Polymer material and preparation method therefor and drug-loading material

Abstract

A polymer material and a preparation method therefor and a drug-loading material, which relate to the technical field of medical polymer materials. The polymer material comprises: a cross-linked polymer, and a plurality of polyelectrolytes which are grafted onto the three-dimensional network structure of the cross-linked polymer via chemical bonds, wherein each of the polyelectrolytes contains a plurality of ionizable groups, and the plurality of ionizable groups are ionized to form a local potential by means of a counterion condensation effect, thereby inducing the aggregation of oppositely charged particles. Compared with a traditional drug-loading microsphere embolic agent, the polymer material can improve the adsorption capacity and adsorption efficiency thereof on oppositely charged particles. When oppositely charged particles are drug particles, the polymer material can improve the drug-loading capacity and shorten the drug-loading time.

Description

Polymer material, preparation method thereof, and drug-carrying material Technical Field

[0001] The present disclosure relates to the technical field of medical polymer materials, and in particular to a polymer material and a preparation method thereof, and a drug-carrying material. Background Art

[0002] Liver cancer is a common cancer worldwide, and transarterial chemoembolization (TACE) is the preferred strategy for treating mid- to late-stage liver cancer. TACE involves the injection of a drug-loaded embolic agent into the target location via a catheter under the guidance of medical imaging equipment. The embolic agent blocks blood flow, while the drug is simultaneously released from the embolic agent to achieve the desired therapeutic effect. It has the advantages of minimal invasiveness, precise targeting, and minimal side effects. Embolization therapy has achieved excellent results in the treatment of malignant tumors, uterine fibroids, hemangiomas, vascular malformations, and hemostasis. In recent years, an increasing number of embolic substances have been approved by the State Food and Drug Administration (CFDA) for clinical embolization of blood vessels and tumors, including polyvinyl alcohol granular embolic agents, polyvinyl alcohol embolic drug-loaded microspheres, and medical polyether polyurethane embolic agents. TACE technology can achieve chemotherapy effects while simultaneously performing embolic therapy. To achieve better embolic chemotherapy effects, higher requirements are placed on the material properties of the embolic agent.

[0003] The current principle of drug adsorption for the preparation of drug-loaded microsphere embolic agents is mainly: using electrostatic adsorption to modify the acidic groups on the basis of the original material. The acidic groups (such as carboxyl groups) can carry negative charges after ionization, so that the material has drug-carrying functions. For example, commonly used clinical embolic agents include polyvinyl alcohol polymer hydrogel microspheres (DC Beads) modified with sulfonic acid groups, polyvinyl alcohol embolic microspheres (Callispheres) and embolic microspheres (Hepaspheres).

[0004] The negatively charged groups in the modified material molecules used in the current drug-loaded microspheres are randomly distributed in space. The number of negatively charged groups is large but the density is not high. It takes 30 minutes to 2 hours or even more than 2 hours to achieve complete drug loading, which is too long. In addition, the degradable microspheres that have been gradually developed in recent years are limited by the structure of the degradable materials. Due to reasons such as spatial steric effects, the total amount of negatively charged groups in the modified molecules is limited and randomly distributed. The drug loading capacity is small, and it is impossible to ensure that a sufficient amount of anti-cancer drugs are loaded for tumor treatment. Figure 1 shows a schematic diagram of the microstructure of an existing drug-loaded microsphere. Taking the drug-loaded microspheres shown in Figure 1 as an example, the carboxyl groups are grafted onto the backbone structure of the polymer material and are dispersed everywhere, showing a random distribution state. Even if the backbone structure of the polymer material has a large number of active sites for carboxyl groups to be grafted, the density of carboxyl groups on the backbone structure of the polymer material is still low.

[0005] Summary of the Invention

[0006] In order to solve the above problems in the prior art, the main purpose of the present disclosure is to provide a polymer material and a preparation method thereof, and a drug-loaded material.

[0007] To achieve the above objectives, in a first aspect, the present disclosure provides a polymeric material comprising:

[0008] cross-linked polymers; and

[0009] A plurality of polyelectrolytes are grafted onto the three-dimensional network structure of the cross-linked polymer through chemical bonds, and each of the polyelectrolytes contains a plurality of ionizable groups. After ionization, the plurality of ionizable groups form a local potential through the counter-ion coagulation effect to induce the aggregation of particles with opposite charges.

[0010] In some embodiments, each of the polyelectrolytes comprises a plurality of ionizable groups, including:

[0011] Each of the polyelectrolytes comprises a plurality of acidic groups, which, after ionization, form a local low potential through the counter-ion coagulation effect to induce aggregation of positively charged particles.

[0012] In some embodiments, each of the polyelectrolytes comprises a plurality of acidic groups, including:

[0013] Each of the polyelectrolytes contains more than three acidic groups.

[0014] In some embodiments, the acidic group includes at least one of a carboxyl group, a sulfonic acid group, a sulfinic acid group, a phosphate group, a phosphite group, or a hypophosphite group.

[0015] In some embodiments, the polyelectrolyte comprises at least one of polyacrylic acid, carboxymethyl cellulose, carboxymethyl chitosan, sodium alginate, G4 dendrimer, polyglutamic acid, or polyaspartic acid.

[0016] In some embodiments, the cross-linked polymer is a degradable cross-linked polymer.

[0017] In some embodiments, the degradable cross-linked polymer includes at least one of cross-linked modified gelatin, chitosan, hyaluronic acid, agarose, chondroitin sulfate, starch, or cellulose.

[0018] In some embodiments, the cross-linked polymer accounts for 1 to 30 parts, and the plurality of polyelectrolytes accounts for 0.2 to 30 parts by weight.

[0019] In some embodiments, the polymer material further includes a bridge between the polyelectrolyte and the polymer for connecting the polyelectrolyte to the polymer.

[0020] In some embodiments, the bridge is a compound with one or more functional groups, and the functional groups of the bridge include at least one of an amino group, a carboxyl group, an aldehyde group, a thiol group, a carbon-carbon double bond, a carbon-carbon triple bond, an acryloyl group, an isobutyl acryloyl group, an azide group, an epoxy group, a vinyl sulfone group, a succinimide group, a biotinyl group, a dibenzylcyclooctyne group, a di(p-nitrobenzene) carbonate group, or a norbornene group.

[0021] In a second aspect, the present disclosure provides a method for preparing a polymeric material, comprising:

[0022] After the cross-linking precursor, the cross-linking agent and the polyelectrolyte are mixed, a cross-linking polymerization reaction is carried out under external conditions to form the polymer material as described in any one of the above items.

[0023] In some embodiments, the preparation method comprises: mixing the cross-linking precursor, the cross-linking agent, the polyelectrolyte and the bridge, and then performing a cross-linking polymerization reaction under external conditions.

[0024] In a third aspect, the present disclosure provides an embolic agent, wherein the embolic agent is made of any of the polymer materials described above.

[0025] In some embodiments, the particle size of the embolic agent is 50-1000 μm.

[0026] In some embodiments, the particle size of the embolic agent is 100-300 μm.

[0027] In a fourth aspect, the present disclosure provides a drug-loaded material, comprising:

[0028] Polymeric materials, including cross-linked polymers,

[0029] A plurality of polyions are grafted onto the three-dimensional network structure of the cross-linked polymer through chemical bonds, and each of the polyions contains a plurality of charged groups. The plurality of charged groups form a local potential through a counter-ion aggregation effect to induce aggregation of drug particles with opposite charges; and

[0030] A plurality of drug particles are adsorbed on the polymer material through electrostatic action.

[0031] In some embodiments, the plurality of polyions include: a plurality of polyanions grafted onto the three-dimensional network structure of the cross-linked polymer via chemical bonds, and each of the polyanions comprises a plurality of negatively charged groups, wherein the plurality of negatively charged groups form a local low potential through a counterion cohesion effect to induce aggregation of positively charged particles; and

[0032] The plurality of drug particles include: a plurality of positively charged drug particles adsorbed on the polymer material through electrostatic action.

[0033] In some embodiments, the drug particles are locally aggregated and adsorbed on the multiple polyanions of the polymeric material through electrostatic interaction.

[0034] In some embodiments, the drug particles are also adsorbed on the negatively charged groups of the cross-linked polymer itself through electrostatic interaction.

[0035] In some embodiments, the drug particles include at least one of doxorubicin hydrochloride, epirubicin, mitomycin, fluorouracil, cisplatin, oxaliplatin, capecitabine, gemcitabine, irinotecan, topotecan, sorafenib, apatinib, lenvatinib, regorafenib, cabozantinib, ramucirumab, nivolumab, or pembrolizumab.

[0036] In some embodiments, the polymer material further comprises a bridge for connecting the polyanion and the polymer.

[0037] In some embodiments, the bridge is a compound with one or more functional groups, and the functional groups of the bridge include at least one of an amino group, a carboxyl group, an aldehyde group, a thiol group, a carbon-carbon double bond, a carbon-carbon triple bond, an acryloyl group, an isobutyl acryloyl group, an azide group, an epoxy group, a vinyl sulfone group, a succinimide group, a biotinyl group, a dibenzylcyclooctyne group, a di(p-nitrobenzene) carbonate group, or a norbornene group.

[0038] In a fifth aspect, the present disclosure provides a method for preparing a drug-loaded material, comprising:

[0039] The drug particles are mixed with a polymer material, and the drug particles are adsorbed on the polymer material under the action of electrostatic force to obtain any of the above-mentioned drug-loaded materials.

[0040] In a sixth aspect, the present disclosure provides a drug-loaded embolic agent, characterized in that the drug-loaded embolic agent is made of any of the drug-loaded materials described above.

[0041] The technical solution disclosed herein can introduce more ionizable groups into the three-dimensional network structure of the cross-linked polymer by grafting polyelectrolytes onto the three-dimensional network structure of the cross-linked polymer, thereby increasing the number of ionizable groups carried by the entire polymer material, and utilizing the counter-ion coagulation effect to form a local potential, thereby increasing the adsorption amount and adsorption efficiency of the polymer material for particles with opposite charges. When the particles with opposite charges are drug particles, the use of the polymer material provided by the present disclosure can increase the drug loading amount and shorten the drug loading time. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the technical solutions in the embodiments of the present disclosure, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present disclosure. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0043] FIG1 shows a schematic diagram of the microstructure of an existing drug-loaded microsphere;

[0044] FIG2 shows a schematic diagram of the microstructure of a polymer material provided according to the present disclosure;

[0045] FIG3 shows a schematic diagram of the microstructure of a drug-carrying material provided according to the present disclosure;

[0046] FIG4 shows a microscopic photograph of a polymeric material (embolic agent) prepared according to an embodiment of the present disclosure;

[0047] FIG5 shows a microscopic photograph of a polymeric material (embolic agent) prepared according to another embodiment of the present disclosure;

[0048] FIG6 shows a microscopic photograph of a polymeric material (embolic agent) prepared according to another embodiment of the present disclosure;

[0049] FIG7 is a schematic diagram showing the maximum drug loading corresponding to a polymeric material (embolic agent) according to an embodiment of the present disclosure;

[0050] FIG8 is a schematic diagram showing the electronegativity of a polymeric material (embolic agent) according to an embodiment of the present disclosure;

[0051] FIG9 is a schematic diagram showing drug loading efficiency of a polymeric material (embolic agent) according to an embodiment of the present disclosure;

[0052] FIG10 is a schematic diagram showing the drug loading rate of polymeric materials (embolic agents) containing different polyanion molecular weights according to an embodiment of the present disclosure;

[0053] FIG11 is a schematic diagram showing the degradation rate and drug release rate of a drug-loaded material (drug-loaded embolic agent) under different conditions according to an embodiment of the present disclosure;

[0054] FIG12 shows a microscopic photograph of a polymeric material (embolic agent) before drug loading according to an embodiment of the present disclosure;

[0055] FIG13 shows a microscopic photograph of doxorubicin hydrochloride and a polymeric material (embolic agent) just after being mixed according to an embodiment of the present disclosure;

[0056] FIG14 shows a microscopic photograph of a drug-loaded material (drug-loaded embolic agent) obtained by loading a drug into a polymeric material (embolic agent) according to an embodiment of the present disclosure;

[0057] FIG15 is a schematic diagram showing the arrangement of a drug-loaded material (drug-loaded embolic agent) in a blood vessel according to an embodiment of the present disclosure;

[0058] FIG16 shows a schematic diagram of the arrangement of drug-loaded materials (drug-loaded embolic agents) in a blood vessel according to an embodiment of the present disclosure; and

[0059] FIG17 is a schematic diagram showing the arrangement of drug-loaded materials (drug-loaded embolic agents) in a blood vessel according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0060] The following description provides specific application scenarios and requirements for this specification, with the goal of enabling those skilled in the art to make and use the contents of this specification. Various modifications to the disclosed embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of this specification. Therefore, this specification is not limited to the embodiments shown, but is intended to be accorded the broadest scope consistent with the claims.

[0061] To facilitate understanding of this specification, a more comprehensive description of the specification will be provided below with reference to the accompanying drawings. The drawings illustrate preferred embodiments of this specification. However, this specification can be implemented in many different forms without departing from the core spirit of this specification and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and comprehensive understanding of the disclosure of this specification.

[0062] The terms used herein are for the purpose of describing specific example embodiments only and are not intended to be limiting. For example, as used herein, the singular forms "a," "an," and "the" may also include the plural forms unless the context clearly indicates otherwise. When used in this specification, the terms "comprise," "include," and / or "contain" are intended to refer to the presence of the associated integers, steps, operations, elements, and / or components, but do not preclude the presence of one or more other features, integers, steps, operations, elements, components, and / or groups or the addition of other features, integers, steps, operations, elements, components, and / or groups in the system / method.

[0063] In this application, unless explicitly stated otherwise, the association relationship between structures can be a direct association relationship or an indirect association relationship. For example, when describing "A is connected to B", unless it is explicitly stated that A is directly connected to B, it should be understood that A can be directly connected to B or indirectly connected to B; for another example, when describing "A is above B", unless it is explicitly stated that A is directly above B (AB are adjacent and A is above B), it should be understood that A can be directly above B or indirectly above B (AB is separated by other elements and A is above B). And so on.

[0064] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this specification pertains. The terms used herein in this specification are for the purpose of describing specific embodiments only and are not intended to limit this specification. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0065] In this application, "X includes at least one of A, B, or C" means that X includes at least A, or X includes at least B, or X includes at least C. In other words, X can include only any combination of A, B, and C, or it can include any combination of A, B, and C as well as other possible contents / elements. The arbitrary combination of A, B, and C can be A, B, C, AB, AC, BC, or ABC.

[0066] For the convenience of description, the terms that may appear in this manual are first explained as follows:

[0067] Cross-linked products: also known as cross-linked polymers and cross-linked macromolecules, are a type of polymer with a three-dimensional network structure.

[0068] Cross-linking reaction: refers to the reaction in which two or more molecules (usually linear molecules) bond and cross-link to form a relatively stable molecule (bulk molecule) network structure. This reaction transforms linear or slightly branched macromolecules into a three-dimensional network structure.

[0069] Polyelectrolytes (also known as polymer electrolytes) are a class of linear or branched synthetic or natural water-soluble polymers whose structural units contain ionizable groups and have good ionic conductivity. After dissolving, polyelectrolytes can ionize into a polyion and many small ions (also known as counterions) with opposite charges to the polyion. After dissolving, polyelectrolytes can ionize into a negatively charged polyion (also known as a polyanion) and many cations with opposite charges to the polyanion; after dissolving, polyelectrolytes can ionize into a positively charged polyion (also known as a polycation) and many anions with opposite charges to the polycation. The electrical properties of the polyion obtained after the polyelectrolyte is ionized depend on the nature of the ionizable groups contained in the polyelectrolyte.

[0070] Electrostatic force refers to the long-range electrical force generated by the interaction between electrons. Electrostatic forces include electrostatic attraction and electrostatic repulsion. Electrostatic forces form ionic bonds between anions and cations formed when atoms gain or lose electrons.

[0071] In a first aspect, the present disclosure provides a polymer material, comprising: a cross-linked polymer; and a plurality of polyelectrolytes grafted onto the three-dimensional network structure of the cross-linked polymer through chemical bonds, and each of the polyelectrolytes contains a plurality of ionizable groups, and after ionization, the plurality of ionizable groups form a local potential through the counter-ion coagulation effect to induce the aggregation of particles with opposite charges.

[0072] In the polymeric material provided by the present disclosure, the three-dimensional network structure of the cross-linked polymer is formed by a plurality of polymer chains interlaced, and each polymer chain also has a variety of groups, which can exhibit different chemical activities according to their own chemical properties. Each polyelectrolyte molecular chain contains a plurality of ionizable groups, wherein the ionizable groups can be acidic groups, which can form polyanions (containing a plurality of negatively charged groups on the polyanion) and a plurality of free cations (such as H + At this time, after the ionization of multiple ionizable groups (acidic groups) on the polyelectrolyte, a local low potential can be formed through the counterion coagulation effect, thereby inducing the aggregation of particles with opposite charges (positively charged particles). The ionizable groups contained in the polyelectrolyte can also be basic groups. After the ionization of the basic groups, polycations (polycations containing multiple positively charged groups) and multiple free anions (such as OH) can be formed. - At this time, after the ionization of multiple ionizable groups (basic groups) on the polyelectrolyte, a local high potential can be formed through the counter-ion coagulation effect, thereby inducing the aggregation of particles with opposite charges (negatively charged particles).

[0073] In addition, the molecular chain of the polyelectrolyte also contains at least one active group, and the polyelectrolyte can react with the groups on the cross-linked polymer macromolecular chain to combine together through at least one active group (that is, the polyelectrolyte can form a chemical bond with the macromolecular chain of the cross-linked polymer), so that multiple polyelectrolytes can be grafted to the three-dimensional network structure of the cross-linked polymer through chemical bonds.

[0074] Compared with traditional drug-loaded microsphere embolic agents, the polymer material provided by the present disclosure can introduce more ionizable groups into the three-dimensional network structure of the cross-linked polymer by grafting polyelectrolytes onto the three-dimensional network structure of the cross-linked polymer, thereby increasing the number of ionizable groups carried by the entire polymer material, thereby increasing the adsorption amount and adsorption efficiency of the polymer material for particles with opposite charges. When the particles with opposite charges are drug particles, the use of the polymer material provided by the present disclosure can increase the drug loading amount and shorten the drug loading time.

[0075] In some embodiments, each of the polyelectrolytes comprises a plurality of ionizable groups, including: each polyelectrolyte comprises a plurality of acidic groups, which upon ionization, form a local low potential through a counter-ion coagulation effect, thereby inducing aggregation of positively charged particles. In this case, the polymeric material provided by the present disclosure comprises: a cross-linked polymer; and a plurality of polyelectrolytes chemically grafted onto the three-dimensional network structure of the cross-linked polymer, each polyelectrolyte comprising a plurality of acidic groups, which upon ionization, form a local low potential through a counter-ion coagulation effect, thereby inducing aggregation of positively charged particles.

[0076] FIG2 shows a schematic diagram of the microstructure of a polymer material provided by the present disclosure. As shown in FIG2 , the polymer material provided by the present disclosure includes a cross-linked polymer and multiple polyelectrolytes. The three-dimensional network structure of the cross-linked polymer is formed by the interlacing of multiple polymer chains, each of which also has various types of groups formed on the polymer chain. These groups can exhibit different chemical activities depending on their chemical properties. Each polyelectrolyte molecular chain contains multiple acidic groups. After ionization, the multiple acidic groups contained in the polyelectrolyte can form polyanions (the polyanion contains multiple negatively charged groups) and multiple cations (hydrogen ions). At this time, the multiple negatively charged groups contained in the polyanion can adsorb positively charged particles (such as positively charged drugs) through electrostatic interaction, thereby achieving drug loading. In addition, the polyelectrolyte molecular chain also contains at least one active group. The polyelectrolyte can react with the groups on the cross-linked polymer polymer chain to bind together (i.e., the polyelectrolyte can form chemical bonds with the polymer polymer chain), thereby allowing multiple polyelectrolytes to be grafted onto the three-dimensional network structure of the cross-linked polymer through chemical bonds. Compared with traditional drug-loaded microsphere embolic agents, the polymer material provided by the present disclosure can introduce more acidic groups into the three-dimensional network structure of the cross-linked polymer by grafting polyelectrolytes onto the three-dimensional network structure of the cross-linked polymer, thereby increasing the number of acidic groups carried by the entire polymer material, thereby increasing the adsorption capacity and adsorption efficiency of the polymer material for positively charged drugs, that is, increasing the drug loading capacity and shortening the drug loading time.

[0077] In the present disclosure, each polyelectrolyte has multiple acidic groups on its molecular chain. The polyanions formed after the ionization of the multiple acidic groups contain multiple negatively charged groups. The aggregation of multiple negatively charged groups on a molecular chain can produce a counterion cohesion effect, so that a local low potential can be formed near the polyelectrolyte, so that the polyelectrolyte can induce a large number of positively charged particles to aggregate toward itself through electrostatic effects. In the polymer material provided by the present disclosure, multiple polyelectrolytes are grafted onto the three-dimensional network structure of the cross-linked polymer through chemical bonds. Therefore, in the polymer material, the negatively charged groups contained in the polyanions after the ionization of the polyelectrolytes can be dispersed on the three-dimensional network structure through the form of local aggregation (local higher density).

[0078] Furthermore, when the total amount of acidic groups is essentially the same, the denser the acidic groups in the polymeric material, the stronger the electrostatic adsorption capacity after ionization. For example, when the total amount of acidic groups is essentially the same, the number of polyelectrolytes is inversely proportional to the number of acidic groups contained on each polyelectrolyte, which can include the following two situations: Type A polymeric material: the number of polyelectrolytes is small, but the number of acidic groups contained on each polyelectrolyte is large (local density is high); Type B polymeric material: the number of polyelectrolytes is large, but the number of acidic groups contained on each polyelectrolyte is small (local density is low). In both of these situations, due to the counterion coagulation effect, Type A polymeric material exhibits a stronger ability to induce positive charge than Type B polymeric material, that is, Type A polymeric material can adsorb a larger number of positively charged particles and has a faster adsorption rate. Therefore, compared with traditional drug-loaded microsphere embolic agents, even when the total amount of acidic groups is basically the same, since the acidic groups in the polymer material provided by the present invention are dispersed in the three-dimensional network structure of the polymer through local aggregation, more positively charged particles can be induced to undergo electrostatic adsorption, and the electrostatic adsorption rate for positively charged particles is faster, thereby increasing the drug loading amount while shortening the drug loading time.

[0079] In some embodiments, each of the polyelectrolytes comprises a plurality of acidic groups, including: each of the polyelectrolytes comprises more than 3 acidic groups.

[0080] In the present disclosure, for each polyelectrolyte in the polymeric material, the number of acidic groups contained on the polyelectrolyte can be ≥3, for example, the number of acidic groups can be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or any number greater than 15. Since the acidic groups contained on the polyelectrolyte can generate negatively charged groups and cations after ionization, when the polyelectrolyte of the present disclosure is in an ionized state, the polyelectrolyte forms a polyanion after ionization, and the number of negatively charged groups on the polyanion is the same as the number of acidic groups contained on the polyelectrolyte. Therefore, the number of negatively charged groups on the polyanion can be ≥3, for example, the number of negatively charged groups can be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or any number greater than 15.

[0081] In the present disclosure, the more acidic groups contained on each polyelectrolyte, the higher the local density of the acidic groups (corresponding to the higher local density of negatively charged groups on the polyanion formed after the polyelectrolyte is ionized). At this time, the stronger the counterion cohesion effect formed by multiple negatively charged groups, the stronger the electrostatic adsorption ability of the polyanion to positively charged particles.

[0082] In some embodiments, the acidic group includes at least one of a carboxyl group, a sulfonic acid group, a sulfinic acid group, a phosphate group, a phosphite group, or a hypophosphite group.

[0083] In the present disclosure, the acidic groups contained in the polyelectrolytes in the polymeric material may be of a single type or of multiple types. Specifically, for one of the polyelectrolytes, the multiple acidic groups contained therein may all be of a single type, such as multiple acidic groups all being any one of carboxyl groups, amino groups, amide groups, phenolic hydroxyl groups, or sulfonylamino groups; or, for one of the polyelectrolytes, the multiple acidic groups contained therein may be of two or more types, such as one polyelectrolyte containing both carboxyl groups and amino groups. In the case where a polyelectrolyte contains two or more acidic groups, the specific optional combinations thereof are not listed here one by one.

[0084] For all polyelectrolytes in a polymeric material, the types of acidic groups they contain depend on the types of acidic groups contained in each polyelectrolyte. For example, when each polyelectrolyte contains only one type of acidic group, and the types of acidic groups contained in each polyelectrolyte are the same, the type of acidic group contained in all polyelectrolytes in the polymeric material is one; when each polyelectrolyte contains only one type of acidic group, but two or more polyelectrolytes contain acidic groups of different types, the type of acidic group contained in the polymeric material is more than one; when each polyelectrolyte contains more than one type of acidic group, the type of acidic group contained in the polymeric material is more than one.

[0085] The type of polyelectrolyte can determine the type of acidic groups contained in the polyelectrolyte, and conversely, the type of acidic groups contained in the polyelectrolyte can determine the type of polyelectrolyte. In some embodiments, the polyelectrolyte can include polyacrylic acid, carboxymethyl cellulose, carboxymethyl chitosan, sodium alginate, G4 dendrimer, or at least one of polyglutamic acid and polyaspartic acid.

[0086] Specifically, the polyelectrolyte in the polymer material disclosed herein may be any one of the above. For example, the polyelectrolyte may be polyacrylic acid, and multiple polyacrylic acids may be grafted to different positions of the polymer three-dimensional network structure through chemical bonds to form a polymer material.

[0087] The polyelectrolyte in the polymeric material disclosed herein may also be a combination of any two or more of the aforementioned polyelectrolytes. For example, if the polyelectrolyte comprises polyacrylic acid and carboxymethyl cellulose, at least one polyacrylic acid may be chemically grafted to different positions of the three-dimensional polymer network structure, and at least one carboxymethyl cellulose may also be chemically grafted to different positions of the three-dimensional polymer network structure, thereby forming the polymeric material. For the case where the polymeric material comprises two or more polyelectrolytes, specific optional combinations are not listed here.

[0088] In some embodiments, the cross-linked polymer may be a degradable cross-linked polymer.

[0089] In the present disclosure, the cross-linked polymer is degradable. During degradation, the macromolecular chains that make up the three-dimensional network structure break. When the polymer is loaded with a drug, the cleavage of the macromolecular chains during degradation promotes drug release. Furthermore, as the cross-linked polymer is completely degraded, the loaded drug is fully released, thereby improving drug utilization.

[0090] In some embodiments, the release rate of the loaded drug can be regulated by regulating the degradation rate of the cross-linked polymer, thereby achieving a long-term sustained release of the drug.

[0091] In the present disclosure, since polymeric materials can be used to load drugs, considering the impact of polymeric materials on organisms during application, cross-linked polymers with good biocompatibility can be selected as raw materials for the polymeric materials.

[0092] In some embodiments, the degradable cross-linked polymer includes at least one of cross-linked modified gelatin, chitosan, hyaluronic acid, agarose, chondroitin sulfate, starch, or cellulose.

[0093] A three-dimensional network structure is a fundamental structural characteristic of cross-linked polymers. The three-dimensional network structure of a cross-linked polymer is typically formed by cross-linking a precursor through modification (including physical, chemical, and biological cross-linking). Physical cross-linking, also known as non-covalent cross-linking, is generally formed by weak interactions such as hydrogen bonds, hydrophobic interactions, electrostatic interactions, and host-guest recognition. Chemical cross-linking, also known as covalent cross-linking, is formed by chemical reactions that generate new chemical bonds. These reactions include classic click chemistry, Diels-Alder (DA) addition reactions, Michael addition reactions, as well as the formation of Schiff bases, disulfide bonds, boronate bonds, and coordination bonds. Biological cross-linking primarily involves enzyme-mediated cross-linking reactions. For example, the numerous carboxyl groups, sulfate groups, and adjacent hydroxyl groups on the sugar chains of chondroitin sulfate provide not only abundant reaction sites for chemical modification but also potential active groups for physical and enzymatic cross-linking.

[0094] Gelatin, chitosan, hyaluronic acid, agarose, chondroitin sulfate, starch, and cellulose can all be cross-linked to form cross-linked polymers with three-dimensional network structures. Since gelatin, chitosan, hyaluronic acid, agarose, chondroitin sulfate, starch, and cellulose are all natural polymers, the resulting cross-linked polymers exhibit excellent biocompatibility and biodegradability.

[0095] For example, gelatin is a natural polymer material derived from the hydrolysis of collagen. It boasts advantages such as biodegradability, good biocompatibility, gelling properties, and low cost. It is non-toxic and harmless, making it widely used in food, medicine, and other fields. Gelatin is a polypeptide chain composed of multiple amino acids, sharing the same repeating sequence as collagen: Gly-XY, where Gly represents glycine, and X and Y represent any amino acid other than glycine. The electrostatic repulsion between proline and hydroxyproline in the gelatin chain causes the chain to form a left-handed α-helix, which plays a crucial role in stabilizing the gelatin structure. Furthermore, the gelatin chain contains reactive groups such as amino, carboxyl, and hydroxyl groups. Currently, gelatin is often used as a temporary embolic agent, such as the clinically used Gelatin Sponge, Gelfoam, and OptiSphere, all of which are resorbable by the body. The gelatin molecular backbone retains the arginine-glycine-aspartic acid peptide (RGD) and matrix metalloproteinase (MMP) peptides, providing excellent cell attachment and degradation properties. By using specific cross-linking reagents to cross-link gelatin or catalyzing reactions of groups on gelatin, a self-crosslinking structure can be formed. Specifically, the cross-linked modified gelatin obtained after cross-linking modification has a three-dimensional network structure. In the present disclosure, when the cross-linked polymer is cross-linked modified gelatin, the polyelectrolyte can be grafted onto the three-dimensional network structure of the cross-linked polymer via double bond cross-linking. The polyelectrolyte can also be grafted via reactions of other active groups contained within the polyelectrolyte with amino, hydroxyl, carboxyl, and other groups on the gelatin backbone.

[0096] The chitosan molecular chain contains a large amount of free amino groups (NH2), hydroxyl groups (OH), N-acetyl groups (CO-NH2) and other multiple reactive functional groups. The amino groups of chitosan can attract anions by electrostatic interaction after ionization. Chitosan can be modified by cross-linking. In the cross-linking reaction, the chitosan molecular chain generates an intermediate product prior to the cross-linking agent, and then generates the three-dimensional network structure of chitosan under certain conditions. The cross-linking agent can be selected from at least one of glutaraldehyde, epichlorohydrin, ethylene glycol diglycidyl ether or tripolyphosphate etc.

[0097] Hyaluronic acid (HA) is a natural mucopolysaccharide. Due to its large molecular weight, it exhibits unique viscoelasticity, excellent biocompatibility, and biodegradability. Chemical modification and cross-linking of HA to form a three-dimensional network structure enhance its mechanical strength and stability.

[0098] Agarose, chondroitin sulfate, starch, cellulose, and the like can be cross-linked and modified to form their own three-dimensional network structures based on the types of functional groups on their molecular chains. A full list of examples is omitted here. Furthermore, when the cross-linked polymer is chitosan, hyaluronic acid, agarose, chondroitin sulfate, starch, or cellulose that has undergone cross-linking and modification, polyelectrolytes can also be grafted onto the three-dimensional network structure of the cross-linked polymer via double bond cross-linking. Polyelectrolytes can also be reactively grafted based on the types of reactive groups contained in the three-dimensional network structure of the cross-linked polymer.

[0099] In the polymeric materials provided herein, the weight percentages of the cross-linked polymer and the polyelectrolyte can be adjusted according to actual conditions. Generally speaking, when the weight of the cross-linked polymer remains unchanged, the greater the weight percentage of the same polyelectrolyte, the greater the number of negatively charged groups (capable of adsorbing positively charged particles) obtained after ionization. In some embodiments, the cross-linked polymer comprises 1 to 30 parts by weight, and the polyelectrolytes comprise 0.2 to 30 parts by weight. For example, in terms of parts by weight, the cross-linked polymer may be 1-2 parts, 2-3 parts, 3-4 parts, 4-5 parts, 5-6 parts, 6-7 parts, 7-8 parts, 8-9 parts, 9-10 parts, 10-11 parts, 11-12 parts, 12-13 parts, 13-14 parts, 14-15 parts, 15-16 parts, 16-17 parts, 17-18 parts, 18-19 parts, 19-20 parts, 20-21 parts, 21-22 parts, 22-23 parts, 23-24 parts, 24-25 parts, 25-26 parts, 26-27 parts, 27-28 parts, 28-29 parts or 29-30 parts in any weight range; the polyelectrolyte may be 0.2-0.3 parts, 0.3-0.4 parts, 0.4- 21-22 parts, 22-23 parts, 23-24 parts, 24-25 parts, 25-26 parts, 26-27 parts, 27-28 parts, 28-29 parts or 29-30 parts in any weight range of parts.

[0100] It should be noted that, in the polymeric material disclosed herein, the weight fractions of the cross-linked polymer and the polyelectrolyte are also related to parameters such as the types of the cross-linked polymer and the polyelectrolyte, their respective molecular weights, and the number of active groups contained in them.

[0101] In the polymeric material disclosed herein, the connection between the cross-linked polymer and the polyelectrolyte can be direct or indirect, wherein direct connection can be understood as the direct reaction and bonding of the active groups on the polyelectrolyte molecular chain with the groups on the cross-linked polymer molecular chain.

[0102] Indirect connection can be understood as the active groups on the polyelectrolyte molecular chain being bound to the molecular chain of the cross-linked polymer through an intermediate substance, wherein the intermediate substance contains at least two active groups, wherein one active group (the first active group) is used to form a connection with the active group group on the polyelectrolyte molecular chain, and the other active group (the second active group) is used to form a connection with the active group group on the cross-linked polymer molecular chain. For example, in some embodiments, the polymer material further includes: a bridge, between the polyelectrolyte and the cross-linked polymer, for connecting the polyelectrolyte to the polymer. The bridge is an intermediate substance that can simultaneously connect the polyelectrolyte molecular chain and the cross-linked polymer molecular chain.

[0103] In the present disclosure, the relative positions of the first active group and the second active group on the bridge have various situations according to the different chemical activities of the bridge itself. When the first active group and the second active group on the bridge are far apart (it can also be understood that the first active group and the second active group are respectively located at the two ends of the bridge molecular chain), in the process of the polyelectrolyte being grafted onto the molecular chain of the cross-linked polymer through the bridge, if the molecular chain length of the bridge is relatively large, under the spacing effect of the bridge, the polyelectrolyte molecular chain can be away from the three-dimensional network structure of the cross-linked polymer and extend outward, thereby reducing the steric hindrance between the polyelectrolyte and the cross-linked polymer. In this case, the acidic groups on the polyelectrolyte can expose more negatively charged groups after ionization, thereby adsorbing more positively charged particles through electrostatic action.

[0104] In some embodiments, the bridge is a compound having one or more functional groups, and the functional groups of the bridge include at least one of amino, carboxyl, aldehyde, sulfhydryl, carbon-carbon double bond, carbon-carbon triple bond, acryloyl, methacryloyl, azido, epoxy, vinyl sulfone, succinimide, biotinyl, dibenzylcyclooctyne, di(p-nitrobenzene) carbonate, or norbornene. For example, the bridge can be a polyethylene glycol derivative having one or more functional groups, and the functional groups of the polyethylene glycol derivative include any one, or a combination of two or more of amino, carboxyl, aldehyde, sulfhydryl, carbon-carbon double bond, carbon-carbon triple bond, acryloyl, methacryloyl, azido, epoxy, vinyl sulfone, succinimide, biotinyl, dibenzylcyclooctyne, di(p-nitrobenzene) carbonate, or norbornene.

[0105] In a second aspect, the present disclosure provides a method for preparing a polymer material, comprising: mixing a cross-linking precursor, a cross-linking agent, and a polyelectrolyte, and then performing a cross-linking polymerization reaction under external conditions to form the polymer material.

[0106] In the present disclosure, the polymer material can be prepared by using a photocrosslinking method, a common chemical crosslinking method (thermal crosslinking method), or a combination of the photocrosslinking method and the common chemical crosslinking method.

[0107] For the process of preparing polymeric materials by photocrosslinking, microfluidics combined with photocrosslinking can be used to prepare polymeric materials with specific shapes and sizes. The preparation method of microfluidics combined with photocrosslinking can include the following steps:

[0108] (1) Preparing an aqueous solution: PBS buffer can be used as a solvent, and then the cross-linking precursor solution is drawn and mixed with the polyelectrolyte solution and the photoinitiator to obtain an aqueous solution;

[0109] Among them, the photocrosslinking group can be selected from photoinitiators such as photonitrene, photocarbene, carbon cation, and free radical, depending on the different active intermediates generated under light irradiation. For example, free radical photoinitiators can include phenyl (2,4,6-trimethylbenzoyl) lithium phosphate (LAP), diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide (TPO), 2,4,6-trimethylbenzoylphenyl phosphonic acid ethyl ester (TPO-L), 2-methyl-1-[4-methylthiophenyl]-2-morpholinyl-1-propanone (907), 2-isopropylthioxanthone (ITX), 1-hydroxycyclohexyl phenyl ketone (184), 2-hydroxy- 2-Methylpropiophenone (1173), 2,2-dimethoxy-2-phenylacetophenone (BDK), 2-benzoylbenzoic acid methyl ester (OMBB), benzophenone (BP), 4-chlorobenzophenone (CBP), 4-phenylbenzophenone (PBZ), 2-phenylbenzyl-2-dimethylamino-1-(4-morphophenylphenyl)butanone (369), 1,1'-(methylenedi-4,1-phenylene)bis[2-hydroxy-2-methyl-1-propanone] (127), 4 -Ethyl dimethylaminobenzoate (EDB), 2-ethylhexyl p-dimethylaminobenzoate (EHA), 4-methylbenzophenone (MBZ), 2,4-diethylthioxanthen-9-one (DETX), 2-(4-methylbenzyl)-2-(dimethylamino)-1-(4-morpholinophenyl)-1-butanone (379), 4-benzoyl-4'-methyl-diphenyl sulfide (BMS), 2,2'-bis(o-chlorophenyl)-4,4',5,5'-tetraphenyl-1,2 at least one of 1,2'-bisimidazole (BCIM), 2,2'-bis(o-chlorophenyl)-4,4',5,5'-tetraphenyl-1,2'-bisimidazole (OXE01), 1-[4-(4-benzoylphenylthio)phenyl]-2-toluenesulfonyl-2-methyl-1-propanone (1001M), 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (2959), methyl benzoylformate (MBF), or 2-ethylanthraquinone (EAQ);

[0110] Cationic photoinitiators may include aromatic sulfonium / iodonium salts, triphenylsulfonium hexafluorophosphate, diphenyliodonium hexafluorophosphate (810), 4-phenylthiophenyl diphenylsulfonium salt, tris[4-[(4-acetylphenyl)thio]phenyl]-hexafluorophosphate (Irgacure 209), 4-dodecyloxyphenyl diphenylsulfonium hexafluoroantimonate (SOC 10), 9-[4-(2-hydroxyethoxy)-phenyl]thianthrenesulfonium hexafluorophosphate (Esacure 1187), 10-(4-biphenyl)-2-isopropylthioxanthonesulfonium hexafluorophosphate (Omnicat 550), [7-(1-methylethyl)-9-oxo-9H-thioxanthen-2yl]bis(4-methylphenyl)sulfonium hexafluoroantimonate (PCI 10), and 1-isopropylthioxanthonesulfonium hexafluorophosphate (Omnicat 550). 061T), bis[(4-diphenylsulfonium)phenyl]sulfide-bis-hexafluorophosphate (UV 6992), 4-phenylthiophenyldiphenylsulfonium salt, 4,4-bis(thiazolin-9-yl)biphenyl hexafluorophosphate, S,S'-(thiodi-4,1-phenylene)bis[S,S-bis[4-(2-hydroxyethoxy)phenyl]sulfonium hexafluorophosphate (antimonate) (SP 150), (4-hydroxyphenyl)methyl(benzyl)hexasulfonium fluorophosphate (PHS SI 100L), 4-acetoxyphenyldimethylsulfonium hexafluoroantimonate (Sanaid SI 150), (4-hydroxyphenyl)methyl[(2-methylphenyl)methyl]-sulfonium hexafluoroantimonate (Sanaid 80L), dodecylmethyl(2-oxo-2-phenylethyl)sulfonium hexafluoroantimonate, diphenyliodonium hexafluorophosphate (Photoinitiator 810), bis(4-methylphenyl)iodonium hexafluorophosphate, bis(4-dodecylphenyl)iodonium hexafluorophosphate, bis(4-isopropylphenyl)iodonium hexafluorophosphate, bis(4-tert-butylphenyl)iodonium hexafluorophosphate, (4-tolyl)[4-(2-methylpropyl)phenyliodonium hexafluorophosphate] (Irgacure 250), or 4-octyloxyphenyliodonium hexafluoroantimonate (UVACURE 1600).

[0111] (2) Selection of oil phase: pure soybean oil (CAS: 8001-22-7), paraffin oil and other vegetable oils or mineral oils can be used;

[0112] (3) Preparation of collection solution: 1*PBS-10*PBS can be used as the collection solution;

[0113] (4) Select UV light of appropriate wavelength and power;

[0114] (5) Building an experimental system: For example, the following method can be used to build an experimental system: infrared lamps, heat preservation boxes, ovens, etc. are used as heat sources to ensure that the cross-linking precursor solution remains in a liquid state in the syringe and the flow channel; the oil phase solution and the water phase solution are respectively sucked into the injection syringe, the needle of the injection syringe is connected to a silicone hose, and a small steel tube is put on the other end of the silicone hose, and the small steel tube is inserted into the cross-shaped liquid inlet to achieve liquid injection, and the injection syringe is installed on a microinjector, and the flow rate of the two solutions is controlled by the microinjector; the water phase solution and the oil phase solution entering the microfluidic chip meet at the intersection of the "cross" structure. Since the oil phase and water are incompatible with each other and the flow rate of the oil phase is set to be large, the photocrosslinkable water phase solution is cut into droplets of a certain length; after the droplets are generated, they are solidified in the pipeline (ultraviolet light irradiates the droplets in the flow channel) and are discharged at the end of the straight tube. The end of the microfluidic chip is immersed in a beaker containing the collection liquid, and heating and stirring the collection liquid can prevent the aggregation of particles;

[0115] (6) Collecting the particulate polymeric material: centrifuging the collected liquid, separating the particulate polymeric material at the bottom, washing and storing it.

[0116] Regarding the process of preparing polymeric materials using conventional chemical cross-linking methods (e.g., emulsion preparation methods) or a combination of photocross-linking and conventional chemical cross-linking methods, considering the widespread use of commercial microspherical embolic agents, glutaraldehyde, paraformaldehyde, formaldehyde, etc. can also be used as cross-linking agents for preparation. The cross-linking agent can adjust the cross-linking degree of the cross-linked polymer.

[0117] In the process of preparing polymer materials by photocrosslinking, conventional chemical crosslinking (thermal crosslinking), or a combination of photocrosslinking and conventional chemical crosslinking, polyelectrolytes can also be grafted onto the three-dimensional network structure of the crosslinked polymer by introducing bridging substances (such as polyethylene glycol derivatives, N-hydroxysuccinimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, acrylamide, etc.).

[0118] Therefore, in some embodiments, the method for preparing a polymeric material further comprises: mixing a crosslinking precursor, a crosslinking agent, a polyelectrolyte, and a bridging agent, and then conducting a crosslinking polymerization reaction under external stimulation. The polymeric material prepared using the above method contains a bridging agent. In the present disclosure, polyethylene glycol derivatives and the like can be used as double bond-introducing agents in the photocrosslinking process for preparing the polymeric material, thereby photocrosslinking with the crosslinked polymer containing double bonds.

[0119] In some embodiments, the preparation of a polymer material using a conventional chemical cross-linking method, using glutaraldehyde as a cross-linking agent and introducing a bridge during the preparation process is described as an example. The preparation method may include the following steps:

[0120] (1) preparing a polyelectrolyte having 3 or more single-chain acidic groups into an aqueous solution;

[0121] (2) adding the bridged substance to the aqueous solution obtained in step (1) to form a reaction solution, and freeze-drying the reaction solution for storage;

[0122] (3) dissolving the cross-linking precursor in a hydrochloric acid solution to obtain a cross-linking precursor solution;

[0123] (4) mixing the reaction solution obtained in step (2) and the cross-linking precursor solution obtained in step (3) to obtain a mixed solution, and controlling the mixed solution to prevent solid precipitation;

[0124] (5) Preparation of oil phase: soybean oil containing a crosslinking agent (glutaraldehyde) is used as the oil phase;

[0125] (6) adding the mixed solution obtained in step (4) to the oil phase obtained in step (5), stirring to obtain a suspension, performing a cross-linking reaction under heating conditions, stopping stirring after the suspension becomes clear, and allowing the suspension to stand for the sedimentation of polymer microspheres, wherein the size of the polymer microspheres is between 50 μm and 1000 μm;

[0126] (7) After removing the oil phase, the oil phase on the surface of the polymer microspheres is washed and removed, and the polymer microspheres can be filtered and sieved step by step to preserve polymer microspheres of different sizes separately.

[0127] In some embodiments, the preparation of a polymer material using a combination of conventional chemical cross-linking methods, using glutaraldehyde as a cross-linking agent and introducing a bridge, is described as an example. The preparation method may include the following steps:

[0128] (1) preparing a polyelectrolyte having 3 or more single-chain acidic groups into an aqueous solution;

[0129] (2) adding the bridged substance to the aqueous solution obtained in step (1) to form a reaction solution, and freeze-drying the reaction solution for storage;

[0130] (3) dissolving the cross-linking precursor in a hydrochloric acid solution to obtain a cross-linking precursor solution;

[0131] (4) mixing the reaction solution obtained in step (2) and the cross-linking precursor solution obtained in step (3) to obtain a mixed solution, and controlling the mixed solution to prevent solid precipitation;

[0132] (5) Preparation of oil phase: soybean oil containing a crosslinking agent (glutaraldehyde) is used as the oil phase;

[0133] (6) adding the mixed solution obtained in step (4) to the oil phase obtained in step (5), stirring to obtain a suspension, and performing a cross-linking reaction under ultraviolet light irradiation. After the suspension becomes clear, the irradiation is stopped, and the suspension is allowed to stand for the sedimentation of the polymer microspheres, wherein the size of the polymer microspheres is between 50 and 1000 μm;

[0134] (7) After removing the oil phase, the oil phase on the surface of the polymer microspheres is washed and removed, and the polymer microspheres can be filtered and sieved step by step to preserve polymer microspheres of different sizes separately.

[0135] In a third aspect, the present disclosure provides an embolic agent, wherein the embolic agent is made from the polymeric material. The polymeric material provided by the present disclosure can be used as an embolic agent. When the polymeric material provided by the present disclosure is used as an embolic agent, the particle size of the polymeric material can be controlled during the preparation process.

[0136] In some embodiments, the particle size of the embolic agent can be 50-1000 μm. For example, the particle size of the embolic agent can be any value between 50-70 μm, 70-100 μm, 100-150 μm, 150-200 μm, 200-250 μm, 250-300 μm, 300-350 μm, 350-400 μm, 400-450 μm, 450-500 μm, 500-550 μm, 550-600 μm, 600-650 μm, 650-700 μm, 700-750 μm, 750-800 μm, 800-850 μm, 850-900 μm, 900-950 μm, or 950-1000 μm.

[0137] In some embodiments, the particle size of the embolic agent may also be 100-300 μm. For example, the particle size of the embolic agent may be any value between 100-110 μm, 110-120 μm, 120-130 μm, 130-140 μm, 140-150 μm, 150-160 μm, 160-170 μm, 170-180 μm, 180-190 μm, 190-200 μm, 200-210 μm, 210-220 μm, 220-230 μm, 230-240 μm, 240-250 μm, 250-260 μm, 260-270 μm, 270-280 μm, 280-290 μm, or 290-300 μm.

[0138] In a fourth aspect, the present disclosure provides a drug-loaded material, comprising: a polymeric material, including: a cross-linked polymer,

[0139] A plurality of polyions are grafted onto the three-dimensional network structure of the cross-linked polymer through chemical bonds, and each of the polyions contains a plurality of charged groups. The plurality of charged groups form a local potential through the counter-ion cohesion effect to induce the aggregation of drug particles with opposite charges; and a plurality of drug particles are adsorbed on the polymer material through electrostatic action.

[0140] The drug-loaded material provided by the present disclosure can be understood as a polymer material after drug loading, and thus the drug-loaded material may include a polymer material and a plurality of drug particles. In the process of using polymer materials to load drugs, for each of the multiple polyelectrolytes contained in the polymer material, the multiple ionizable groups contained on the polyelectrolyte are ionized to form a plurality of polyions, wherein, if the ionizable groups are acidic groups, the polyions obtained by ionization are polyanions, and accordingly, each polyanion contains a plurality of negatively charged groups, and the multiple negatively charged groups can form a local low potential through the counterion coagulation effect, thereby attracting positively charged drug particles. Positively charged drug particles may include

[0141] If the ionizable group is a basic group, the polyion obtained by ionization is a polycation. Accordingly, each polycation contains multiple positively charged groups. Multiple positively charged groups can form a local high potential through the counterion coagulation effect, thereby adsorbing negatively charged drug particles.

[0142] Compared with traditional drug-loaded microsphere embolic agents, the drug-loaded material provided by the present disclosure can introduce more ionizable groups into the three-dimensional network structure of the cross-linked polymer by grafting polyelectrolytes onto the three-dimensional network structure of the cross-linked polymer, thereby increasing the number of ionizable groups carried by the entire polymer material, thereby increasing the adsorption amount and adsorption efficiency of the polymer material for drug particles with opposite charges. That is, the drug-loaded material provided by the present application can have a higher drug loading capacity and a shorter drug loading time.

[0143] In some embodiments, the drug-carrying material includes: a polymer material, including: a cross-linked polymer, a plurality of polyanions, which are grafted onto the three-dimensional network structure of the cross-linked polymer through chemical bonds, and each of the polyanions contains a plurality of negatively charged groups, and the plurality of negatively charged groups form a local low potential through the counter-ion coagulation effect to induce the aggregation of positively charged particles; and a plurality of positively charged drug particles, which are adsorbed on the polymer material through electrostatic action.

[0144] FIG3 shows a schematic diagram of the microstructure of a drug-carrying material provided by the present disclosure. The polyion in FIG3 is a polyanion. In combination with FIG2 and FIG3, the drug-carrying material provided by the present disclosure includes positively charged drug particles and the polymer material shown in FIG2, wherein the positively charged drug particles can be adsorbed on multiple polyanions (or ionized polyelectrolytes) contained in the polymer material through electrostatic action, so that the drug particles are mainly in a state of local aggregation; in addition, the positively charged drug particles can also be adsorbed on the negatively charged groups carried by the cross-linked polymer itself through electrostatic action. Since the number of negatively charged groups carried by the cross-linked polymer itself is much lower than the number of negatively charged groups contained in the polyanion, and the negatively charged groups carried by the cross-linked polymer itself are randomly distributed (it is difficult to form a counterion cohesion effect), the number of drug particles directly adsorbed on the negatively charged groups carried by the cross-linked polymer itself is small and is randomly distributed.

[0145] The properties of the drug particles can determine the therapeutic efficacy of the drug-loaded materials provided herein. Depending on the type of drug particles electrostatically adsorbed onto the polymeric material, the therapeutic efficacy of the drug-loaded material can vary. In the present disclosure, the drug particles can be selected from a variety of drug molecules that can be charged upon ionization. For example, in some embodiments, the drug particles can include at least one of doxorubicin hydrochloride, epirubicin, mitomycin, fluorouracil, cisplatin, oxaliplatin, capecitabine, gemcitabine, irinotecan, topotecan, sorafenib, apatinib, lenvatinib, regorafenib, cabozantinib, ramucirumab, nivolumab, or pembrolizumab.

[0146] As previously mentioned, the drug-loaded material provided herein can be understood as a drug-loaded polymeric material, and in addition to containing a cross-linked polymer and multiple polyions, the polymeric material may also contain a bridge. Thus, in some embodiments, the polymeric material contained in the drug-loaded material further includes a bridge for connecting the polyanion to the polymer. Furthermore, the bridge plays the same role in the drug-loaded material as it does in the polymeric material, i.e., the bridge can serve as an intermediate substance that simultaneously connects the polyion molecular chains and the cross-linked polymer molecular chains.

[0147] In addition, depending on the chemical activity of the bridge itself, the relative positions of the first active group and the second active group on the bridge have various situations. When the first active group and the second active group on the bridge are far apart (it can also be understood that the first active group and the second active group are respectively located at the two ends of the bridge molecular chain), in the process of the polyion being grafted onto the molecular chain of the cross-linked polymer through the bridge, if the molecular chain length of the bridge is large, under the spacing effect of the bridge, the polyion molecular chain can be away from the three-dimensional network structure of the cross-linked polymer and extend outward, thereby reducing the steric hindrance between the polyion and the cross-linked polymer. At this time, for the case where the polyion is a polyanion, the polyanion can expose more negatively charged groups, thereby being able to adsorb more positively charged drug particles through electrostatic action. Accordingly, the more drug particles are contained on the drug-loaded material.

[0148] In some embodiments, the bridge included in the drug-loaded material may include at least one of a polyethylene glycol derivative (NH2-PEG-Acrylate), N-hydroxysuccinimide (NHS), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC), or acrylamide. For example, the bridge may be any one of polyethylene glycol derivatives, N-hydroxysuccinimide, or acrylamide, or the bridge may be a combination of any two or more of polyethylene glycol derivatives, N-hydroxysuccinimide, or acrylamide.

[0149] In a fifth aspect, the present disclosure provides a method for preparing a drug-loaded material, comprising: mixing drug particles with a polymer material, wherein the drug particles are adsorbed on the polymer material under the action of electrostatic force to obtain the drug-loaded material.

[0150] In the present disclosure, the methods used to prepare the polymeric material (or embolic agent) are the same as those described above and are not described in detail here. After the polymeric material (or embolic agent) is prepared, the drug particles can be mixed with the polymeric material (or embolic agent). Specifically, the drug particles can be dissolved and then mixed with the polymeric material (or embolic agent). The drug particles can be adsorbed onto the polymeric material (or embolic agent) under the action of electrostatic forces, thereby producing a drug-loaded material.

[0151] In a sixth aspect, the present disclosure further provides a drug-loaded embolic agent, which is made using the drug-loaded material. The drug-loaded material provided herein can be used as a drug-loaded embolic agent. When the drug-loaded material provided herein is used as a drug-loaded embolic agent, the particle size of the drug-loaded material can be controlled during the preparation process to accommodate the drug-loaded embolic agent at different sites of action.

[0152] The content of the present disclosure is described below with reference to specific embodiments.

[0153] Example 1

[0154] This embodiment uses a photocrosslinking method and a conventional chemical crosslinking method to prepare a polymeric material (embolic agent), which includes the following steps:

[0155] (1) Weigh 50-500 mg of modified gelatin (GelMA) solid foam and 0-200 mg of modified carboxyl macromolecule (polyacrylic acid, PA) into a centrifuge tube, add 1-5 ml of 1*PBS buffer, and dissolve in a 40-65°C water bath to obtain a 5-25 wt% GelMA solution as the aqueous phase solution;

[0156] (2) Weigh 50-500 g of soybean oil into a beaker, add 0-5 g of Span80, stir at 100-100 rpm for half an hour at 40-65 °C, centrifuge and collect the upper oil as the oil phase solution;

[0157] (3) Add the aqueous phase solution and the oil phase solution into a beaker at the same time, stir at 200-5000 rpm for 10-100 min, and irradiate with ultraviolet light for curing and crosslinking;

[0158] (4) According to the above experimental settings, the two-phase mixed solution was mechanically stirred for 10-100 minutes, the UV lamp was removed, and the obtained solid-liquid mixture was transferred to a centrifuge tube, centrifuged and the upper oil was removed, acetone solution was added, and the mixture was shaken and washed, and the mixture was centrifuged and precipitated. After washing, PBS buffer was added, shaken and washed, and the mixture was centrifuged and precipitated. After washing, the polymer material (embolic agent) was obtained.

[0159] Figure 4 shows a microscopic photograph of the polymeric material (embolic agent) prepared in Example 1. As shown in Figure 4 , the polymeric material (embolic agent) is spherical in shape and has a wide range of particle size distribution.

[0160] Figure 5 shows a microscopic photograph of the polymeric material (embolic agent) prepared in Example 1. As shown in Figure 5 , the polymeric material (embolic agent) is spherical in shape and has a wide range of particle size distribution.

[0161] Example 2

[0162] This embodiment uses a microfluidics combined with a photocrosslinking method to prepare a polymeric material (embolic agent), including the following steps:

[0163] (1) Weigh 50-500 mg of modified gelatin (GelMA) solid foam and 0-200 mg of modified carboxyl macromolecule (polyacrylic acid, PA) into a centrifuge tube, add 1-5 ml of 1*PBS buffer, and dissolve in a 40-65°C water bath to obtain a 5-25 wt% GelMA solution as the aqueous phase solution;

[0164] (2) Measure 50-500 ml of soybean oil as the oil phase solution;

[0165] (3) Weigh 50-500 g soybean oil into a beaker, add 0-5 g span80, stir at 100-100 rpm for half an hour at 40-65 °C, centrifuge and take the upper oil liquid as the oil phase solution;

[0166] (4) The oil phase solution and the aqueous phase solution were respectively drawn into two 1-20 mL syringes. The needles of the syringes were connected to silicone hoses (inner diameter 0.5 mm, outer diameter 2 mm). The oil phase solution was connected to a silicone hose of 1-100 cm, and the aqueous phase solution was connected to a silicone hose of 1-100 cm. The ends of the two silicone hoses were covered with capillary steel tubes with an outer diameter of 1-100 mm. The capillary steel tubes were then inserted into the injection port at the "T" structure of the microfluidic chip.

[0167] (5) Place the beaker containing hot water on a heating stirrer, set the temperature of the heating stirrer to 40-100°C, install two syringes on two microinjection instruments, set the flow rate of the oil phase solution to 1-1000 L / min, and the flow rate of the aqueous phase solution to 1-1000 L / min;

[0168] (6) When the discharged material is observed to be long and stable, ultraviolet light is irradiated on the droplets in the channel of the microfluidic chip to solidify the droplets. The end of the microfluidic chip is immersed in the collection liquid (the collection liquid just covers the discharge port of the gelatin embolic agent). The collection liquid is stirred at 80°C and 400 rpm. After solidification, the ultraviolet light is removed and the microspheres prepared by the emulsion method are washed;

[0169] (7) According to the above experimental settings, the two-phase solution was injected for 1 hour, the microfluidic chip was removed, the collected liquid was transferred to a centrifuge tube, centrifuged, the upper oil was removed, acetone solution was added, oscillated and washed, centrifuged and precipitated, PBS buffer was added, oscillated and washed, centrifuged and precipitated, and the polymer material (embolic agent) was obtained after washing.

[0170] Figure 6 shows a microscopic photograph of the polymeric material (embolic agent) prepared in Example 2. As shown in Figure 6 , the polymeric material (embolic agent) is in the shape of a long strip, with a length of about 400-1000 μm and a width of about 300-500 μm.

[0171] Example 3

[0172] In this example, the polymeric material (embolic agent) prepared in Example 1 was used to prepare a drug-loaded material (drug-loaded embolic agent), comprising the following steps: 50 mg of doxorubicin hydrochloride (excess) was added to 1 ml of ultrapure water, and the mixture was sonicated for 30 minutes to completely dissolve the doxorubicin hydrochloride in the ultrapure water; the doxorubicin hydrochloride aqueous solution was added to 1 mL of the polymeric material (embolic agent) prepared in Example 1, and the mixture was shaken on a shaker to allow the doxorubicin hydrochloride to be adsorbed on the polymeric material (embolic agent), thereby obtaining the drug-loaded material (drug-loaded embolic agent).

[0173] Figure 7 shows the maximum drug loading of polymeric materials (embolic agents) containing different polyacrylic acid mass fractions. As shown in Figure 7, as the polyacrylic acid mass fraction gradually increases, the maximum drug loading of the polymeric material (embolic agent) gradually increases, and the mass fraction of polyacrylic acid is linearly positively correlated with the maximum drug loading of the polymeric material (embolic agent). Figure 8 shows that the electronegativity of the polymeric material (embolic agent) containing polyacrylic acid is significantly increased due to the presence of polyacrylic acid compared to the polymeric material (embolic agent) without polyacrylic acid.

[0174] Example 4

[0175] In this example, the polymeric material (embolic agent) prepared in Example 1 was used to prepare a drug-loaded material (drug-loaded embolic agent), comprising the following steps: adding 25 mg of doxorubicin hydrochloride (appropriate amount) to 1 ml of ultrapure water, sonicating for 30 minutes to completely dissolve the doxorubicin hydrochloride in the ultrapure water, adding the doxorubicin hydrochloride aqueous solution to 1 mL of the polymeric material (embolic agent) prepared in Example 1, and shaking on a shaker to allow the doxorubicin hydrochloride to be adsorbed on the polymeric material (embolic agent), thereby obtaining a drug-loaded material (drug-loaded embolic agent).

[0176] Figure 9 shows the drug loading efficiency of polymeric materials (embolic agents) containing different mass fractions of polyacrylic acid. As shown in Figure 9, the polymeric material (embolic agent) containing 2.2% polyacrylic acid has a higher drug loading efficiency than the polymeric material (embolic agent) without polyacrylic acid. The polymeric material (embolic agent) containing 2.2% polyacrylic acid can adsorb over 97% of the drug. The polymeric material (embolic agent) without polyacrylic acid adsorbs less than 40% of the drug, with over 60% of the drug remaining in the aqueous solution.

[0177] Figure 10 shows the drug loading rates of polymeric materials (embolic agents) containing equivalent polyacrylic acid mass fractions but varying polyacrylic acid molecular weights. As shown in Figure 10, the higher molecular weight polyacrylic acid (2000 Da) exhibited faster drug loading and greater drug loading compared to the 1200 Da polyacrylic acid (1200 Da), demonstrating that higher molecular weight polyanions exhibit a stronger counterion aggregation effect due to their higher anion density.

[0178] Figure 11 shows the degradation rate and drug release rate of the same drug-loaded material (drug-loaded embolic agent) under different conditions. As shown in Figure 11, under enzyme-catalyzed conditions, the drug-loaded material (drug-loaded embolic agent) can be degraded, and under enzyme-catalyzed conditions, the drug can be released in a substantially linear manner (the drug release rate is substantially proportional to time), and complete drug release can be achieved.

[0179] Example 5

[0180] In this example, the polymeric material (embolic agent) prepared in Example 2 was used to prepare a drug-loaded material (drug-loaded embolic agent), comprising the following steps: adding 25 mg of doxorubicin hydrochloride (appropriate amount) to 1 ml of ultrapure water, sonicating for 30 minutes to completely dissolve the doxorubicin hydrochloride in the ultrapure water, adding the doxorubicin hydrochloride aqueous solution to 1 mL of the polymeric material (embolic agent) prepared in Example 1, and shaking on a shaker to allow the doxorubicin hydrochloride to be adsorbed on the polymeric material (embolic agent), thereby obtaining a drug-loaded material (drug-loaded embolic agent).

[0181] Figures 12 to 14 show the changes in the polymeric material (embolic agent) from before drug loading to after drug loading. Among them, Figure 12 shows a microscopic photograph of the polymeric material (embolic agent) before drug loading. Figure 13 shows a microscopic photograph of the doxorubicin hydrochloride and the polymeric material (embolic agent) just after mixing. Since the doxorubicin hydrochloride solution itself has a color (orange-red), when the doxorubicin hydrochloride solution is just mixed with the polymeric material (embolic agent), the whole presents the same color as the doxorubicin hydrochloride solution. Figure 14 shows a microscopic photograph of the drug-loaded material (drug-loaded embolic agent) obtained after the polymeric material (embolic agent) is loaded with drug. At this time, since doxorubicin hydrochloride has been adsorbed into the polymeric material (embolic agent), the originally colorless polymeric material (embolic agent) turns black and red, thereby obtaining a drug-loaded material (drug-loaded embolic agent).

[0182] Example 6

[0183] In this example, the drug-loaded material (drug-loaded embolic agent) prepared in Example 5 was injected into the decellularized liver of a rabbit through a 10 cm flat-blade needle to observe its embolic and drug-loading effects.

[0184] Figure 15 shows the arrangement of a drug-loaded material (drug-loaded embolic agent) in a blood vessel, demonstrating the effect of drug release along the vessel. Figure 16 shows the arrangement of a drug-loaded material (drug-loaded embolic agent) in a blood vessel, demonstrating the effect of drug release along the vessel. Figure 17 shows the arrangement of a drug-loaded material (drug-loaded embolic agent) in a blood vessel, demonstrating the effect of drug release along the vessel.

[0185] As shown in FIG16 , the drug-loaded material (drug-loaded embolic agent) prepared in Example 5 can be arranged in a straight line at the end of the blood vessel to achieve deeper embolism. It is densely arranged and stably distributed in the blood vessel, and is not prone to positional displacement. At the same time, the drug-loaded material (drug-loaded embolic agent) prepared in Example 5 can be observed to slowly release doxorubicin hydrochloride through the circulation of physiological saline in the blood vessel.

[0186] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned 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.

[0187] The embodiments described above only express several embodiments of the present invention, and their descriptions are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present invention, several variations and improvements can be made, which all fall within the scope of protection of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are all within the scope of protection of the claims attached to the present invention. Therefore, the scope of protection of the patent of the present invention shall be based on the attached claims, and the description and drawings can be used to interpret the content of the claims.

Claims

1. A polymer material, characterized in that include: Cross-linked polymers; as well as A plurality of polyelectrolytes are grafted onto the three-dimensional network structure of the cross-linked polymer through chemical bonds, and each of the polyelectrolytes contains a plurality of ionizable groups. After ionization, the plurality of ionizable groups form a local potential through the counter-ion coagulation effect to induce the aggregation of particles with opposite charges.

2. The polymer material according to claim 1, characterized in that Each of the polyelectrolytes comprises a plurality of ionizable groups, including: Each of the polyelectrolytes comprises a plurality of acidic groups, which, after ionization, form a local low potential through the counter-ion coagulation effect to induce aggregation of positively charged particles.

3. The polymer material according to claim 2, characterized in that Each of the polyelectrolytes comprises a plurality of acidic groups, including: Each of the polyelectrolytes contains more than three acidic groups.

4. The polymer material according to claim 2, characterized in that The acidic group includes at least one of a carboxyl group, a sulfonic acid group, a sulfinic acid group, a phosphoric acid group, a phosphite group or a hypophosphite group.

5. The polymer material according to claim 1, characterized in that The polyelectrolyte comprises at least one of polyacrylic acid, carboxymethyl cellulose, carboxymethyl chitosan, sodium alginate, G4 dendrimer, polyglutamic acid or polyaspartic acid.

6. The drug-carrying material according to any one of claims 1 to 5, characterized in that The cross-linked polymer is a degradable cross-linked polymer.

7. The polymer material according to claim 5, characterized in that The degradable cross-linked polymer includes cross-linked modified gelatin, chitosan, hyaluronic acid, At least one of lipose, chondroitin sulfate, starch or cellulose.

8. The polymer material according to any one of claims 1 to 7, characterized in that In terms of weight, the cross-linked polymer is 1 to 30 parts, and the plurality of polyelectrolytes are 0.2 to 30 parts.

9. The polymer material according to any one of claims 1 to 8, characterized in that Also includes: A bridger, a compound with one or more functional groups, is between the polyelectrolyte and the polymer and is used to connect the polyelectrolyte and the polymer.

10. The polymer material according to claim 9, characterized in that The functional groups of the bridge include at least one of an amino group, a carboxyl group, an aldehyde group, a thiol group, a carbon-carbon double bond, a carbon-carbon triple bond, an acryloyl group, an isobutylacryloyl group, an azido group, an epoxy group, a vinyl sulfone group, a succinimide group, a biotinyl group, a dibenzylcyclooctyne group, a di(p-nitrobenzene) carbonate group, or a norbornene group.

11. A method for preparing a polymer material, characterized in that: include: After the cross-linking precursor, the cross-linking agent and the polyelectrolyte are mixed, a cross-linking polymerization reaction is carried out under external conditions to form the polymer material as claimed in any one of claims 1 to 10.

12. The preparation method according to claim 11, characterized in that: include: After the cross-linking precursor, the cross-linking agent, the polyelectrolyte and the bridge are mixed, a cross-linking polymerization reaction is carried out under external conditions to form the polymer material as claimed in any one of claims 9 to 10.

13. An embolic agent, characterized in that: The embolic agent is made of the polymer material according to any one of claims 1-10.

14. The embolic agent according to claim 13, characterized in that The particle size of the embolic agent is 50-1000 μm.

15. A drug-carrying material, characterized in that: include: Polymeric materials, including cross-linked polymers, A plurality of polyions are grafted onto the three-dimensional network structure of the cross-linked polymer through chemical bonds, and each of the polyions contains a plurality of charged groups, and the plurality of charged groups form a local potential through a counter-ion coagulation effect to induce aggregation of drug particles with opposite charges; and A plurality of drug particles are adsorbed on the polymer material through electrostatic action.

16. The drug-carrying material according to claim 15, characterized in that: The multiple polyions include: multiple polyanions, which are grafted onto the three-dimensional network structure of the cross-linked polymer through chemical bonds, and each of the polyanions contains multiple negatively charged groups, and the multiple negatively charged groups form a local low potential through the counter-ion coagulation effect to induce the aggregation of positively charged particles; and The plurality of drug particles include: a plurality of positively charged drug particles adsorbed on the polymer material through electrostatic action.

17. The drug-carrying material according to claim 16, characterized in that: The plurality of drug particles are locally aggregated and adsorbed on the plurality of polyanions of the polymer material through electrostatic action.

18. The drug-carrying material according to claim 16, characterized in that: The multiple drug particles are also adsorbed on the multiple negatively charged groups carried by the cross-linked polymer itself through electrostatic action.

19. The drug-carrying material according to claim 16, characterized in that: The drug particles include at least one of doxorubicin hydrochloride, epirubicin, mitomycin, fluorouracil, cisplatin, oxaliplatin, capecitabine, gemcitabine, irinotecan, topotecan, sorafenib, apatinib, lenvatinib, regorafenib, cabozantinib, ramucirumab, nivolumab, or pembrolizumab.

20. The drug-carrying material according to any one of claims 15 to 19, characterized in that: The polymeric material also includes: Bridgers, compounds with one or more functional groups, are used to connect the polyanion to the polymer.

21. The drug-carrying material according to claim 20, characterized in that: The one or more functional groups of the bridge include at least one of an amino group, a carboxyl group, an aldehyde group, a thiol group, a carbon-carbon double bond, a carbon-carbon triple bond, an acryloyl group, an isobutylacryloyl group, an azide group, an epoxy group, a vinyl sulfone group, a succinimide group, a biotinyl group, a dibenzylcyclooctyne group, a di(p-nitrobenzene) carbonate group, or a norbornene group.

22. A method for preparing a drug-carrying material, characterized in that: include: The drug particles are mixed with a polymer material, and the drug particles are adsorbed on the polymer material under the action of electrostatic force, so as to obtain the drug-loaded material as claimed in any one of claims 15 to 21.

23. A drug-loaded embolic agent, characterized in that: The drug-loaded embolic agent is made of the drug-loaded material according to any one of claims 15-21.

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