CN110628005A

CN110628005A - Iodine-containing polyester material and preparation method and application thereof

Info

Publication number: CN110628005A
Application number: CN201910696501.0A
Authority: CN
Inventors: 俞麟; 雷科文; 丁建东
Original assignee: Fudan University; Zhuhai Fudan Innovation Research Institute
Current assignee: Fudan University; Zhuhai Fudan Innovation Research Institute
Priority date: 2019-07-30
Filing date: 2019-07-30
Publication date: 2019-12-31
Anticipated expiration: 2039-07-30
Also published as: CN110628005B

Abstract

The invention discloses an iodine-containing polyester material, which introduces iodine atoms into a molecular chain in a chemical covalent bond mode and has adjustable X-ray developing performance. The invention also discloses a preparation method of the iodine-containing polyester material, which comprises the following steps of firstly, taking olefine acid as an initial raw material, and reacting with simple substance iodine in a sodium bicarbonate aqueous solution by a one-step method to obtain an iodine-containing lactone monomer with a six-membered ring lactone structure, wherein the reaction is simple and mild, safe and environment-friendly, and simple in separation and purification; and then the iodic lactone monomer can be subjected to ring-opening polymerization reaction with different lactone, lactide or carbonate monomers under the catalysis of different catalysts to obtain the target polymer. The reaction has strong controllability, and can realize the regulation and control of the molecular weight, the molecular weight distribution, the chain structure and the developing performance of the target polymer. Meanwhile, the iodine-containing polyester material designed and synthesized by the invention has better application prospect in the fields of drug sustained-release carriers, tissue repair scaffolds, tissue markers or vascular embolization agents and the like.

Description

Iodine-containing polyester material and preparation method and application thereof

Technical Field

The invention belongs to the field of medical polymer materials, and particularly relates to an iodine-containing polyester material, and a preparation method and application thereof.

Background

The degradable polyester medical polymer material has the advantages of good biocompatibility, adjustable degradation rate and the like, and has important application value in various medical fields of drug slow release, tissue engineering, prevention of postoperative adhesion and the like. In these medical applications, the polyester-based material generally needs to be implanted in vivo to exert a therapeutic effect, and once implanted in vivo, the polyester-based material undergoes a complex degradation process under the in vivo microenvironment, including cell invasion, body fluid erosion, hydrolysis and enzymolysis inside the material, and the like, which continuously changes the properties of the polyester-based material, thereby finally affecting the therapeutic effect. Therefore, the research on the degradation process of the polyester material in the human body has important guiding significance for the optimal design of the material and the achievement of the expected treatment effect.

In recent years, the development and popularization of in vivo imaging technology has made possible the non-invasive tracer material degradation process. The in vivo imaging technology can realize real-time nondestructive detection of the material degradation process, compare in traditional dissection sample observation, can reduce the consumption of sample and animal by a wide margin, can realize the long-term tracer to same sample simultaneously, provide very big facility for studying the material in vivo degradation process. At present, the imaging means for studying the in vivo degradation process of the material mainly comprises fluorescence imaging, X-ray imaging, nuclear magnetic resonance imaging and the like. Among them, the X-ray-based CT imaging is a common technique for clinical diagnosis, and has the characteristics of deep imaging depth, low cost, simple equipment, and the like, and can construct a three-dimensional image to obtain structural information of a material under study, and is a good means for studying in-vivo degradation of the material. The principle of CT imaging is to distinguish the internal structure of the target object according to the difference in the X-ray absorption capacity of each part of the target object, and polyester medical polymer materials generally contain only elements with low atomic mass, such as C, N, H, O, and are similar to human tissues, so it is generally difficult to trace them by CT imaging. Therefore, in order to realize CT imaging of polyester medical polymer materials, it is necessary to introduce an X-ray contrast agent to impart X-ray development properties. X-ray contrast agents can generally be introduced by two methods:

1) a polyester-based polymer material having X-ray developability is obtained by physically mixing an X-ray contrast agent. Although simple and effective, according to the reports in the literature, the physically mixed contrast agent risks to diffuse rapidly from the material to the surrounding tissue, and the resulting increase in local concentration of the contrast agent may also cause toxic side effects to the surrounding tissue. Clearly, too rapid release of contrast agent does not allow long-term tracking of the material degradation process.

2) Groups with X-ray development characteristics are introduced into a molecular chain by means of chemical covalent bonds. The method can obtain a system with stable X-ray developing performance, and can realize long-term imaging tracing in the material degradation process. According to the reports of the existing documents, the method can be divided into two categories, one category is that the synthesized polyester material is directly modified, the method is simple and direct, but the polyester material can be degraded to a certain degree in the modification process, so that the material performance becomes uncontrollable; the other type is that firstly an iodine-containing lactone monomer is synthesized, and then the polyester material with the X-ray developing characteristic is obtained by the copolymerization of the iodine-containing lactone monomer and other monomers.

However, the existing iodine-containing lactone monomers which can be used for obtaining polyester materials with X-ray development characteristics through ring-opening polymerization are only one example of alpha-iodo-epsilon-caprolactone, and the iodine-containing lactone has the disadvantages of harsh synthesis conditions, low yield and no potential for large-scale production. In addition, the iodine-containing lactone itself has poor stability, is not suitable for long-term storage, and is easy to decompose in the ring-opening polymerization process, so that the controllability of the ring-opening polymerization reaction is poor.

Therefore, the development of an iodine-containing polyester material with controllable molecular weight and adjustable developability and a ring-opening polymerization method for preparing the material with mild conditions and high yield are the problems which need to be solved by the technical personnel in the field.

Disclosure of Invention

In view of the above, the present invention provides an iodine-containing polyester material with controllable molecular weight and adjustable developability, which is directed to the problems in the prior art.

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

an iodine-containing polyester material comprises a structural unit A of a structural formula (I),

and the content of the structural unit A in the iodine-containing polyester material is 10-100 mol%.

It is worth to say that the iodine atoms with X-ray development characteristics are introduced into the molecular chain in a chemical covalent bond mode, so that the iodine-containing polyester material has stable X-ray development performance. Also, the present invention specifically defines the content of the structural unit a in the iodine-containing polyester material, considering that the X-ray developing performance of the iodine-containing polyester material is closely related to the content of the structural unit a having a developing group in the iodine-containing polyester material. However, it should be understood that the regulation of the X-ray developing performance of the material can be realized by adjusting the content of the structural unit a in the iodine-containing polyester material, and at this time, the content of all other structural units a obtained by those skilled in the art without making creative efforts falls within the protection scope of the present invention.

Preferably, the iodine-containing polyester material further comprises a structural unit B, wherein the structural unit B is one or more of structural formulas (III) to (XIV),

it is worth to say that, in the iodine-containing polyester material composed of the structural unit a and the structural unit B, the sequences of the structural unit a and the structural unit B are randomly distributed.

Preferably, the iodine-containing polyester material further comprises functional end groups, wherein the functional end groups comprise one or more of hydroxyl, amino, carboxyl, imidazolyl, aldehyde, cyano, nitro, alkyl, sterol, alkoxy, aryl, aromatic heterocyclic group, amide ester group, halogen atom, trichloromethyl, ester group and sulfhydryl.

The invention also aims to provide a preparation method of the iodine-containing polyester material.

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

in the preparation method of the iodine-containing polyester material, under the action of an initiator and a catalyst, the compound (II) is subjected to ring-opening polymerization to obtain the iodine-containing polyester material,

the initiator comprises a hydroxyl compound or an amino compound;

the catalyst comprises any one of diphenyl phosphate, 1,5, 7-triazabicyclo [4.4.0] dec-5-ene, stannous trifluoromethanesulfonate, triethylaluminum, diethyl zinc, bis (bistrimethylsilyl) amine zinc and novacin lipase 435.

Preferably, the ring-opening polymerization is ring-opening homopolymerization or ring-opening copolymerization, and the comonomers of the ring-opening copolymerization comprise one or more of D, L-lactide, D-lactide, L-lactide, glycolide, epsilon-caprolactone, epsilon-alkyl substituted caprolactone, delta-valerolactone, 1,4, 8-trioxaspiro [4,6] -9-undecanone, p-dioxane ketone and trimethylene carbonate.

Preferably, the preparation method of the compound (II) is to react 5-hexenoic acid as a raw material with iodine in an aqueous solution of sodium bicarbonate in the dark to obtain the compound (II).

The invention also aims to provide application of the iodine-containing polyester material in preparing a drug sustained-release carrier, a tissue repair stent, a tissue marker or a vascular embolization agent.

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

the invention takes olefine acid as raw material, reacts with simple substance iodine in sodium bicarbonate aqueous solution, obtain the required iodine-containing lactone monomer with hexatomic ring lactone structure through one-step reaction of iodine lactonization, the method has advantages such as simple and mild, safe and environment-friendly, simple separation and purification, is suitable for large-scale production; the synthesized iodine-containing lactone monomer has good ring-opening polymerization activity, can generate ring-opening polymerization reaction with different lactone, lactide or carbonic ester monomers under the catalysis of different catalysts, and has strong polymerization reaction controllability, thereby providing a convenient and feasible preparation means for developing degradable polyester medical high polymer materials which can be traced in vivo without damage.

Meanwhile, the obtained iodine-containing polyester material introduces groups with X-ray development characteristics into a molecular chain in a chemical covalent bond mode, and compared with a small-molecular contrast agent, the polyester material has the advantages of lower osmotic pressure, stronger form selectivity, better thermal stability and convenience for storage, processing and application of the material.

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 hydrogen nuclear magnetic spectrum of IMVL, an iodine-containing lactone monomer in example 2.

FIG. 2 is a hydrogen nuclear magnetic spectrum of iodine-containing block Copolymer Copolymer-7 of example 12.

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

The preparation method of the iodine-containing polyester material comprises the steps of adding 5.0g of 5-hexenoic acid into a 250mL single-neck bottle, placing the single-neck bottle in an ice bath, and then slowly adding 100mL of sodium bicarbonate-elemental iodine solution (NaHCO) under stirring₃,9.3g,2.5eq；I₂16.7g,1.5eq), and the reaction is continued to be stirred in ice bath for 1.5h under dark condition after the addition is finished. After the reaction was completed, 100mL of a saturated sodium sulfite solution was added for washing, followed by extraction with 300mL of dichloromethane. Drying the extract with anhydrous magnesium sulfate, and finally performing rotary evaporation to remove dichloromethane to obtain the iodic lactone monomer (IMVL), wherein the yield is about 80%.

Example 2

The preparation method of the iodine-containing polyester material comprises the steps of adding 10g of 5-hexenoic acid into a 500mL single-neck bottle, placing the single-neck bottle in an ice bath, and then slowly adding 200mL of sodium bicarbonate-elemental iodine solution (NaHCO) under stirring₃,22.2g,6.0eq；I₂44.4g,4.0eq), and the reaction is continued to be stirred at 25 ℃ for 2 hours in the dark after the addition is finished. After the reaction, 200mL of saturated sodium sulfite solution was added and washed, followed by extraction with 500mL of dichloromethane. Drying the extract with anhydrous magnesium sulfate, and rotary evaporating to remove dichloromethane to obtain iodic lactone monomer (IMVL) with yield of about 90%, using deuterated chloroform as solvent, tetramethylsilane as internal standard, and FIG. 1 as structural representation¹HNMR map.

Example 3

A method for preparing iodine-containing polyester material comprises adding 8.0g of 5-hexenoic acid into a 250mL single-neck bottle, placing the single-neck bottle in an ice bath, and slowly adding 150mL of sodium bicarbonate-elemental iodine solution (NaHCO) under stirring₃,11.8g,2.0eq；I₂17.8g,1.0eq), and the reaction is continued to be stirred at 25 ℃ in the dark for 1 hour after the addition is finished. After the reaction was completed, 150mL of a saturated sodium sulfite solution was added to wash the reaction solution, and then the reaction solution was extracted with 400mL of dichloromethane. Drying the extract with anhydrous magnesium sulfate, and finally performing rotary evaporation to remove dichloromethane to obtain the iodic lactone monomer (IMVL), wherein the yield is about 85%.

The invention provides a preparation method of an iodine-containing polyester material, which comprises a preparation method of an iodine-containing lactone monomer according to embodiments 1-3 disclosed by the invention, wherein the iodine-containing lactone monomer can be used as a reaction monomer for subsequent ring-opening homopolymerization and/or ring-opening copolymerization.

Example 4

A preparation method of an iodine-containing polyester material comprises the steps of adding 18mg of isoamyl alcohol into a 250mL single-neck bottle with an air valve, then adding 150mL of anhydrous toluene for dissolving, stirring for a while, sequentially adding IMVL (12.0g) and diphenyl phosphate (DPP,50mg), and then stirring and reacting for 48 hours at room temperature under an argon atmosphere. After the reaction is finished, excessive ethyl ether is added for precipitation for 24 hours, then the supernatant is poured out, the lower precipitate is dissolved by dichloromethane and filtered, and finally the dichloromethane is removed by rotary evaporation to obtain the product PIMVL homopolymer (polymer-1), wherein the yield is about 73%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 36400 and 47700, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.31.

Example 5

A preparation method of iodine-containing polyester material comprises the steps of adding 56mg of propiolic alcohol into a 250mL single-neck bottle with an air vent, then adding 100mL of anhydrous toluene for dissolving, stirring for a while, and then sequentially adding IMVL (8.00g) and stannous trifluoromethanesulfonate (Sn (OTf))₂0.45g) was added, followed by stirring the reaction at room temperature under an argon atmosphere for 36 hours. After the reaction is finished, excessive ethyl ether is added for precipitation for 24 hours, then the supernatant is poured, the lower precipitate is dissolved by dichloromethane and filtered, and finally the dichloromethane is removed by rotary evaporation to obtain the product PIMVL homopolymer (polymer-2), wherein the yield is about 64%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 4940 and 6820, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.38.

Example 6

A method for preparing iodine-containing polyester material comprises adding 6.75g polyethylene glycol (PEG, MW 1500) into 250mL single-neck bottle with air valve, and adding 150mL toluene for dissolving. After complete dissolution, the PEG was azeotropically distilled under argon to remove residual moisture. When about 80mL of toluene remained, the system was stopped from distillation and returned to room temperature, and then IMVL (9.00g) and diphenyl phosphate (DPP,1.10g) were added in this order and the reaction was stirred at room temperature under an argon atmosphere for 24 hours. After the reaction is finished, an initial product is obtained by precipitation with excessive ethyl ether, then the initial product is dissolved by dichloromethane and filtered, and finally the product PIMVL-PEG-PIMVL triblock polymer (copolymer-1) is obtained by rotary evaporation of dichloromethane, and the yield is about 76%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 2090 and 2610, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.25.

Example 7

A preparation method of an iodine-containing polyester material comprises the steps of adding 18mg of isoamyl alcohol into a 250mL single-neck bottle with an air vent valve, then adding 150mL of anhydrous toluene for dissolving, stirring for a while, sequentially adding IMVL (8.20g), epsilon-caprolactone (CL,7.80g) and diphenyl phosphate (DPP,50mg), and then stirring and reacting at room temperature for 48 hours under an argon atmosphere. After the reaction is finished, adding excessive diethyl etherPrecipitation was carried out for 24h, the supernatant was poured off, the lower precipitate was dissolved in dichloromethane and filtered, and finally the dichloromethane was removed by rotary evaporation to give the product P (IMVL-co-CL) copolymer (copolymer-2) in about 70% yield. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 57800 and 76900, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.33.

Example 8

A method for preparing iodine-containing polyester material comprises adding 110mg benzyl alcohol into 250mL single-neck bottle with vent valve, adding 100mL anhydrous toluene for dissolving, stirring for a while, sequentially adding IMVL (8.60g), 1,4, 8-trioxa spiro [4,6] to the solution]-9-undecanone (TOSUO,2.11g) and diphenyl phosphate (DPP,240mg), followed by a reaction with stirring at room temperature under an argon atmosphere for 24 h. After the reaction is finished, precipitation is carried out for 24 hours by using excessive diethyl ether, then the supernatant is poured, the lower precipitate is dissolved by using dichloromethane and filtered, and finally, dichloromethane is removed by rotary evaporation to obtain the product P (IMVL-co-TOSUO) copolymer (copolymer-3) with the yield of about 72 percent. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 8150 and 10400, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.28.

Example 9

A preparation method of iodine-containing polyester material comprises the steps of adding 35mg of isoamyl alcohol into a 250mL single-neck bottle with an air valve, then adding 80mL of anhydrous toluene for dissolving, stirring for a while, and then sequentially adding IMVL (2.40g), delta-valerolactone (VL,5.0g) and stannous trifluoromethanesulfonate (Sn (OTf)₂170mg), and then the reaction was stirred at room temperature under an argon atmosphere for 36 hours. After the reaction is finished, adding excessive ether into the system for precipitation to obtain an initial product. The initial product was dissolved in dichloromethane and filtered, and the final product, P (IMVL-co-VL) copolymer (biopolymer-4), was obtained after removal of the dichloromethane by rotary evaporation, with a yield of about 65%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 13100 and 18600, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.42.

Example 10

A preparation method of an iodine-containing polyester material comprises the steps of adding 55mg of isoamyl alcohol into a 100mL single-neck bottle with an air valve, then adding 50mL of anhydrous toluene for dissolving, stirring for a while, sequentially adding IMVL (3.40g), p-dioxane ketone (PDO,1.43g) and novacin lipase 435(Novozyme 435,0.50g), and then stirring and reacting at room temperature for 48 hours under an argon atmosphere. After the reaction, the product P (IMVL-co-PDO) copolymer (biopolymer-5) is obtained with a yield of about 64% after precipitation with excess ether, dissolving the obtained initial product with dichloromethane and filtering, and finally removing dichloromethane by rotary evaporation. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 5820 and 8440, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.45.

Example 11

A preparation method of an iodine-containing polyester material comprises the steps of adding 1.10g of monomethoxy polyethylene glycol (mPEG, MW 550) into a 250mL single-neck bottle with an air valve, and then adding 100mL of toluene for dissolution. After complete dissolution, residual moisture in mPEG was removed by azeotropic distillation under argon atmosphere. When about 50mL of toluene remained, the distillation of the system was stopped and the system was returned to room temperature, followed by addition of IMVL (2.30g), ε -caprolactone (CL,3.70g) and diphenyl phosphate (DPP,0.45g) in this order and reaction with stirring under argon at room temperature for 24 h. After the reaction is finished, adding excessive diethyl ether for precipitation for 24 hours, then pouring out supernatant, dissolving lower precipitate with dichloromethane, filtering, and removing dichloromethane by rotary evaporation to obtain the product mPEG-P (IMVL-co-CL) block copolymer (copolymer-6) with the yield of about 82%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 2360 and 2990, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.27.

Example 12

A method for preparing iodine-containing polyester material comprises adding 5.00g polyethylene glycol (PEG, MW 1500) into 250mL single-neck bottle with air valve, and adding 150mAnd dissolving the mixture by using L toluene. After complete dissolution, the PEG was azeotropically distilled under argon to remove water. When about 100mL of toluene remained, the distillation of the system was stopped and the system was returned to room temperature, followed by addition of IMVL (3.30g), ε -caprolactone (CL,7.60g) and diphenyl phosphate (DPP,0.80g) in this order and reaction with stirring under argon at room temperature for 24 h. After the reaction is finished, an excessive amount of ether is used for precipitation to obtain a primary product, dichloromethane is used for dissolving the primary product and filtering, the dichloromethane is removed through rotary evaporation to obtain a product P (IMVL-co-CL) -PEG-P (IMVL-co-CL) block copolymer (copolymer-7), the yield is about 70 percent, deuterated chloroform is used as a solvent, tetramethylsilane is used as an internal standard, and the structure of the product is represented as shown in figure 2¹HNMR map. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 3680 and 4860 molecular weight distribution coefficient (M)_n/M_w) Is 1.32.

Example 13

A method for preparing iodine-containing polyester material comprises adding 8.00g of amino-terminated functionalized polyethylene glycol (H) into 250mL single-neck bottle with vent valve₂N-PEG-NH₂MW 4000) and then dissolved by adding 150mL of toluene. After complete dissolution, the PEG was azeotropically distilled under argon to remove water. Upon leaving about 80mL of toluene, the system was stopped and brought to room temperature, followed by the sequential addition of IMVL (8.20g), ε -caprolactone (CL,1.80g) and stannous triflate (Sn (OTf)₂0.90g) and the reaction stirred at room temperature under argon atmosphere for 36 h. After the reaction is finished, an excessive amount of ether is used for precipitation to obtain a primary product, the primary product is dissolved by dichloromethane and filtered, and the dichloromethane is removed by rotary evaporation to obtain a product P (IMVL-co-CL) -PEG-P (IMVL-co-CL) block copolymer (copolymer-8), wherein the yield is about 76%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 5630 and 7140, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.27.

Example 14

A method for preparing iodine-containing polyester material comprises adding 55mg phenylpropanol into 250mL single-necked bottle with vent valve, and adding 120mL non-iodine polyester materialThe mixture was dissolved in water and toluene, and after stirring for a while, IMVL (7.50g), D, L-lactide (DLLA,4.50g) and diphenyl phosphate (DPP,95mg) were added in this order, followed by reaction under stirring at room temperature under an argon atmosphere for 36 hours. After the reaction is finished, the mixture is precipitated by ether for 24 hours, then dichloromethane is used for dissolving the lower precipitate, the lower precipitate is filtered, and finally dichloromethane is rotated and evaporated to obtain a product P (IMVL-co-DLLA) copolymer (copolymer-9) with the yield of about 68 percent. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 20400 and 27500, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.35.

Example 15

A preparation method of an iodine-containing polyester material comprises the steps of adding 3.00g of polyethylene glycol (PEG, MW 1500) into a 250mL single-neck bottle with an air valve, and then adding 150mL of toluene for dissolution. After complete dissolution, the PEG was azeotropically distilled under argon to remove residual moisture. When about 60mL of toluene remained, the system was stopped from distillation and returned to room temperature, followed by addition of IMVL (7.20g), D, L-lactide (DLLA,0.80g) and diphenyl phosphate (DPP,0.50g) in this order and reaction with stirring under argon at room temperature for 24 h. After the reaction is finished, an excessive amount of ether is used for precipitation to obtain a primary product, the primary product is dissolved in dichloromethane and filtered, and the dichloromethane is removed through rotary evaporation to obtain a product P (IMVL-co-DLLA) -PEG-P (IMVL-co-DLLA) block copolymer (copolymer-10), wherein the yield is about 70%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 3410 and 4810, respectively, molecular weight distribution coefficient (M)_n/M_w) Was 1.41.

Example 16

A method for preparing iodine-containing polyester material comprises adding 1.50g polyethylene glycol (PEG, MW 2000) into 250mL single-neck bottle with air valve, and adding 120mL toluene for dissolving. After complete dissolution, the PEG was azeotropically distilled under argon to remove residual moisture. When about 60mL of toluene remained, the system was stopped from distillation and returned to room temperature, followed by the sequential addition of IMVL (1.80g), L-lactide (LLA,6.20g) and Novozyme 435(Novozyme 435,0.40g) under argon atmosphereThe reaction was stirred at room temperature for 48 h. After the reaction, the product P (IMVL-co-LLA) -PEG-P (IMVL-co-LLA) block copolymer (copolymer-11) is obtained with a yield of about 74 percent after the initial product is obtained by precipitation with excess ether, the obtained initial product is dissolved with dichloromethane and filtered, and finally dichloromethane is removed by rotary evaporation. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 7140 and 9710, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.36.

Example 17

42mg of propiolic alcohol is added into a 250mL single-neck bottle with an air vent valve, 150mL of anhydrous toluene is added for dissolution, IMVL (4.30g), glycolide (GA,10.70g) and diphenyl phosphate (DPP,0.20g) are sequentially added after stirring for a while, and then the mixture is stirred and reacted for 24 hours at room temperature under the argon atmosphere. After the reaction is finished, adding excessive ether into the system to precipitate to obtain a primary product, dissolving the primary product with dichloromethane, filtering, and finally removing the dichloromethane by rotary evaporation to obtain a product P (IMVL-co-GA) copolymer (copolymer-12) with the yield of about 66%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 15600 and 19200, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.23.

Example 18

A preparation method of an iodine-containing polyester material comprises the steps of adding 1.50g of monomethoxy polyethylene glycol (mPEG, MW 750) into a 250mL single-neck bottle with an air valve, and then adding 150mL of toluene for dissolution. After complete dissolution, residual moisture in mPEG was removed by azeotropic distillation under argon atmosphere. Upon leaving about 80mL of toluene, the system stops distilling and returns to room temperature, followed by the sequential addition of IMVL (5.30g), glycolide (GA,4.70g) and stannous triflate (Sn (OTf)₂0.85g) and the reaction stirred at room temperature under argon atmosphere for 36 h. Precipitating with excessive diethyl ether to obtain initial product, dissolving the initial product with dichloromethane, filtering, and rotary evaporating to remove dichloromethane to obtain mPEG-P (IMVL-co-GA) block copolymer (copolymer-13) with yield of aboutThe content was 70%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 4200 and 5420, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.29.

Example 19

A method for preparing iodine-containing polyester material comprises adding 6.70g polyethylene glycol (PEG, MW 1000) into 250mL single-neck bottle with air valve, and adding 160mL toluene for dissolving. After complete dissolution, the PEG was azeotropically distilled under argon to remove residual moisture. When about 120mL of toluene remained, the system was stopped from distillation and returned to room temperature, followed by addition of IMVL (11.20g), glycolide (GA,4.80g) and diphenyl phosphate (DPP,1.60g) in this order and reaction with stirring at room temperature under an argon atmosphere for 24 h. After the reaction is finished, excess ether is added, and a crude product is obtained by precipitation. The crude product was dissolved in dichloromethane and filtered, and the dichloromethane was removed by rotary evaporation to obtain the product P (IMVL-co-GA) -PEG-P (IMVL-co-GA) block copolymer (copolymer-14) with a yield of about 73%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 2450 and 3280, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.34.

Example 20

A method for preparing iodine-containing polyester material comprises adding 3.30g of polyethylene glycol (PEG, MW 1500) into a 250mL single-neck bottle with an air valve, and adding 120mL of toluene for dissolving. After complete dissolution, the PEG was azeotropically distilled under argon to remove residual moisture. When about 80mL of toluene remained, the distillation of the system was stopped and the system was returned to room temperature, followed by addition of IMVL (6.40g), trimethylene carbonate (TMC,1.60g) and diphenyl phosphate (DPP,0.55g) in this order and reaction with stirring at room temperature under an argon atmosphere for 24 h. After the reaction is finished, excessive ether is added to precipitate the product, the obtained crude product is dissolved by dichloromethane and filtered, and finally, the dichloromethane is removed by rotary evaporation to obtain the product P (IMVL-co-TMC) -PEG-P (IMVL-co-TMC) block copolymer (copolymer-15), wherein the yield is about 76%. The number average and weight average molecular weight of the polymer were determined by GPC (using THF as mobile phase and PS as standard)Quantum (M)_n，M_w) 3570 and 5570, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.56.

Example 21

A preparation method of an iodine-containing polyester material comprises the steps of adding 110mg of benzyl alcohol into a 250mL single-neck bottle with an air valve, then adding 100mL of anhydrous toluene for dissolving, stirring for a while, sequentially adding IMVL (8.60g), epsilon-caprolactone (CL,0.68g), delta-valerolactone (VL, 0.6g) and diphenyl phosphate (DPP,240mg), and then stirring and reacting at room temperature for 24 hours under an argon atmosphere. After the reaction is finished, precipitation is carried out for 24 hours by using excessive diethyl ether, then the supernatant is poured, the lower precipitate is dissolved by using dichloromethane and filtered, and finally, the dichloromethane is removed by rotary evaporation to obtain the product P (IMVL-co-CL-co-VL) copolymer (copolymer-16) with the yield of about 70 percent. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 8010 and 10490, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.31.

Example 22

A preparation method of iodine-containing polyester material comprises the steps of adding 35mg of isoamyl alcohol into a 250mL single-neck bottle with an air vent valve, then adding 80mL of anhydrous toluene for dissolving, stirring for a while, and then sequentially adding IMVL (2.40g), delta-valerolactone (VL,3.0g), p-dioxane ketone (PDO,2.04g) and bis (trimethylsilyl) amine zinc (Zn (HMDS))₂300mg) was added to the reaction solution, and the reaction was stirred at room temperature under an argon atmosphere for 36 hours. After the reaction is finished, adding excessive ether into the system for precipitation to obtain an initial product. The initial product was dissolved in dichloromethane and filtered, and the dichloromethane was removed by rotary evaporation to obtain product P (IMVL-co-VL-co-PDO) copolymer (copolymer-17) with a yield of about 63%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard)_n，M_w) 11150 and 16170, respectively, molecular weight distribution coefficient (M)_n/M_w) Is 1.45.

The molecular parameters of the copolymers or block copolymers synthesized in examples 4-22 according to the present disclosure are listed in Table 1 below. The invention can be seen in that the iodine-containing lactone monomer IMVL can perform ring-opening polymerization reaction with different lactone monomers under the catalysis of different catalysts to obtain various iodine-containing polyester materials, so that the introduction of a group with X-ray developing property into a molecular chain in a chemical covalent bond manner is realized, and the polyester material with stable X-ray developing property is obtained. The polymerization reaction has strong controllability, and the molecular weight, the molecular weight distribution and the chain structure of the polyester material can be regulated and controlled by regulating the variety of the lactone monomers and the molar ratio of the polyester blocks.

TABLE 1

Example 23

The iodine-containing polyester material is applied to in vivo nondestructive tracking, 4.2g of copolymer-9 is added into 11g of dichloromethane to be dissolved overnight, the mixture is poured into 50mL of 0.4 wt% PVA aqueous solution after being uniformly shaken, and the mixture is stirred for two minutes by a high-speed homogenizer at 6000 rpm. The emulsion was poured into 1280mL of water, stirred at room temperature for 30 minutes, and then warmed to 30 ℃ to cure for 6 hours. Filtration, washing with water (5X 40mL), and vacuum drying afforded 1.6g of polymeric microspheres. The particle size and the particle size distribution of the polymer microspheres are measured by a laser particle size analyzer, and the average particle size is 150 micrometers. 30mg of microspheres are uniformly dispersed in 0.15mL of Tween 80 aqueous solution containing 0.2 wt%, then the microsphere solution is injected to the back subcutaneous of a mouse, and Micro-CT scanning is respectively carried out 10 days, 20 days and 30 days after the injection, and the result shows that the injected microspheres can still be clearly seen under the Micro-CT after 30 days of the injection.

Example 24

The iodine-containing polyester material is applied to in vivo nondestructive tracking, 4.2g of copolymer-4 is added into 11g of dichloromethane to be dissolved overnight, the mixture is uniformly shaken and then poured into 50mL of 0.4 wt% PVA aqueous solution, and the mixture is stirred for two minutes by a high-speed homogenizer at the speed of 5000 rpm. The emulsion was poured into 1280mL of water, stirred at room temperature for 30 minutes, and then warmed to 30 ℃ to cure for 6 hours. Filtration, washing with water (5X 40mL), and vacuum drying gave 1.5g of polymeric microspheres. The particle size and the particle size distribution of the polymer microspheres are measured by a laser particle size analyzer, and the average particle size is 170 micrometers. 30mg of microspheres are uniformly dispersed in 0.15mL of Tween 80 aqueous solution containing 0.2 wt%, then the microsphere solution is injected to the back subcutaneous of a mouse, and Micro-CT scanning is respectively carried out 15 days, 30 days and 45 days after the injection, and the result shows that the injected microspheres can still be clearly seen under the Micro-CT after the injection for 45 days.

To further verify the excellent effects of the present invention, the inventors also conducted the following comparative experiments:

comparative example 1

The products obtained in examples 4 to 22 and conventional X-ray developers such as iopamidol and alumina were placed in PMMA plexiglass tubes, respectively, and sealed, and scanned and photographed under the same conditions using Micro-CT, and the results are shown in table 2. The method can realize the regulation and control of the X-ray development performance of the material by regulating the copolymerization ratio of the iodine-containing lactone monomer, so that the iodine-containing polyester material disclosed by the invention has great application potential in the field of degradable polyester medical high polymer materials which can not be traced in vivo.

TABLE 2

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. An iodine-containing polyester material is characterized by comprising a structural unit A of a structural formula (I),

2. The iodine-containing polyester material of claim 1, further comprising a structural unit B, wherein said structural unit B is one or more of structural formulas (III) to (XIV),

3. the iodine-containing polyester material of any one of claims 1 or 2, further comprising functional end groups, wherein the functional end groups comprise one or more of hydroxyl, amino, carboxyl, imidazolyl, aldehyde, cyano, nitro, alkyl, sterol, alkoxy, aromatic heterocyclic, amide ester, halogen atom, trichloromethyl, ester, and mercapto.

4. The method for preparing the iodine-containing polyester material as claimed in any one of claims 1 to 2, wherein the compound (II) is subjected to ring-opening polymerization under the action of an initiator and a catalyst to obtain the iodine-containing polyester material,

the initiator comprises a hydroxyl compound or an amino compound;

5. The method for producing iodine-containing polyester material according to claim 4, wherein said ring-opening polymerization is ring-opening homopolymerization or ring-opening copolymerization, and said ring-opening copolymerization comonomer comprises one or more of D, L-lactide, D-lactide, L-lactide, glycolide, epsilon-caprolactone, epsilon-alkyl substituted caprolactone, delta-valerolactone, 1,4, 8-trioxaspiro [4,6] -9-undecanone, p-dioxanone, trimethylene carbonate.

6. The method for preparing the iodine-containing polyester material according to claim 4, wherein the compound (II) is prepared by reacting 5-hexenoic acid serving as a raw material with elemental iodine in an aqueous solution of sodium bicarbonate in the absence of light to obtain the compound (II).

7. The use of the iodine-containing polyester material of any one of claims 1 to 3 for the preparation of a drug delivery vehicle, a tissue repair scaffold, a tissue marker or a vascular embolization agent.