阅读说明：本技术 肿瘤细胞粘附材料及其制备方法和应用 (Tumor cell adhesion material and preparation method and application thereof ) 是由 欧来良 于 2020-06-29 设计创作，主要内容包括：本发明提供了一种肿瘤细胞粘附材料及其制备方法和应用,涉及医药技术领域,本发明提供的肿瘤细胞粘附材料,包括载体、包覆于载体表面的抗污聚合物、设于载体表面的分子手臂和偶联的小分子粘附配基,其中,抗污聚合物能够有效提高改肿瘤细胞粘附材料的血液相容性,将肿瘤亲和性小分子粘附配基通过连接体偶联到载体上,使得本发明提供的肿瘤细胞粘附材料对肿瘤细胞具有强粘附能力,能够特异性粘附血液、体液或手术区溶液中的肿瘤细胞,从而减少原发性癌症因血液转移或手术创伤播散导致的转移癌的发生,为癌症治疗提供了一种辅助治疗方法。并且,该材料制备简单、成本低、使用中易于操作,具有重要的临床价值与经济、社会效益。(The invention provides a tumor cell adhesion material and a preparation method and application thereof, and relates to the technical field of medicines. In addition, the material is simple to prepare, low in cost and easy to operate in use, and has important clinical value and economic and social benefits.)

1. A tumor cell adhesion material, which is characterized by comprising a carrier, an anti-fouling polymer, a connector and a small molecule adhesion ligand;

the anti-fouling polymer is coated on the surface of the carrier;

the connector is arranged on the surface of the carrier and is used for coupling the small molecule adhesion ligand.

2. The tumor cell adhesion material of claim 1, wherein the carrier comprises a magnetic carrier or a non-magnetic carrier.

3. The tumor cell adhesion material of claim 2, wherein the magnetic carrier comprises magnetic iron oxide;

optionally, the non-magnetic carrier comprises polyvinyl alcohol, chitosan, cellulose, agarose, polymethacrylates, or polystyrene.

4. The tumor cell adhesion material of claim 1, wherein the anti-fouling polymer comprises polyvinyl alcohol, polycaprolactone, polyethylene glycol, or polyacrylate.

5. The tumor cell adhesion material of claim 1, wherein the linker comprises a molecular arm or a cross-linking agent;

preferably, the molecular arm bears a bifunctional group;

preferably, the molecular arm carries one or more of an amine group, a carboxyl group, an aldehyde group or a hydroxyl group.

6. The tumor cell adhesion material of claim 1, wherein the small molecule adhesion ligand comprises one or more of a small molecule pectin, a polypeptide, a folate, or a polyamine compound.

7. The tumor cell adhesion material of any one of claims 1-6, wherein the shape of the tumor cell adhesion material comprises a tube, a sheet, a flocculent, a block, a powder or a sphere.

8. The method for preparing the tumor cell adhesion material of any one of claims 1 to 7, which comprises treating a carrier with an anti-fouling polymer, activating the carrier with a linker, and coupling small molecule adhesion ligands to obtain the tumor cell adhesion material.

9. Use of a tumor cell adhesion material according to any one of claims 1 to 7 for the elimination of tumor cells; and/or the presence of a gas in the gas,

the application in preparing products for preventing and treating tumor metastasis.

10. A medical device comprising the tumor cell adhesion material of any one of claims 1 to 7.

Technical Field

The invention relates to the technical field of medicines, in particular to a tumor cell adhesion material and a preparation method and application thereof.

Background

Cancer diseases are continuously high, cancer becomes the first cause of death in cities, the death rate of cancer patients is not reduced by the improvement of science and technology, and the death rate of cancer patients is shown by investigation, and 90 percent of cancer patients are caused by recurrent metastasis of cancer. Therefore, how to prevent and reduce the metastasis of tumor becomes a significant problem.

How to effectively reduce the metastasis of the tumor is an important factor for improving the prognosis of the tumor. However, there are many types of tumors, and metastasis has already occurred when the tumor is found, which is also one of the reasons for poor prognosis of tumor treatment. However, it is generally considered that the metastasis of tumor is mainly based on several ways, one of which is blood metastasis, and the metastasis accounts for more than 80% of tumor metastasis; the second is lymphatic metastasis; the third is wound spreading, such as local shedding of tumor cells caused by operation. Therefore, how to block the metastasis of tumor cells will be an important issue for the tumor treatment.

Among the factors causing tumor metastasis, Circulating Tumor Cells (CTCs) refer to tumor cells released into peripheral blood circulation from solid tumors or metastases during diagnosis and treatment operations, and the local scattering and scattering in the operation area account for more than 90% of tumor metastasis. Therefore, if circulating tumor cells or tumor cells scattered in the operation area can be effectively eliminated, the risk of tumor metastasis can also be effectively reduced.

The rapid adhesion technology of tumor cells is reported in the detection of circulating tumor cells both at home and abroad, and most of cell adhesion materials for tumor cell detection adopt methods of antigen-antibody, exosome, DNA, RNA and the like for identification, for example, the technology for capturing CTC based on the CTC surface marker principle includes: CTC-chip (CTC-chip), iFISH-CTC (immunofluorescence staining in combination with FISH technology), and the like. The inventor also bases on the surface grafting of multiple antibodies on the anti-fouling material for capturing and detecting tumor cells (patent application number: 201910485658.9), and the technology based on biomolecule recognition has a wide detection prospect, has very few researches on clearing CTC, and is rarely reported for clearing scattered tumor cells in an operation area. Because the adhesion materials based on biomacromolecules (antibodies, exosomes, DNA and the like) as ligands have acceptable cost when being used for trace detection, but have no feasibility in aspects of manufacturing process, cost and the like when being used for removing a large number of tumor cells.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The main object of the present invention is to provide a tumor cell adhesion material to alleviate at least one of the technical problems of the prior art.

The second object of the present invention is to provide a method for preparing the tumor cell adhesion material.

The third purpose of the invention is to provide the application of the tumor cell adhesion material.

The fourth purpose of the invention is to provide a medical appliance comprising the tumor cell adhesion material provided by the invention.

The invention provides a tumor cell adhesion material, which comprises a carrier, an anti-fouling polymer, a connector and a small molecule adhesion ligand;

the anti-fouling polymer is coated on the surface of the carrier;

the connector is arranged on the surface of the carrier and is used for coupling the small molecule adhesion ligand.

Further, the carrier includes a magnetic carrier or a non-magnetic carrier.

Further, the magnetic carrier includes magnetic iron oxide;

optionally, the non-magnetic carrier comprises polyvinyl alcohol, chitosan, cellulose, agarose, polymethacrylates, or polystyrene.

Further, the anti-fouling polymer comprises polyvinyl alcohol, polycaprolactone, polyethylene glycol or polyacrylate.

Further, the linker comprises a molecular arm or a cross-linking agent;

preferably, the molecular arm bears a bifunctional group;

preferably, the molecular arm carries one or more of an amine group, a carboxyl group, an aldehyde group or a hydroxyl group.

Further, the small molecule adhesion ligand comprises one or more of a small molecule pectin, a polypeptide, a folate, or a polyamine compound.

Further, the shape of the tumor cell adhesion material comprises a tube shape, a sheet shape, a flocculent shape, a block shape, a powder shape or a spherical shape.

The invention also provides a preparation method of the tumor cell adhesion material, which comprises the steps of treating the carrier by the anti-fouling polymer, activating by the connector, and coupling the small molecule adhesion ligand to obtain the tumor cell adhesion material.

The invention also provides the application of the tumor cell adhesion material in removing tumor cells; and/or the presence of a gas in the gas,

the application in preparing products for preventing and treating tumor metastasis.

In addition, the invention also provides a medical appliance, which comprises the tumor cell adhesion material.

Compared with the prior art, the invention has the following beneficial effects:

the tumor cell adhesion material provided by the invention comprises a carrier, an anti-fouling polymer coated on the surface of the carrier, a molecular arm arranged on the surface of the carrier and a coupled small molecular adhesion ligand, wherein the anti-fouling polymer can effectively improve the blood compatibility of the tumor cell adhesion material, and the tumor affinity small molecular adhesion ligand is coupled to the carrier through a connector, so that the tumor cell adhesion material provided by the invention has strong adhesion capacity to tumor cells and can specifically adhere to the tumor cells in blood, body fluid or solution in an operation area, thereby reducing the occurrence of metastatic cancer caused by blood metastasis or surgical wound dissemination of primary cancer, and providing an auxiliary treatment method for cancer treatment. In addition, the material is simple to prepare, low in cost and easy to operate in use, and has important clinical value and economic and social benefits.

The preparation method of the tumor cell adhesion material provided by the invention is simple in process, convenient to operate and suitable for popularization and application.

Detailed Description

The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The invention aims to solve the problems of tumor metastasis and the like caused by local scattering of tumor cells caused by clinical circulating tumor cells and operation and the like, and provides a tumor cell adhesion material which is simple to operate, short in treatment time, reliable in result, moderate in price and capable of effectively removing scattered tumor cells in blood and operation areas and a preparation method thereof.

According to one aspect of the present invention, there is provided a tumor cell adhesion material comprising a carrier, an anti-fouling polymer, a linker and a small molecule adhesion ligand;

the anti-fouling polymer is coated on the surface of the carrier;

the connector is arranged on the surface of the carrier and is used for coupling the small molecule adhesion ligand.

In the tumor cell adhesion material provided by the invention, the anti-fouling polymer can effectively improve the blood compatibility of the tumor cell adhesion material, and the tumor affinity small molecule adhesion ligand is coupled to the carrier through the connector, so that the tumor cell adhesion material provided by the invention has strong adhesion capability to tumor cells, and can specifically adhere to the tumor cells in blood, body fluid or solution in an operation area, thereby reducing the occurrence of metastatic cancer caused by blood metastasis or surgical wound dissemination of primary cancer, and providing an auxiliary treatment method for cancer treatment. In addition, the material is simple to prepare, low in cost and easy to operate in use, and has important clinical value and economic and social benefits.

In the present invention, the carrier may include a magnetic carrier or a non-magnetic carrier.

According to the actual adsorption requirement, different materials can be selected as carriers to prepare the tumor cell adhesion material. For example, non-magnetic carriers can be used to remove tumor cells directly from blood, body fluids, or surgical field solutions; the magnetic carrier can be dispersed in blood, body fluid or solution, and then the magnetic carrier is adsorbed by the magnet, thereby eliminating tumor cells in the blood, body fluid or solution in an operation area.

An alternative magnetic carrier comprises magnetic iron oxide.

Alternative non-magnetic carriers include polyvinyl alcohol, chitosan, cellulose, agarose, polymethacrylates, or polystyrene.

In the invention, after the carrier material is subjected to surface anti-fouling treatment by the anti-fouling polymer, the required material with excellent blood compatibility can be obtained.

The specific choice of the antifouling polymer is not limited, and any high molecular substance capable of increasing the blood compatibility of the carrier can be used. Preferably, the anti-fouling polymer comprises polyvinyl alcohol, polycaprolactone, polyethylene glycol or polyacrylate, chitosan, polyamino acid and the like according to different uses of the tumor cell adhesion material. For example, when the anti-fouling polymer is used for removing tumor cells from blood, materials with excellent blood compatibility are required, and polyvinyl alcohol, polyethylene glycol, polycaprolactone, polyacrylate and the like can be selected as the anti-fouling polymer; for the removal of tumor cells in non-blood, such as tissue fluid or surgical solution, materials with excellent tissue compatibility, including chitosan, polyamino acids, polyacrylic acids, etc., can be used as the anti-fouling polymer of the present invention.

In the invention, the linker is used for activating the surface of the carrier, so that the activated surface of the carrier can be coupled with a small molecule adhesion ligand having affinity to tumor cells.

Typical linkers may be molecular arms or cross-linkers.

The type of the molecular arm functional group is generally determined according to the functional group of the ligand to be grafted, so as to ensure that the two functional groups can chemically react, and in the present invention, the molecular arm preferably has a bifunctional group, such as, but not limited to, one or more of an amine group, a carboxyl group, an aldehyde group, or a hydroxyl group.

It should be noted that the meaning of "one or more" means that the specific selection of the bifunctional group can be one of an amine group, a carboxyl group, an aldehyde group or a hydroxyl group, or two, three or four of them, according to different applications. The invention is not limited in this regard.

In the invention, the micromolecule adhesion ligand has high affinity to the tumor cells, and the effective adsorption to the tumor cells can be realized by coupling the micromolecule adhesion ligand. The small molecule adhesion ligand comprises one or more of a small molecule pectin, a polypeptide, a folate, or a polyamine compound, depending on the use of the tumor cell adhesion material. For example, when the polypeptide, the pectin and the folic acid are used for removing tumor cells in blood, the polypeptide, the pectin and the folic acid are generally used as the small molecule adhesion ligands in the invention, and the compatibility with blood is better; when the polypeptide is used for removing tissue fluid or liquid tumor cells in an operation area, besides the aglycone, polyamine aglycone can be used.

Likewise, "one or more" means that the particular choice of small molecule adhesion ligand may be one, or two, three or four, of small molecule pectin, polypeptide, folate or polyamine compounds, depending on the application. The invention is not limited in this regard.

Among them, the polypeptide is preferably a polypeptide having 18 or less amino acids, for example, RKEM, RHCLS, RHCLSGGGRKEM, etc.

In the present invention, the carrier may have any shape, and for example, but not limited to, a tube shape, a sheet shape, a flocculent shape, a block shape, a powder shape, or a spherical shape.

When the carrier is tubular, spherical or blocky, the carrier can be more suitable for removing tumor cells in circulating blood; when the carrier is in the form of powder, sheet, flocculent or sphere, the carrier can be more suitable for removing tumor cells in body fluid or operation area solution.

According to a second aspect of the present invention, the present invention further provides a preparation method of the tumor cell adhesion material, comprising the steps of treating the carrier with the anti-fouling polymer, activating the carrier with the linker, and coupling the small molecule adhesion ligand to obtain the tumor cell adhesion material.

The preparation method of the tumor cell adhesion material provided by the invention is simple in process, convenient to operate and suitable for popularization and application.

Based on the beneficial effects of the tumor cell adhesion material provided by the invention, the invention also provides the application of the tumor cell adhesion material in removing tumor cells. And the application of the tumor cell adhesion material in preparing products for preventing and treating tumor metastasis.

The tumor cell adhesion material provided by the invention can adsorb all types of tumor cells and can adhere to the tumor cells in blood, body fluid and operating area exudate. It can be used for preventing tumor cell metastasis before or after operation.

By the specific adhesion effect of the tumor cell adhesion material on tumor cells, the tumor cell adsorption material can be applied to the existing medical instruments, is convenient for clinical operation or use, and can be used as a coating material of extracorporeal circulation or venous circulation system pipelines during operation; also can be used for the membrane surface coating of a dialyzer or hemofilter; and the like, in combination with the above medical instruments, and the present invention is not limited thereto.

In addition, the invention also provides a medical appliance, which comprises the tumor cell adhesion material.

The invention is further illustrated by the following examples. The materials in the examples are prepared according to known methods or are directly commercially available, unless otherwise specified.