissolved in 80mL of toluene and distilled to 30mL of the system to remove residual water in the polymer. Then 60g (416.6mmol) of trimethylene carbonate (TMC) and 1mL of a solution containing 60mg of Sn (Oct)₂And refluxing at 120 ℃ for 24 h. After the reaction is finished, diethyl ether is added into the solution to precipitate to obtain a crude product. The resulting crude product was dissolved in 30mL of dichloromethane and the solution was slowly added to cold ether to allow it to settle and allowed to stand at-20 ℃ for 24 h. And finally pouring the upper layer solution, and drying the precipitate in vacuum for about 12h to remove residual solvent to obtain the diblock copolymer MPEG-PTMC (P6).

The number average and weight average molecular weights (M) of P6 were determined by GPC (tetrahydrofuran as the mobile phase and polystyrene as the standard)_n,M_w) 5280 and 7180, respectivelyMolecular weight distribution coefficient (M)_w/M_n) Is 1.36.

Example 14

An amphiphilic block copolymer and a method for preparing the same, comprising:

0.50g (0.25mmol) of MPEG were weighed₂₀₀₀-NH₂The water was removed by azeotropy with 50mL of toluene, and the system was sealed and cooled to room temperature until the remaining solvent volume was 5 mL. 0.501g (4.35mmol)_LAla-NCA and 0.119g (0.62mmol)_LPhe-NCA monomer was added to 20mL of anhydrous magnesium sulfate-dried CHCl₃In DMF (v/v3:1) mixed solvent, and magnetically stirred at room temperature for 30 min. Transferring the mixed monomer solution to dry MPEG under argon atmosphere₂₀₀₀-NH₂Then, the temperature of the system was raised to 37 ℃ and the reaction was magnetically stirred under an argon atmosphere for 3 days. After 3 days, the system was cooled to room temperature and 20mL of CHCl were added₃After the reaction product was completely dissolved, the reaction product was added dropwise to glacial ethyl ether to carry out precipitation, and the above operation was repeated three times. Finally, the product was dried in a vacuum oven at 25 ℃ for 48h to give the white solid product MPEG₂₀₀₀-PAF(P7)。

The number average and weight average molecular weights (M) of the diblock copolymer P7 were determined by GPC (using N, N-dimethylformamide as the mobile phase and polymethyl methacrylate as the standard)_n,M_w) 3010 and 3823, respectively, molecular weight distribution coefficient (M)_w/M_n) Is 1.27.

Example 15

An amphiphilic block copolymer and a method for preparing the same, comprising:

1.25g (0.25mmol) of MPEG were weighed₅₀₀₀-NH₂The water was removed by azeotropy with 50mL of toluene, and the system was sealed and cooled to room temperature until the remaining solvent volume was 5 mL. 1.22g (10.60mmol)_LAla-NCA and 0.292g (1.53mmol)_LPhe-NCA monomer was added to 20mL of anhydrous magnesium sulfate-dried CHCl₃In DMF (v/v3:1) mixed solvent, and magnetically stirred at room temperature for 30 min. Transferring the mixed monomer solution to dry MPEG under argon atmosphere₅₀₀₀-NH₂Then the temperature of the system is raised to 37 ℃ under argonAnd (3) magnetically stirring to react for 3d under the atmosphere of gas. After reaction for 3d, the system was cooled to room temperature and 20mL of CHCl was added₃After the reaction product was completely dissolved, the reaction product was added dropwise to glacial ethyl ether to carry out precipitation, and the above operation was repeated three times. Finally, the product was dried in a vacuum oven at 25 ℃ for 48h to give the white solid product MPEG₅₀₀₀-PAF(P8)。

The number average and weight average molecular weights (M) of the diblock copolymer P8 were determined by GPC (using N, N-dimethylformamide as the mobile phase and polymethyl methacrylate as the standard)_n,M_w) 7700 and 9940, respectively, molecular weight distribution coefficient (M)_w/M_n) Is 1.29.

Example 16

An amphiphilic block copolymer and a method for preparing the same, comprising:

0.5g (0.250mmol) NH were weighed₂-PEG₂₀₀₀-NH₂The water was removed by azeotropy with 50mL of toluene, and the system was sealed and cooled to room temperature until the remaining solvent volume was 5 mL. 0.783g (6.80mmol)_LAla-NCA and 0.186g (0.973mmol)_LPhe-NCA monomer was added to 20mL of anhydrous magnesium sulfate-dried CHCl₃In DMF (v/v3:1) mixed solvent, and magnetically stirred at room temperature for 30 min. Transferring the mixed monomer solution to dry NH under argon atmosphere₂-PEG₂₀₀₀-NH₂Then, the temperature of the system was raised to 37 ℃, and the reaction was magnetically stirred for 3d under an argon atmosphere. After reaction for 3d, the system was cooled to room temperature and 20mL of CHCl was added₃After the reaction product was completely dissolved, the reaction product was added dropwise to glacial ethyl ether to carry out precipitation, and the above operation was repeated three times. Finally, the product is placed in a vacuum oven at 25 ℃ for drying for 48h to obtain a white solid product PAF-PEG₂₀₀₀-PAF(P9)。

The number average and weight average molecular weights (M) of the diblock copolymer P9 were determined by GPC (using N, N-dimethylformamide as the mobile phase and polymethyl methacrylate as the standard)_n,M_w) 4200 and 5250, respectively, molecular weight distribution coefficient (M)_w/M_n) Is 1.25.

Example 17

An amphiphilic block copolymer and a method for preparing the same, comprising:

11g (20mmol) of monomethoxy-terminated MPEG (M) were weighed_n550) was dissolved in 80mL of toluene and distilled to 30mL of the system to remove residual water in the polymer. Then, 21g (183.9mmol) of CL and 1mL of 96mg Sn (Oct) were added₂And refluxing at 120 ℃ for 24 h. Then 1.62mL of 4,4' -dicyclohexylmethane diisocyanate (HMDI) was added and reacted at 60 ℃ for 7 h. After the reaction is finished, diethyl ether is added into the solution to precipitate to obtain a crude product. The resulting crude product was dissolved in 30mL of dichloromethane and the solution was slowly added to cold ether to allow it to settle and allowed to stand at-20 ℃ for 24 h. And finally pouring the upper layer solution, drying the precipitate in vacuum for about 12h to remove residual solvent, and obtaining the triblock copolymer MPEG-PCL-MPEG (P10) after drying.

The number average and weight average molecular weights (M) of P10 were determined by GPC (tetrahydrofuran as the mobile phase and polystyrene as the standard)_n,M_w) 5170 and 6250, respectively, molecular weight distribution coefficient (M)_w/M_n) Is 1.21.

The characterization results and the related properties of the amphiphilic block copolymer-containing polymers of examples 8-17 are summarized in Table 2.

TABLE 2

Example 18

An aqueous amphiphilic block copolymer solution was prepared by weighing 1.5g of P1 polymer in a 25mL butterfly bottle (containing magnetons), adding 8.5g of physiological saline thereto, and sealing with a cap. Then, quenching operation is carried out: placing the butterfly bottle in hot water of 65 deg.C, stirring, and then observing that the polymer is dispersed in the water solution in white viscous state, and at this time, continuously stirring for about 5 min; then the butterfly bottle is quickly transferred to ice water to be stirred for 5min, and the system gradually becomes uniform and transparent, thus obtaining the 15 wt% P1 polymer aqueous solution. The rheological behavior of the aqueous polymer solution at elevated temperature was measured by a stress-controlled rheometer, and the sol-gel phase transition temperature was 33.0 ℃ when the storage modulus G' and loss modulus G "values were equal, as shown in fig. 5 (a).

Example 19

An aqueous amphiphilic block copolymer solution was prepared by weighing 1.5g of P2 polymer in a 25mL butterfly bottle (containing magnetons), adding 8.5g of physiological saline thereto, sealing, and stirring in a refrigerator at 4 ℃. After about 3 days, the system became homogeneous and transparent, i.e.a 15% by weight aqueous solution of P2 polymer was obtained. The rheological behavior of the aqueous polymer solution at elevated temperature was measured by a stress-controlled rheometer, and the sol-gel phase transition temperature was 31.0 ℃ when the storage modulus G' and loss modulus G "values were equal, as shown in fig. 5 (a).

Example 20

An aqueous amphiphilic block copolymer solution was prepared by weighing 1.5g of P3 polymer in a 25mL butterfly bottle (containing magnetons), adding 8.5g of physiological saline thereto, and sealing with a cap. Then, quenching operation is carried out: placing the butterfly bottle in hot water of 65 deg.C, stirring, and then observing that the polymer is dispersed in the water solution in white viscous state, and at this time, continuously stirring for about 5 min; then the butterfly bottle is quickly transferred to ice water to be stirred for 5min, and the system gradually becomes uniform and transparent, thus obtaining the 15 wt% P3 polymer aqueous solution. The rheological behavior of the aqueous polymer solution at elevated temperature was measured by a stress-controlled rheometer, and the sol-gel phase transition temperature was 32.7 ℃ when the storage modulus G' and loss modulus G "values were equal, as shown in fig. 5 (a).

Example 21

An aqueous amphiphilic block copolymer solution was prepared by weighing 3.0g of P1 polymer in a 25mL butterfly bottle (containing magnetons) and adding 7.0g of pure water thereto to prepare a 30 wt% aqueous solution of P1 polymer. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 31.9 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal.

Example 22

An aqueous amphiphilic block copolymer solution was prepared by weighing 3.0g of P5 polymer in a 25mL butterfly bottle (containing magnetons) and adding 7.0g of phosphoric acid buffer solution to the bottle to prepare a 30 wt% aqueous solution of P5 polymer. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 37.0 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal.

Example 23

An amphiphilic block copolymer aqueous solution is prepared by weighing 1/1 mass ratio of P1 and P5 polymers in a 25mL butterfly bottle (containing magnetons), and adding a certain amount of physiological saline to the butterfly bottle to obtain a 30 wt% P1P5 polymer aqueous solution. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 35.7 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal.

Example 24

0.6mL of different concentrations of aqueous solutions of P1, P2, P3, P5 and P1P5 polymers were taken by pipette and equilibrated at 4 ℃ for 12h in a 2mL glass sample bottle (d: 7mm) to eliminate air bubbles generated during the sample application. And (3) carrying out Micro-CT test by taking alumina powder as a control group, and analyzing by using CTAn software after scanning reconstruction to obtain the gray value of the alumina powder. The resulting Micro-CT scans are shown. The difference in the average gray value between the aqueous polymer solution and the alumina powder is shown in Table 3:

TABLE 3

Sample name	Concentration of	Mean gray value^a	Relative to alumina powder^b
				P1	15	16.5	-19.3
P2	15	16.9	-18.9
				P3	15	16.4	-19.4
P1	30	17.3	-18.5
				P5	30	17.1	-18.7
P1P5	30	16.7	-19.1
				Alumina powder	/	35.8	/

Note:^athe gray value analysis of each sample was the sameAn equal range of intensity windows;^b"+" indicates greater than, "-" indicates less than.

Example 25

An X-ray developing thermotropic hydrogel is prepared by weighing 1/1 mass ratio of block polymers P1 and PI1, and preparing 40 wt% of aqueous polymer solution P1PI1 with water for injection. The solution has thermogelling properties. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 32.9 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal. The X-ray developing effect of the Micro-CT image is better than that of the aluminum oxide powder.

Example 26

An X-ray developing thermotropic hydrogel is prepared by weighing 1/1 mass ratio of block polymers P1 and PI2, and preparing 30 wt% of aqueous solution of the polymers P1PI2 with physiological saline. The solution has thermogelling properties. The rheological behavior of the aqueous polymer solution at elevated temperature was measured by a stress-controlled rheometer, and the sol-gel phase transition temperature was 33.2 ℃ when the storage modulus G' and loss modulus G "values were equal, as shown in fig. 5 (b). The Micro-CT images were taken and the X-ray development effect was better than that of the alumina powder, as shown in FIG. 6.

Example 27

An X-ray developing thermotropic hydrogel is prepared by weighing 1/1 mass ratio of block polymers P2 and PI2, and preparing 30 wt% of P2PI2 aqueous polymer solution by physiological saline. The solution has thermogelling properties. The rheological behavior of the aqueous polymer solution at elevated temperature was measured by a stress-controlled rheometer, which showed a sol-gel phase transition temperature of 32.6 ℃ when the storage modulus G' and loss modulus G "values were equal, as shown in FIG. 5 (b). The Micro-CT images were taken and the X-ray development effect was better than that of the alumina powder, as shown in FIG. 6.

Example 28

An X-ray developing thermotropic hydrogel is prepared by weighing 1/1 mass ratio of block polymers P3 and PI2, and preparing 30 wt% of aqueous solution of the polymers P3PI2 with physiological saline. The solution has thermogelling properties. The rheological behavior of the aqueous polymer solution at elevated temperature was measured by a stress-controlled rheometer, and the sol-gel phase transition temperature was 31.8 ℃ when the storage modulus G' and loss modulus G "values were equal, as shown in fig. 5 (b). The Micro-CT images were taken and the X-ray development effect was better than that of the alumina powder, as shown in FIG. 6.

Example 29

An X-ray developing thermotropic hydrogel is prepared by weighing 3/1 mass ratio of block polymers P5 and PI2, and preparing 40 wt% of aqueous solution of the polymers P5PI2 with physiological saline. The solution has thermogelling properties. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 35.1 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal. The X-ray developing effect of the Micro-CT image is better than that of the aluminum oxide powder.

Example 30

An X-ray developing thermotropic hydrogel is prepared by weighing 1/1 mass ratio block polymers P1 and PI2, and preparing 40 wt% P1PI2 aqueous polymer solution by phosphoric acid buffer solution. The solution has thermogelling properties. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 31.2 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal. The X-ray developing effect of the Micro-CT image is better than that of the aluminum oxide powder.

Example 31

An X-ray developing thermotropic hydrogel is prepared by weighing 1/1/2 mass ratio of block polymers P1, P5 and PI2, and preparing 40 wt% of aqueous solution of the polymer P1P5PI2 with water for injection. The solution has thermogelling properties. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 34.0 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal. The X-ray developing effect of the Micro-CT image is better than that of the aluminum oxide powder.

Example 32

An X-ray developing thermotropic hydrogel is prepared by weighing 2/1 mass ratio of block polymers P1 and PI3, preparing 40 wt% of polymer aqueous solution P1PI3 with physiological saline, and adding hyaluronic acid to make its mass fraction be 0.8 wt% of solvent. The solution has thermogelling properties. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 35 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal. The X-ray developing effect of the Micro-CT image is better than that of the aluminum oxide powder.

Example 33

An X-ray developing thermotropic hydrogel is prepared by weighing 4/1 mass ratio of block polymers P4 and PI3, preparing 40 wt% P4PI3 aqueous solution of polymer with physiological saline, and adding polyethylene glycol-400 to make its mass fraction 3 wt% of solvent. The solution has thermogelling properties. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 29.4 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal. The X-ray developing effect of the Micro-CT image is better than that of the aluminum oxide powder.

Example 34

An X-ray developing thermotropic hydrogel is prepared by weighing 9/11 mass ratio of block polymers P7 and PI4, preparing 20 wt% of polymer aqueous solution P7PI4 with tissue culture solution, and adding chitosan to make its mass fraction be 0.5 wt% of solvent. The solution has thermogelling properties. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 32.2 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal. The X-ray developing effect of the Micro-CT image is better than that of the aluminum oxide powder.

Example 35

An X-ray developing thermotropic hydrogel is prepared by weighing 1/1 mass ratio of block polymer P8 and PI5, preparing 20 wt% of polymer water solution P8PI5 with physiological saline, and adding Tween 20 to make its mass fraction be 2 wt% of solvent. The solution has thermogelling properties. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 29.3 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal. The X-ray developing effect of the Micro-CT image is better than that of the aluminum oxide powder.

Example 36

An X-ray developing thermotropic hydrogel is prepared by weighing 2/3 mass ratio block polymers P9 and PI6, and preparing 20 wt% P9PI6 aqueous polymer solution by phosphoric acid buffer solution. The solution has thermogelling properties. The rheological behavior of the polymer aqueous solution under the condition of temperature rise is tested by a stress control type rheometer, and the sol-gel phase transition temperature is 28.6 ℃ when the values of the storage modulus G 'and the loss modulus G' are equal. The X-ray developing effect of the Micro-CT image is better than that of the aluminum oxide powder.

Example 37

0.6mL of aqueous solutions of different concentrations of P1PI1, P1PI2, P2PI2, P3PI2, P5PI2, P1P5PI2, P1PI3, P4PI3, P7PI4, P8PI5 and P9PI6 polymers were taken with a pipette and equilibrated at 4 ℃ for 12h in a 2mL glass sample bottle (d ═ 7mm) to eliminate air bubbles generated during the sample application. And (3) carrying out Micro-CT test by taking alumina powder as a control group, and analyzing by using CTAn software after scanning reconstruction to obtain the gray value of the alumina powder. The resulting Micro-CT scans are shown. The difference in the average gray value between the aqueous polymer solution and the alumina powder is shown in Table 4:

TABLE 4

Note:^athe gray value analysis of each sample is performed by taking an intensity window in the same range;^b"+" indicates greater than, "-" indicates less than.

Example 38

The aqueous solution of the polymer P1PI2, P2PI2 and P3PI2 with the concentration of 30% is injected into the two sides of the mouse vertebra by subcutaneous injection, and the injection volume of each sample is 0.1 mL. 10min after injection of the sample, the mice were scanned systemically using Micro-CT, the scan results are shown in FIG. 7. The difference in grey value between the 30% aqueous solution of each polymer and the soft tissue in vivo is shown in table 5:

TABLE 5

Sample name	Mean gray value^a	Relative to the soft tissue in the body^b
			P1PI2	84.4	+67.7
P2PI2	82.2	+65.5
			P3PI2	85.8	+69.1
Soft tissue in vivo	16.7	/

The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. 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

1. The X-ray development thermotropic hydrogel is characterized by comprising 5-20% of an iodine-containing polycarbonate polymer, 5-40% of a thermotropic gelation amphiphilic block copolymer and the balance of a solvent by mass; the iodine-containing polycarbonate polymer has the structure:

wherein, x is 12-45, and y is 2-20.

2. The X-ray developing thermotropic hydrogel as defined in claim 1, wherein the thermotropic gelled amphiphilic block copolymer comprises a hydrophilic block A and a hydrophobic block B, the hydrophilic block A is a polyethylene glycol (PEG) block with an average molecular weight of 400-8000g/mol, the hydrophobic block B is a polyester block or a polyamino acid block with an average molecular weight of 500-40000g/mol, and the mass of the hydrophilic block A accounts for 10-90% of the mass of the amphiphilic block copolymer, and the mass of the hydrophobic block B accounts for 10-90% of the mass of the amphiphilic block copolymer.

3. The X-ray developable thermotropic hydrogel of claim 2, wherein the polyester blocks comprise one or more of polyglycolide, polylactide, polyepsilon caprolactone, polyorthoester, polyepsilon-alkyl substituted caprolactone, poly-valerolactone, poly-1, 4, 8-trioxaspiro [4,6] -9-undecanone, poly-p-dioxanone, polyesteramide, polycarbonate, polyacrylate, polyetherester, and copolymers of the foregoing polyesters; and the number of the first and second electrodes,

the polyamino acid block comprises one or more of polyalanine, polylysine, polyglutamic acid and polyaspartic acid, and copolymer of the polyamino acid.

4. The X-ray developable thermotropic hydrogel according to claim 2, wherein the amphiphilic block copolymer is a triblock copolymer of ABA type or BAB type, a diblock copolymer of AB type, a graft copolymer of A-g-B or B-g-A type, (A-B)_nOr (B-A)_nA star block copolymer of (A), (BA)_nOr B (AB)_nOne or more of a multi-block copolymer of configuration, wherein n is an integer from 2 to 10.

5. The thermally induced hydrogel for X-ray imaging according to claim 1, wherein the solvent comprises one or more of pure water, water for injection, physiological saline, buffer solution, body fluid of animals, plants or human body, and tissue culture solution.

6. The X-ray development thermotropic hydrogel according to claim 1, further comprising a regulator in an amount of 0.01 to 15% by mass of the solvent, wherein the regulator comprises one or more of tween 20, tween 40, tween 80, sodium carboxymethylcellulose, carbomer, simethicone, propylene glycol, mannitol, sorbitol, xylitol, oligosaccharide, chondroitin, chitin, chitosan, gelatin, albumin glue, hyaluronic acid, and polyethylene glycol.

7. The X-ray developable thermotropic hydrogel according to claim 1, wherein the X-ray developable thermotropic hydrogel has a sol-gel phase transition temperature of between 4 and 37 ℃.

8. The preparation method of the X-ray development thermal hydrogel as claimed in any one of claims 1 to 7, wherein the preparation method comprises the steps of firstly stirring the mixture in an environment lower than the sol-gel phase transition temperature of the thermal gelation amphiphilic block polymer to fully dissolve the amphiphilic block polymer in a solvent, and then adding a certain amount of iodine-containing polycarbonate polymer to continue stirring the mixture to form a uniform and stable polymer aqueous system, thereby obtaining the polymer aqueous solution of the X-ray development thermal hydrogel.

9. The application of the thermally induced hydrogel for X-ray development according to any one of claims 1 to 7, wherein the thermally induced hydrogel is applied to the field of preparation of drug sustained-release carriers, tissue repair scaffolds, tissue markers or vascular embolization agents.