Self-developing high molecular polymer, method for preparing the same and liquid embolic agent

Abstract

The present application relates to a kind of self-developing high molecular polymer and its preparation method and liquid embolic agent.The self-developing high molecular polymer is the gelling gum derivative of side chain grafting iodine benzyl group.The self-developing high molecular polymer of the present application uses natural gelling gum as matrix, and self-developing group is chemically bonded, and its own gel-forming property and viscosity play the embolism effect, avoid the potential toxicity of heavy metal developing agent (such as tantalum powder), with excellent biocompatibility and safety.The grafted iodine benzyl group has high grafting rate and stable structure, provides sustained and uniform developing effect under X-ray, does not need intraoperative mixing, simplifies the operation process, and has reliable self-developing performance.When used for liquid embolic agent, it can form a gel with adhesion, can closely adhere to the vessel wall, and realize stable embolism effect.

Description

Technical Field

[0001] This invention relates to the field of embolic agents, and in particular to a self-illuminating polymer, its preparation method, and a liquid embolic agent. Background Technology

[0002] In modern minimally invasive vascular interventional surgery, therapeutic embolization of hemangiomas is a common procedure. This involves safely and effectively introducing a material into the affected hemangioma site to create an obstruction, slowing or stopping blood flow and thus controlling bleeding and embolizing the hemangioma. Unlike coil-type solid metal embolic agents, liquid embolic agents are delivered to the hemangioma site in liquid form, forming a gel in situ within a short time to embolize the hemangioma. Furthermore, liquid embolic agents diffuse well within the hemangioma, especially into the tiny capillaries and vessel walls.

[0003] Minimally invasive interventional treatment of hemangiomas relies on catheter-directed embolization. Digital subtraction angiography (DSA) is used to diagnose the lesion, and an embolic agent is injected via catheter for treatment. Currently, liquid embolization polymers used for embolizing hemangioma lesions are non-radioactive, requiring the addition of contrast agents during the procedure. For example, when using Onyx non-adhesive liquid embolization clinically, tantalum powder must be added as a contrast agent. This requires vortexing for at least 20 minutes before use and continuous mixing during catheter delivery. This cumbersome procedure also means that the contrast agent may precipitate and accumulate over time, potentially leading to serious adverse clinical reactions. To overcome the inherent limitations of physical blending of embolization polymers and contrast agents, introducing iodine into the polymer molecular chain to prepare self-radioactive polymer liquid embolization agents shows promising research potential. However, traditionally used polymers (such as polyvinyl alcohol) are primarily synthetic polymers, and their biocompatibility and bioabsorbability are unclear, limiting their application, especially in intracranial liquid embolization.

[0004] Therefore, there is still a need to develop polymer liquid embolization systems with excellent imaging, embolization, and biocompatibility. Summary of the Invention

[0005] Therefore, it is necessary to provide a self-developing polymer with excellent imaging effect, embolization effect and biocompatibility, as well as its preparation method and liquid embolizing agent.

[0006] A self-developing polymer, wherein the self-developing polymer is a gellan gum derivative with iodine benzyl groups branched on the side, and the chemical structural formula of the self-developing polymer includes any one or more of the following structures:

[0007] , , , or .

[0008] First, the self-illuminating polymer of this invention uses natural gellan gum as a matrix, making the material itself safe and biodegradable. The chemically bonded self-illuminating groups, with their gelling properties and viscosity, provide an embolic effect, avoiding the potential toxicity of heavy metal contrast agents (such as tantalum powder), and exhibiting excellent biocompatibility and safety. Second, the grafted iodobenzyl groups in the self-illuminating polymer of this invention have a high grafting rate and stable structure, providing continuous and uniform imaging under X-rays. No intraoperative mixing is required, simplifying the surgical procedure and demonstrating reliable self-illuminating performance. Third, when used as a liquid embolic agent, the self-illuminating polymer of this invention can form an adhesive gel that adheres tightly to the blood vessel wall, achieving a stable embolizing effect.

[0009] In one embodiment, the molecular weight of the self-developing polymer is 100,000 to 600,000.

[0010] A method for preparing the self-developing polymer as described above includes the following steps:

[0011] Natural polysaccharide gellan gum was dissolved in water, then reacted with an oxidizing agent to cleave the sugar chains. Following reduction, purification, and freeze-drying, the cleaved gellan gum was obtained.

[0012] Under an inert atmosphere, the cut gellan gum is dissolved in an anhydrous organic solvent, and iodobenzyl bromide and alkali are added. After the reaction is complete, a gellan gum derivative with iodobenzyl groups branched on the side is obtained, which is a self-developing polymer.

[0013] The preparation method of this invention precisely controls the molecular weight of gellan gum through oxidative cutting to improve its flexibility, and stably bonds iodobenzyl groups to the side chains through a sequentially controlled grafting reaction, thereby efficiently producing a self-illuminating polymer that combines excellent biocompatibility, uniform self-illumination ability, and stable gelation embolization performance, providing an ideal material basis for safe, convenient, and effective vascular interventional therapy.

[0014] In one embodiment, the natural polysaccharide gellan gum is dissolved in water, then reacted with an oxidizing agent to cleave the sugar chains, followed by reduction, purification, and freeze-drying.

[0015] Natural polysaccharide gellan gum is dissolved in water and heated to 40℃~80℃ to fully dissolve it, forming a homogeneous and transparent solution;

[0016] An oxidizing agent is added to the homogeneous and transparent solution to induce oxidative cleavage of sugar chains.

[0017] Add ethylene glycol and allow it to react completely;

[0018] Add a reducing agent and allow the reaction to proceed fully; and

[0019] The sample was purified by chromatography and then freeze-dried into powder.

[0020] In one embodiment, the oxidant is sodium periodate.

[0021] In one embodiment, the reducing agent is sodium borohydride.

[0022] In one embodiment, the process of dissolving the cutting gellan gum in an anhydrous organic solvent, adding iodobenzyl bromide and an alkali, and reacting fully under an inert atmosphere is as follows:

[0023] Under an inert atmosphere, the cutting gellan gum is dissolved in an anhydrous organic solvent and heated to 90°C~100°C until fully dissolved to obtain a cutting gellan gum solution; and

[0024] The cut gellan gum solution is cooled to 50°C~60°C, then iodobenzyl bromide is added. After the reaction is complete, alkali is added, and after the reaction is complete, it is cooled to room temperature. Solid-liquid separation is performed and the solid is retained. The solid is the gellan gum derivative with iodobenzyl groups branched on the side.

[0025] In one embodiment, the anhydrous organic solvent is dimethyl sulfoxide.

[0026] In one embodiment, the iodobenzyl bromide comprises one or a mixture of more than one selected from 2-iodobenzyl bromide, 3-iodobenzyl bromide, 4-iodobenzyl bromide, 3,4-diiodobenzyl bromide, and 2,3,5-triiodobenzyl bromide; and / or

[0027] The alkali is sodium hydroxide.

[0028] A liquid embolizing agent comprising the above-mentioned autoradiographic polymer and an organic solvent.

[0029] The liquid embolizing agent of this invention possesses a uniform and stable self-illuminating function, eliminating the need for external contrast agents. This reduces the cumbersome steps of physical blending contrast agents in existing technologies and avoids the damage to the human body caused by the leaching of heavy metal contrast agents used in physical blending, greatly improving its biocompatibility. Simultaneously, the liquid embolizing agent of this invention exhibits good biocompatibility, smooth delivery, and rapid gelation within blood vessels to form a stable embolism. Furthermore, it significantly simplifies the surgical procedure, enhancing the safety and operability of interventional treatment.

[0030] In one embodiment, the ratio of the self-developing polymer to the organic solvent is (0.26g~0.36g):10mL; and / or

[0031] The organic solvent is dimethyl sulfoxide. Attached Figure Description

[0032] Figure 1 This is a flowchart of a method for preparing a self-developing polymer according to an embodiment of the present invention;

[0033] Figure 2 The above is the 1H NMR spectrum of the self-developing polymer A obtained in Example 1 of this invention;

[0034] Figure 3 This is an image showing the complete embolization of a porcine aneurysm model during performance testing of this invention. Detailed Implementation

[0035] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0037] One embodiment of the self-developing polymer is a gellan gum derivative with side-linked iodine benzyl groups, and the chemical structural formula of the self-developing polymer includes any one or more of the following structures:

[0038] , , , or .

[0039] The developing group of the aforementioned self-developing polymer is an iodobenzyl group. The introduction of the iodobenzyl group enables the polymer to continuously and uniformly develop self-images, which are visible when using X-ray imaging.

[0040] Based on the aforementioned embodiments, the molecular weight of the self-developing polymer is 100,000 to 600,000. Further, the molecular weight of the self-developing polymer is preferably 250,000 to 350,000. Further, the molecular weight of the self-developing polymer can be, but is not limited to, 100,000, 150,000, 200,000, 250,000, 300,000, 350,000, 400,000, 450,000, 500,000, 550,000, or 600,000. In this invention, an iodine-containing compound is grafted onto the side chains of gellan gum after oxidative sugar chain cleavage. Due to the elongation of the side chains, the polymer molecular weight increases, flexibility improves, and rigidity decreases, allowing it to be flexibly injected into the catheter without sticking or blocking it.

[0041] First, the self-illuminating polymer of this invention uses natural gellan gum as a matrix, making the material itself safe and biodegradable. The chemically bonded self-illuminating groups, with their gelling properties and viscosity, provide an embolic effect, avoiding the potential toxicity of heavy metal contrast agents (such as tantalum powder), and exhibiting excellent biocompatibility and safety. Second, the grafted iodobenzyl groups in the self-illuminating polymer of this invention have a high grafting rate and stable structure, providing continuous and uniform imaging under X-rays. No intraoperative mixing is required, simplifying the surgical procedure and demonstrating reliable self-illuminating performance. Third, when used as a liquid embolic agent, the self-illuminating polymer of this invention can form an adhesive gel that adheres tightly to the blood vessel wall, achieving a stable embolizing effect.

[0042] Please see Figure 1 The method for preparing a self-developing polymer according to an embodiment of the present invention includes the following steps:

[0043] S10. Dissolve the natural polysaccharide gellan gum in water, then react it with an oxidant to oxidize and cleave the sugar chains. After reduction, purification and freeze-drying, the cleaved gellan gum is obtained.

[0044] The structural formulas of the constituent units involved in the reaction in natural polysaccharide gellan gum are as follows:

[0045] .

[0046] The natural polysaccharide gellan gum used in this embodiment is a natural polysaccharide polymer approved for use by the U.S. Food and Drug Administration (FDA), and commercially available products exist (such as Phytagel from Sigma Aldrich). Furthermore, numerous studies have demonstrated that gellan gum possesses excellent gelling properties and biocompatibility, and it is widely being developed as a matrix material for osteogenic repair, drug delivery, and tissue engineering.

[0047] In one embodiment, the natural polysaccharide gellan gum is dissolved in water, then reacted with an oxidizing agent to cleave the sugar chains, followed by reduction, purification, and freeze-drying.

[0048] Natural polysaccharide gellan gum is dissolved in water and heated to 40℃~80℃ to fully dissolve it, forming a homogeneous and transparent solution;

[0049] An oxidizing agent is added to a homogeneous, transparent solution, and the reaction proceeds to oxidatively cleave sugar chains.

[0050] Add ethylene glycol and allow it to react completely;

[0051] Add a reducing agent and allow the reaction to proceed fully; and

[0052] The sample was purified by chromatography and then freeze-dried into powder.

[0053] In the above embodiments, the added oxidant (such as sodium periodate, NaIO4) undergoes a specific oxidation reaction with the vicinal diol structure (i.e., two adjacent hydroxyl groups) in the natural gellan gum chain, namely periodate oxidation. This reaction leads to the breakage of the carbon-carbon bonds between the vicinal diols, generating two aldehyde groups, thereby achieving directional cleavage of the sugar chain. This process can effectively control the molecular weight of the polysaccharide, providing a polymer backbone of suitable length for subsequent functionalization grafting.

[0054] In the above embodiments, ethylene glycol contains a vicinal diol structure, which can react rapidly with the unreacted sodium periodate remaining in the system, thereby quenching excess oxidant, preventing it from continuing to oxidize the cleaved sugar chains, and ensuring that the reaction is controllable and reproducible.

[0055] In the above embodiments, the addition of a reducing agent (such as sodium borohydride, NaBH4) reduces the aldehyde groups generated by oxidative cleavage to primary alcohol hydroxyl groups, thereby converting the cleaved sugar chain ends into stable alcohol structures. This step avoids side reactions (such as condensation and cross-linking) of the aldehyde groups during subsequent storage or reactions, ensuring uniform product structure and good solubility, and providing stable reaction sites for subsequent grafting modification.

[0056] In the above embodiments, the oxidation reaction time can be, but is not limited to, 12 hours to 48 hours, and the reaction time after adding ethylene glycol can be, but is not limited to, 10 minutes to 60 minutes. Further, the oxidation reaction time can be, but is not limited to, 12 hours, 24 hours, 36 hours, or 48 hours, and the reaction time after adding ethylene glycol can be, but is not limited to, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, or 60 minutes.

[0057] In one embodiment, the oxidant is sodium periodate. Using sodium periodate as the oxidant allows for highly selective, mild, and controllable oxidative cleavage of the natural gellan gum ring structure, precisely achieving molecular weight regulation (100,000–600,000), thus providing an ideal framework for subsequent grafting reactions.

[0058] In one embodiment, the reducing agent is sodium borohydride. Using sodium borohydride as a reducing agent can efficiently and thoroughly reduce the aldehyde groups generated by oxidation to stable hydroxyl groups, avoiding cross-linking or side reactions caused by residual aldehyde groups, and ensuring a uniform product structure and good solubility.

[0059] The combined use of the above-mentioned oxidizing and reducing agents can avoid introducing impurities. The entire oxidation process... The reduction system features mild reaction conditions, simple operation, and safe and readily available reagents, which together provide a reliable process basis for obtaining self-developing polymers with well-defined structures and controllable properties.

[0060] S20. Under an inert atmosphere, the cut gellan gum obtained in step S10 is dissolved in an anhydrous organic solvent, and iodobenzyl bromide and alkali are added. After the reaction is complete, a gellan gum derivative with iodobenzyl groups branched on the side is obtained, which is a self-developing polymer.

[0061] The reaction process of one self-developing polymer is described using it as an example; the reaction processes of self-developing polymers containing other chemical structures are similar. Specifically, in one embodiment, the repeating unit reaction process of the method for preparing the self-developing polymer is as follows:

[0062] .

[0063] In one embodiment, the process of dissolving the cutting gellan gum in an anhydrous organic solvent, adding benzyl iodide bromide and an alkali, and reacting fully under an inert atmosphere is as follows:

[0064] Under an inert atmosphere, cutting gellan gum is dissolved in an anhydrous organic solvent and heated to 90°C~100°C until fully dissolved to obtain a cutting gellan gum solution; and

[0065] The gellan gum solution was cooled to 50℃~60℃, then iodobenzyl bromide was added. After the reaction was complete, alkali was added, and after the reaction was complete, it was cooled to room temperature. Solid-liquid separation was performed and the solid was retained. The solid was the gellan gum derivative with iodobenzyl groups attached to its side.

[0066] In the above embodiments, after adding iodobenzyl bromide, it dissolves and disperses uniformly in a gellan gum cleavage solution at 50°C~60°C, achieving sufficient intermolecular contact with the active hydroxyl groups (-OH) on the gellan gum chains, thus preparing for the subsequent nucleophilic substitution reaction. At this point, no significant covalent bond formation reaction has occurred.

[0067] The addition of a base is the key step that triggers and drives the entire grafting reaction. The sequence of chemical reactions it initiates is as follows:

[0068] Step 1: Hydroxyl activation

[0069] Alkali (OH)- First, it undergoes a deprotonation reaction with the hydroxyl groups (-OH) on the gellan gum chain to generate the more reactive alkoxide anion (-O). - ).

[0070] R–OH + OH - → R–O - + H2O

[0071] Step 2: Nucleophilic substitution reaction (SN2 mechanism)

[0072] Activated alkoxy anions (R–O) - As a nucleophile, bromine attacks the partially positively charged benzyl carbon atom in the iodobenzyl bromide molecule, initiating a nucleophilic substitution reaction. The bromine atom (Br) - The ) is replaced as a leaving group, thereby forming a stable ether bond (R–O–CH2–Ar–I3).

[0073] R–O - + I3–Ar–CH2–Br → R–O–CH2–Ar–I3+ Br -

[0074] Step 3: Reaction Equilibrium and Byproduct Treatment

[0075] The bromide ions (Br) generated in the reaction - ) and sodium ions (Na) in the alkali + The iodide is combined to form sodium bromide (NaBr). The entire reaction is carried out in an inert atmosphere, which effectively prevents side reactions such as iodide oxidation and ensures that the iodobenzyl group is efficiently and stably grafted onto the gellan gum side chain via ether bonds.

[0076] In the above embodiments, the stirring time after heating can be, but is not limited to, 10 to 20 minutes; the stirring time of the reaction mixture after adding iodobenzyl bromide can be, but is not limited to, 10 to 20 minutes; after adding iodobenzyl bromide and reacting fully, the base is added within 10 minutes to slowly start the reaction, prevent the reaction from being too vigorous, and make the reaction more complete. The stirring time can be, but is not limited to, 5 to 8 hours.

[0077] In the above embodiments, the solid-liquid separation method is to use cold water for precipitation, filter after solid precipitate appears, and wash with methanol.

[0078] In one embodiment, the anhydrous organic solvent is dimethyl sulfoxide.

[0079] In one embodiment, the base is sodium hydroxide. Its strong alkalinity and high reactivity effectively promote the nucleophilic substitution reaction between iodobenzyl bromide and the hydroxyl groups of gellan gum, significantly improving the grafting reaction rate and efficiency. Sodium hydroxide is inexpensive, readily available, and easy to treat (it can be removed by neutralization and washing with water), making the entire process cost-effective and convenient to operate while ensuring efficient modification, thus facilitating large-scale production conversion.

[0080] The preparation method of this invention precisely controls the molecular weight of gellan gum through oxidative cutting to improve its flexibility, and stably bonds iodobenzyl groups to the side chains through a sequentially controlled grafting reaction, thereby efficiently producing a self-illuminating polymer that combines excellent biocompatibility, uniform self-illumination ability, and stable gelation embolization performance, providing an ideal material basis for safe, convenient, and effective vascular interventional therapy.

[0081] One embodiment of the liquid embolic agent comprises any of the above-described self-developing polymers and organic solvents.

[0082] Based on the aforementioned embodiments, the ratio of the self-developing polymer to the organic solvent is (0.26g~0.36g):10mL. That is, each 10mL of organic solvent contains 0.26g~0.36g of the self-developing polymer.

[0083] Based on the aforementioned embodiments, the organic solvent is dimethyl sulfoxide.

[0084] Specifically, under anhydrous and aseptic conditions, gellan gum containing iodine and side-linked ligands is weighed, heated to approximately 55°C, and uniformly dissolved in the organic solvent dimethyl sulfoxide (DMSO). It is then refrigerated for later use. The principle of liquid embolic agents is that upon contact with the aqueous phase, the organic phase dimethyl sulfoxide rapidly disperses, and the effective embolic substance solidifies within a very short time. Therefore, the entire process requires ensuring that the embolic agent is prepared under anhydrous conditions.

[0085] The liquid embolizing agent of this invention possesses a uniform and stable self-illuminating function, eliminating the need for external contrast agents. This reduces the cumbersome steps of physical blending contrast agents in existing technologies and avoids the damage to the human body caused by the leaching of heavy metal contrast agents used in physical blending, greatly improving its biocompatibility. Simultaneously, the liquid embolizing agent of this invention exhibits good biocompatibility, smooth delivery, and rapid gelation within blood vessels to form a stable embolism. Furthermore, it significantly simplifies the surgical procedure, enhancing the safety and operability of interventional treatment.

[0086] Referring to the above embodiments, in order to make the technical solution of the present invention more specific, clear and easy to understand, examples of the technical solution of the present invention are given below. However, it should be noted that the content to be protected by the present invention is not limited to the following embodiments.

[0087] Example 1

[0088] (1) Oxidation of sugar chains cleaves natural polysaccharides into gelatin:

[0089] Weigh 8g of the natural polysaccharide gellan gum (Phytagel, Sigma Aldrich), disperse it in 1000mL of deionized water, heat to 75℃ and stir to dissolve, forming a homogeneous and transparent solution. Cool and maintain at 45℃, then add 5mL of 0.4M sodium periodate aqueous solution as an oxidant. Stir evenly for 6h, 12h, 24h, and 48h respectively, then add a small amount of ethylene glycol and stir for 30 minutes to terminate the oxidation. Subsequently, add 0.1M sodium borohydride to the above reaction solution for reduction, stir overnight, and obtain five groups of samples with different degrees of oxidation. The five groups of samples were purified by Sephadex® G25 SEC chromatography, then lyophilized into powder to obtain five groups of cleaved gellan gum.

[0090] Using natural polysaccharide gellan gum that has not undergone oxidative sugar chain cleavage as a comparison, the intrinsic viscosity [η] was measured using an automatic viscometer, and the molecular weight of the product was calculated using the Kuhn-Mark-Houwink equation. The results are shown in Table 1.

[0091] Table 1

[0092]

[0093] (2) Preparation of cold gel with laterally branched iodine benzyl groups:

[0094] Under a nitrogen atmosphere, 500 mg of cleaved gellan gum powder (oxidative sugar chain cleavage for 48 hours) was weighed and dissolved uniformly in 20 mL of anhydrous dimethyl sulfoxide, an organic solvent. The solution was heated to 95 °C and stirred for 15 minutes. Then, the temperature was lowered to 55 °C, and 5 g of 2-iodobenzyl bromide was added to the gellan gum solution. The reaction mixture was stirred for 15 minutes. Then, 500 mg of ground sodium hydroxide powder was added over 10 minutes. The reaction was continued for 6 hours, then cooled to room temperature. Precipitation was performed using 50 mL of cold water. After a solid precipitate appeared, the precipitate was filtered and washed with methanol to obtain the gellan gum derivative with side-linked iodobenzyl groups of Example 1, which is the self-developing polymer A.

[0095] like Figure 2 The table shows the H NMR (deuterated DMSO) of the prepared self-developing polymer A, and its characteristic peaks are shown in Table 2.

[0096] Table 2

[0097]

[0098] from Figure 2As shown in Table 2, HNMR structure confirmation revealed that 2-iodobenzyl groups were grafted onto the main chain of the natural polysaccharide gellan gum, resulting in the desired gellan gum derivative with iodobenzyl groups grafted onto its side, namely, self-developing polymer A.

[0099] The grafting rate of the 2-iodobenzyl group = (0.75*S2) / S4, from Figure 2 According to calculations in Table 2, the grafting rate of the self-developing polymer A is 58%.

[0100] Example 2

[0101] Under a nitrogen atmosphere, 500 mg of cleaved gellan gum powder (oxidized sugar chain cleavage for 48 hours in Example 1) was weighed and dissolved uniformly in 20 mL of anhydrous dimethyl sulfoxide, an organic solvent. The solution was heated to 100°C and stirred for 20 minutes. Then, the temperature was lowered to 60°C, and 5 g of 3-iodobenzyl bromide was added to the gellan gum solution. The reaction mixture was stirred for 20 minutes. Then, 500 mg of ground sodium hydroxide powder was added over 10 minutes. The reaction was continued for 6 hours, then cooled to room temperature. Precipitation was performed using 50 mL of cold water. After a solid precipitate formed, the precipitate was filtered and washed with methanol to obtain the gellan gum derivative with iodobenzyl groups grafted onto its side, which is the self-developing polymer B of Example 2. The grafting rate of the 3-iodobenzyl groups was calculated in the same way as in Example 1, and the grafting rate of the self-developing polymer B was calculated to be 56%.

[0102] Example 3

[0103] Under a nitrogen atmosphere, 500 mg of cleaved gellan gum powder (oxidized sugar chain cleavage for 48 hours in Example 1) was weighed and dissolved uniformly in 20 mL of anhydrous dimethyl sulfoxide, an organic solvent. The solution was heated to 90°C and stirred for 10 minutes. Then, the temperature was lowered to 50°C, and 5 g of 4-iodobenzyl bromide was added to the gellan gum solution. The reaction mixture was stirred for 10 minutes. Then, 500 mg of ground sodium hydroxide powder was added over 10 minutes. The reaction was continued for 5 hours, then cooled to room temperature. Precipitation was performed using 50 mL of cold water. After a solid precipitate formed, the precipitate was filtered and washed with methanol to obtain the gellan gum derivative with side-linked iodobenzyl groups of Example 3, which is the self-developing polymer C. The grafting rate of the 4-iodobenzyl groups was calculated in the same way as in Example 1, and the grafting rate of the self-developing polymer C was calculated to be 55%.

[0104] Example 4

[0105] Add 3,4 Diiodobenzoic acid (2 mol), stirred continuously, in a 0°C ice-water bath, then borane was added. Tetrahydrofuran solution (borane 4 mol, borane) The concentration of borane in the tetrahydrofuran solution was 1 mol / L. After stirring for 4 hours, a white solid precipitated. Cold ethanol was added, and stirring continued for another 4 hours. Then, the solvent was removed by rotary evaporation to obtain a white solid 3,4. Diiodobenzyl alcohol was purified by recrystallization from ethanol.

[0106] The obtained 3,4 1 mol of diiodobenzyl alcohol was added to a round-bottom flask and stirred continuously in an ice-water bath at 0°C. Then, 1.5 mol of phosphorus tribromide was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the flask, and the mixture was extracted with dichloromethane in small batches. The organic phase was then washed with sodium bicarbonate solution until neutral. Next, the solvent was removed by rotary evaporation, and the organic phase was concentrated to obtain 3,4-diiodobenzyl bromide.

[0107] Using the 3,4-diiodobenzyl bromide obtained above as a raw material, a self-developing polymer D was prepared. The specific preparation method is as follows:

[0108] Under a nitrogen atmosphere, 500 mg of cleaved gellan gum powder (oxidized sugar chain cleavage for 48 hours in Example 1) was weighed and dissolved uniformly in 20 mL of anhydrous dimethyl sulfoxide, an organic solvent. The solution was heated to 100°C and stirred for 20 minutes. Then, the temperature was lowered to 60°C, and 10 g of 3,4-diiodobenzyl bromide was added to the gellan gum solution. The reaction mixture was stirred for 20 minutes. Then, 500 mg of ground sodium hydroxide powder was added over 10 minutes. The reaction was continued for 8 hours, then cooled to room temperature. Precipitation was performed using 100 mL of cold water. After a solid precipitate formed, the precipitate was filtered and washed with methanol to obtain the gellan gum derivative with side-linked iodobenzyl groups as described in Example 4, which is the self-developing polymer D. The grafting rate of the 3,4-diiodobenzyl groups was calculated in the same way as in Example 1, and the grafting rate of the self-developing polymer D was calculated to be 52%.

[0109] Example 5

[0110] Add 2, 3, and 5 to the round-bottom flask. Triiodobenzoic acid (2 mol), stirred continuously, in a 0°C ice-water bath, then borane was added. Tetrahydrofuran solution (borane 4 mol, borane) The concentration of borane in the tetrahydrofuran solution was 1 mol / L. After stirring for 3 hours, a white solid precipitated. Cold ethanol was added, and stirring continued for another 3 hours. Then, the solvent was removed by rotary evaporation to obtain white solids 2,3,5. Triiodobenzyl alcohol was purified by recrystallization from ethanol.

[0111] The obtained 2, 3, 5 Triiodobenzyl alcohol (1 mol) was added to a round-bottom flask and stirred continuously under an ice-water bath at 0°C. Phosphorus tribromide (1.5 mol) was then added, and the mixture was stirred at room temperature for 3 hours. Water was added to the flask, and the mixture was extracted with dichloromethane in small batches. The organic phase was then washed with sodium bicarbonate solution until neutral. The solvent was then removed by rotary evaporation, and the organic phase was concentrated to obtain 2,3,5 Triiodobenzyl bromide.

[0112] Using the 2,3,5 obtained above Using triiodobenzyl bromide as a raw material, a self-developing polymer E was prepared. The specific preparation method is as follows:

[0113] Under a nitrogen atmosphere, 500 mg of cleaved gellan gum powder (oxidized sugar chain cleavage for 48 hours in Example 1) was weighed and dissolved uniformly in 20 mL of anhydrous dimethyl sulfoxide, an organic solvent. The solution was heated to 100°C and stirred for 20 minutes. Then, the temperature was lowered to 60°C, and 10 g of 2,3,5-dimethyl sulfoxide was added to the gellan gum solution. Triiodobenzyl bromide was reacted by stirring the reaction mixture for 20 minutes; then, 500 mg of ground sodium hydroxide powder was added over 10 minutes. The reaction was continued for 8 hours, then cooled to room temperature, and precipitated using 120 mL of cold water. After the solid precipitate formed, it was filtered and washed with methanol to obtain the gellan gum derivative with side-linked iodobenzyl groups as described in Example 5, which is the self-developing polymer E. 2,3,5 The grafting rate of the triiodobenzyl group was calculated in the same way as in Example 1, and the grafting rate of the self-developing polymer E was calculated to be 50%.

[0114] Example 6

[0115] Preparation of liquid embolic agents:

[0116] Under anhydrous and aseptic conditions, the gellan gum derivative (i.e., self-developing polymer A) with side-linked iodine benzyl groups from Example 1 was weighed, heated to about 55°C, and uniformly dissolved in the organic solvent dimethyl sulfoxide. It was then refrigerated for later use to obtain a liquid embolizing agent.

[0117] Performance testing:

[0118] After the liquid embolizing agent is prepared, it needs to be refrigerated at 4°C and heated in a 37°C water bath for 15 minutes before use. The liquid embolizing agent prepared in Example 6 is drawn into a 10mL syringe and injected into physiological saline using an 18G needle. It precipitates rapidly within 3 minutes, forming a viscous substance, indicating that the polymeric liquid embolizing agent of this invention can rapidly precipitate in the blood to achieve embolization.

[0119] Liquid embolization agents are suitable for intracranial vascular segments. Following the recommendations of animal testing institutions, large white pigs were selected as experimental animals. First, a white pig aneurysm model was established. Preoperative routine arteriography was performed, and the aneurysm model was observed to be in good condition. A microcatheter and guidewire were inserted into the vascular lumen via arterial puncture. Angiography was performed again to monitor the process, and the microcatheter and guidewire were advanced along the artery to the aneurysm lumen entrance of the aneurysm model. The guidewire was removed, and the microcatheter opening was stabilized at approximately 3 / 4 of the way into the aneurysm lumen. The liquid embolization agent prepared in Example 6 was then injected at a rate of 0.2 mL / min, allowing real-time observation of the aneurysm embolization process. Once the aneurysm lumen was completely embolized, the injection was stopped, and the microcatheter was withdrawn. Figure 3 As shown, digital subtraction angiography (DSA) revealed that the porcine aneurysm model was completely embolized, with no filamentous residue at the aneurysm opening and no embolic agent drift observed distal to the aneurysm-bearing artery. The aneurysm was subsequently ligated and sutured, and the animals continued to be fed. Furthermore, the animals generally showed no abnormalities post-operatively.

[0120] The above results indicate that the polymer liquid embolizing agent prepared in this invention has excellent autoradiography, embolization effect, and biocompatibility.

[0121] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0122] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A self-developing high molecular polymer, characterized by, The self-developing high molecular polymer is a gellan gum derivative side-linked with iodobenzyl groups, and the chemical structural formula of the self-developing high molecular polymer comprises any one or more of the following structures: , , , or .

2. The self-developing high molecular polymer according to claim 1, characterized in that, The molecular weight of the self-developing high molecular polymer is 100,000-600,000.

3. A method of preparing a self-developing high molecular polymer as claimed in claim 1 or 2, characterized in that, The method comprises the following steps: The natural polysaccharide gellan gum is dissolved in water, and then subjected to oxidative sugar chain cutting by reacting with an oxidizing agent, and then subjected to reduction, purification, and freeze-drying in sequence to obtain cut gellan gum; and The cut gellan gum is dissolved in anhydrous organic solvent under an inert atmosphere, iodobenzyl bromide and a base are added, and the reaction is fully carried out to obtain the gellan gum derivative side-linked with iodobenzyl groups, i.e., the self-developing high molecular polymer.

4. The method for preparing the self-developing polymer according to claim 3, characterized in that, The natural polysaccharide gellan gum is dissolved in water, heated to 40-80°C to fully dissolve, and a uniform transparent solution is formed; An oxidizing agent is added to the uniform transparent solution to cut the oxidative sugar chain; Ethylene glycol is added to fully react; A reducing agent is added to fully react; and Impurities are removed by a chromatographic column, and then freeze-dried into powder. The oxidizing agent is sodium periodate.

5. The method for preparing the self-developing polymer according to claim 3 or 4, characterized in that, The reducing agent is sodium borohydride.

6. The method for preparing the self-developing polymer according to claim 4, characterized in that, The cut gellan gum is dissolved in anhydrous organic solvent under an inert atmosphere, iodobenzyl bromide and a base are added, and the reaction is fully carried out to obtain the gellan gum derivative side-linked with iodobenzyl groups, i.e., the self-developing high molecular polymer.

7. The method for preparing the self-developing polymer according to claim 3, characterized in that, The cut gellan gum is dissolved in anhydrous organic solvent under an inert atmosphere, heated to 90-100°C, fully dissolved to obtain a cut gellan gum solution; and The cut gellan gum solution is cooled to 50-60°C, then iodobenzyl bromide is added, fully reacted, a base is added, fully reacted, and then cooled to room temperature, solid-liquid separation is carried out, and the solid is retained, which is the gellan gum derivative side-linked with iodobenzyl groups. The anhydrous organic solvent is dimethyl sulfoxide; 8. The method for preparing the self-developing polymer according to claim 3 or 7, characterized in that, The iodobenzyl bromide comprises one or more of 2-iodobenzyl bromide, 3-iodobenzyl bromide, 4-iodobenzyl bromide, 3,4-diiodobenzyl bromide, and a mixture of 2,3,5-triiodobenzyl bromide; and / or The base is sodium hydroxide. The self-developing high molecular polymer comprises the self-developing high molecular polymer and an organic solvent.

9. A liquid embolic agent, characterized in that, The ratio of the self-developing high molecular polymer to the organic solvent is (0.26-0.36 g):10 mL; and / or 10. The liquid embolic agent of claim 9, wherein, The organic solvent is dimethyl sulfoxide. ​

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