Application of cellulose copolymer-based hydrogel in tumor PDX model

Abstract

The invention relates to a cellulose matrigel formed by a cellulose copolymer, a cellulose derivative copolymer or a blend thereof, the cellulose matrigel is of a net structure composed of ultramicro fibers, has a highly-ordered three-dimensional micro-nano structure, is used for constructing an efficient and stable tumor CDX or PDX model, is simple to operate and has good application prospects. The method has high similarity with clinical tumors, and a solution is provided for clinical curative effect prediction and preclinical research.

Description

[0001] The present invention claims the priority benefit of the prior application filed by the applicant with the State Intellectual Property Office of China on April 15, 2024, with patent application number CN202410450789.4 and invention name “Application of a cellulose copolymer-based hydrogel in a tumor PDX model”. The contents of the above application are incorporated into this text by reference. Technical Field

[0002] The present invention belongs to the field of biotechnology, and in particular relates to the application of a cellulose matrix glue formed by a cellulose copolymer, a cellulose derivative copolymer or a blend thereof in a tumor CDX or PDX model. Background Art

[0003] A tumor is a neoplasm formed when a cell in a local tissue loses normal genetic regulation of its growth under the influence of various carcinogenic factors, leading to its clonal abnormal proliferation. It is generally believed that tumor cells are monoclonal, that is, all tumor cells in a tumor are descendants of a single mutated cell. The main malignant tumors in my country currently include gastric cancer, lung cancer, intestinal cancer, esophageal cancer, and breast cancer, which have high morbidity and mortality rates and poor prognosis. Currently, due to the lack of research models that characterize the occurrence and development characteristics of tumors such as gastric cancer, the research on the pathogenesis of gastric cancer and the development of therapeutic drugs are subject to certain limitations.

[0004] Traditional cell line models are the most commonly used models for human tumor research, but these models differ significantly from the human tumor microenvironment, resulting in lower predictive value in clinical trials. During the passage of traditional tumor cell lines, cellular characteristics undergo significant changes, such as the insertion and loss of genetic information, changes in growth and invasion characteristics, and the loss of specific cell populations. Tumor tissue is composed of highly heterogeneous subpopulations of cancer cells with different characteristics, and the tumor microenvironment is indispensable in the occurrence and development of tumors. Therefore, in clinical research, cell line tumor research models cannot represent the complex heterogeneity of tumors. For the above reasons, traditional cell line tumor research models cannot meet the needs of clinical tumor model research, especially in terms of the needs of tumor research translation.

[0005] The CDX model, known as Cell-Derived Xenograft (CDX), involves inoculating in vitro cultured tumor cells into immunodeficient mice. Due to its well-defined tumor growth kinetics, ease of genetic manipulation, high tumorigenicity, low cost, and ability to generate consistent and reproducible data, it is widely used in cancer research and anticancer drug development, and is a preferred model for in vivo drug screening. CDX models are typically inoculated subcutaneously, intravenously, intraarterially, or orthotopically.

[0006] The PDX model is called a patient-derived tumor xenograft model. Its full name is Patient-Derived tumorXenograft. It is a human-derived xenograft model established by directly transplanting the patient's tumor tissue into immunodeficient mice. This model is characterized by retaining most of the characteristics of the primary tumor at the histopathological, molecular biological and genetic levels. It has good predictive power for clinical efficacy and is widely used in new drug development, especially in patient screening for clinical trials of target drugs and research on predictive biomarkers. The PDX model is one of the most promising models. Studies have shown that the response of clinical patients to cytotoxic drugs is highly consistent with the results of the PDX model. The PDX model has high tumor heterogeneity, a short modeling time, and is close to the human tumor microenvironment. Therefore, this model has gradually become the preferred preclinical research tool.

[0007] The CDX or PDX model construction method requires the use of Matrigel. For example, the commonly used Matrigel is a basement membrane matrix extracted from EHS mouse tumors, which are rich in extracellular matrix proteins. Its main components include laminin, type IV collagen, heparin sulfate glycoprotein, and entactin, as well as various growth factors and matrix metalloproteinases. However, Matrigel currently has several issues: 1) supply shortages due to animal welfare concerns; 2) large and difficult-to-control batch-to-batch variability, with the nutrients and protein content being significantly affected by batch; 3) animal-derived proteins and nucleic acids can interfere with downstream experiments such as drug efficacy evaluation and fluorescence detection; and 4) the temperature sensitivity of Matrigel itself imposes stringent temperature requirements for storage and operation.

[0008] Currently, animal models of solid tumors cannot meet the needs of preclinical research, which hinders the prediction of clinical efficacy and preclinical research. Therefore, it is necessary to establish efficient and stable tumor CDX or PDX models. Summary of the Invention

[0009] In order to solve the above technical problems, the present invention uses cellulose copolymers, cellulose derivative copolymers or their blends as raw materials to prepare cellulose matrix glue, which has incomparable advantages over animal-derived matrix glue in terms of performance, ease of use, batch-to-batch stability, process amplification stability, and automation compatibility. At the same time, a method for constructing a tumor CDX or PDX model using the above-mentioned cellulose matrix glue is provided, and a human tumor xenograft model is constructed.

[0010] Specifically, the present invention provides the following technical solutions:

[0011] A cellulose matrix adhesive formed by a cellulose copolymer, a cellulose derivative copolymer or a blend thereof, wherein the matrix is ​​a cellulose copolymer, a cellulose derivative copolymer or a blend thereof.

[0012] According to an embodiment of the present invention, the cellulose copolymer is a graft copolymer, and the graft copolymer includes cellulose grafted biodegradable polyester (such as grafted polylactic acid, grafted polycaprolactone, grafted polyadipate, etc.), cellulose grafted polyethylene glycol, cellulose grafted polyurethane, cellulose grafted cyclodextrin, cellulose grafted monosaccharide / disaccharide / polysaccharide, cellulose grafted polyacrylamide, cellulose grafted poly(meth)acrylic acid, cellulose grafted polymethyl (meth)acrylate, cellulose grafted polystyrene or cellulose grafted polyester, etc.

[0013] According to an embodiment of the present invention, the cellulose derivative copolymer is a graft copolymer of a cellulose derivative: for example, cellulose acetate grafted polylactic acid, cellulose acetate grafted polycaprolactone, cellulose propionate grafted polyethylene carbonate, cellulose butyrate grafted polypropylene carbonate or cellulose acetate grafted polydioxanone.

[0014] According to an embodiment of the present invention, the blend comprises at least one of the above-mentioned cellulose copolymers and cellulose derivative copolymers.

[0015] According to an embodiment of the present invention, the cellulose matrix glue is composed of ultrafine fibers forming a network structure with a highly ordered three-dimensional micro-nanostructure. According to an embodiment of the present invention, the diameter of the fibers is 0.01 μm to 0.10 μm, for example, 0.01 μm, 0.02 μm, 0.03 μm, 0.04 μm, 0.05 μm, 0.06 μm, 0.07 μm, 0.08 μm, 0.09 μm or 0.10 μm. The inventors have found that the cellulose network structure of the present invention is more suitable for 3D cell culture, and the transparency of the matrix glue is better, which is more conducive to observing the cell state.

[0016] According to an embodiment of the present invention, the particle size of the matrix in the matrix gel is 1 μm-50 μm, for example, 1 μm, 5 μm, 8 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm or 50 μm.

[0017] According to an embodiment of the present invention, the solid content of the matrix glue is 0.1-3.0 wt%, for example, 0.1 wt%, 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt% or 3.0 wt%.

[0018] The present invention also provides a method for preparing the above-mentioned cellulose matrix glue, which comprises the following steps:

[0019] 1) preparing cellulose copolymers, cellulose derivative copolymers or blends thereof from cellulose or cellulose derivatives as raw materials, hereinafter referred to as products;

[0020] 2) dispersing the product of step 1) in pure water, or pouring the product solution into a coagulation bath, and washing with pure water to obtain the cellulose matrix glue.

[0021] According to an embodiment of the present invention, in step 1), the cellulose includes microcrystalline cellulose, wood pulp cellulose, refined cotton, cotton pulp or wood pulp.

[0022] According to an embodiment of the present invention, in step 1), the cellulose is dissolved in a cellulose solvent, and the cellulose solvent is any good solvent known in the art that can dissolve (including complete dissolution and partial dissolution) cellulose. Preferably, the cellulose solvent can be selected from one or more of the following systems: copper ammonia solution, copper ethylenediamine solution, organic solvent, ionic liquid, mixed solvent of ionic liquid and organic solvent, choline-type ionic liquid deep eutectic solvent system, organic solvent / salt system, amine oxide system (NMMO), carbamate system, alkali / water system, alkali / urea system, alkali / thiourea system, liquid ammonia / NH4SCN, organic acid, aqueous solution of metal salt, alcohol solution of metal salt hydrate, water-alcohol mixed solution of metal salt hydrate, and the like solvent system.

[0023] The organic solvent may be selected from one or more of N,N-dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), N-methylimidazole, imidazole, pyridine, ethylenediamine, hexafluoroacetone, hexafluoroisopropanol, glycerol, methyl isobutyl ketone, tetrahydrofuran, dioxane, and γ-valerolactone (GVL).

[0024] The organic solvent / salt system can be selected from one or more of N,N-dimethylacetamide / lithium chloride (DMAc / LiCl) system, N-methyl-2-pyrrolidone / NMP, and N,N-dimethyl sulfoxide / tetrabutylammonium fluoride system (DMSO / TBAF).

[0025] The alkali / water system can be selected from one or both of NaOH / H2O and KOH / H2O.

[0026] Wherein, the alkali / urea system can be selected from NaOH / Urea.

[0027] Wherein, the alkaline / thiourea system is selected from NaOH / thio-urea.

[0028] The organic acid can be selected from one or more of formic acid, acetic acid, propionic acid, butyric acid, succinic acid, lactic acid, glutamic acid, glycine, dichloroacetic acid, trichloroacetic acid, and toluenesulfonic acid.

[0029] Among them, the metal salt aqueous solution is preferably selected from aqueous solutions of metal salts such as CaCl2, ZnCl2, LiClO4, Ca(SCN)2, and LiSCN.

[0030] The alcohol solution of the metal salt hydrate can be selected from a methanol solution of CaBr2·H2O and a methanol solution of CaCl2·2H2O.

[0031] The water-alcohol mixed solution of the metal salt hydrate can be selected from a methanol aqueous solution of CaBr2·H2O and a methanol aqueous solution of CaCl2·2H2O.

[0032] The amine oxide system may be a NMMO / H2O / DMSO system, a NMMO / H2O / diethyltriamine system, or a NMMO / H2O system.

[0033] The ionic liquid is selected from an organic molten salt formed by cations and anions with a melting point lower than 100° C., preferably an organic molten salt that can dissolve the biomass natural polymer.

[0034] For example, the cation of the ionic liquid is selected from one or more substituted or unsubstituted imidazole, pyridine, pyrrole, amine, phosphine, choline, diazabicyclic, amino acid type cations; for example, the substituent can be C 1-6 Alkyl, C 1-6 One or more of alkenyl, phenyl or substituted phenyl; preferably one or more of methyl, ethyl, butyl and allyl;

[0035] Preferably, the cation is selected from one or more of the following cations: 1-ethyl-3-methylimidazolium cation ([EMIM]), 3-methylimidazolium cation ([MIM]), 1-propyl-3-methylimidazolium cation ([PMIM]), 1-allyl-3-methylimidazolium cation ([AMIM]), 1-butyl-3-methylimidazolium cation ([BMIM]), 1-butyl-2,3-dimethylimidazolium cation ([BMMIM]), 1,3-dimethylimidazolium cation ([MMIM]), 1-methoxyethyl-3-methylimidazolium cation ([MeOEMIM]), 1-methoxymethyl-3-methylimidazolium cation ([MeOMMIM]), 1-hydroxy-3-methylimidazolium cation ([HMIM]), 1-(2-hydroxyethyl)-3-methylimidazolium cation ([HOEMIM]), 1-methyl-3-benzylimidazolium cation ([MBzIM]), 1 cations include 1-pentyl-3-methylimidazolium cation ([PeMIM]), 1-benzyl-3-methylimidazolium cation ([BzMIM]), 1-m-methoxybenzyl-3-methylimidazolium cation ([MeOBzMIM]), 1-m-methylbenzyl-3-methylimidazolium cation ([MeBzMIM]), N-methylpyridinium cation ([MPyr]), N-ethylpyridinium cation ([EPyr]), N-butylpyridinium cation ([BPyr]), N-n-hexylpyridinium cation ([HPyr]), 1-butyl-3-methylpyrrolidinium ion ([BMPyrr]), tris(2-hydroxyethyl)methylamine ([THEMA]), tetrabutylamine ([TBA]), tetrabutylphosphine ([PBu4]), glycine cation ([Gly]), choline cation ([Ch]), and 1,5-diazabicyclo[4.3.0]one-5-ene ([DBNH]).

[0036] More preferably, the cation is selected from one or more of the following cations: 1-ethyl-3-methylimidazolium cation ([EMIM]), 1-allyl-3-methylimidazolium cation ([AMIM]), 1-butyl-3-methylimidazolium cation ([BMIM]), choline cation ([Ch]).

[0037] For example, the anion is selected from one or more of halogen anions, organic acid radical ions, organic acid ester anions, amino acid type anions, and the like.

[0038] Preferably, the anion is selected from one or more of the following anions: chloride ([Cl]), bromide ([Br]), fluoride ([F]), formate ([HCOO]), acetate ([CH3COO] or [Ac]), glycolate ([HOCH2COO]), propionate ([CH3CH2COO] or [OPr]), butyrate ([CH3CH2CH2COO] or [OBu]), octanoate ([Oct]), benzoate ([C6H5COO] or [PhCOO]), lactate ([CH3CH(OH)COO] or [Lac]), thioglycolate ([HSCH2COO]) , hexafluorophosphate ion ([PF6]), trifluoroborate ([BF3]), methyl phosphate ion ([(MeO)HPO2] or [MP]), dimethyl phosphate ion ([(MeO)2PO2] or [DMP]), diethyl phosphate ion ([(EtO)2PO2] or [DEP]), methyl sulfonate anion ([MeOSO3]), trifluoromethylsulfonate anion ([CF3SO3]), glycine anion ([Gly]), lysine anion ([Lys]), valine anion ([Val]), dicyanamide anion ([N(CN)2] or [DCA]), bistrifluoromethylsulfonimide ([Tf2N]) and the like anion or more.

[0039] More preferably, the anion is selected from one or more of the following anions: chloride ion ([Cl]), formate ion ([HCOO]), acetate ion ([Ac]), methyl phosphate ion ([(MeO)HPO2] or [MP]), dimethyl phosphate ion ([(MeO)2PO2] or [DMP]) and dicyanamide anion ([N(CN)2] or [DCA]).

[0040] According to an embodiment of the present invention, the ionic liquid can be selected from one or more of the following ionic liquids: 1-ethyl-3-methylimidazolium chloride ionic liquid ([EMIM][Cl]), 1-ethyl-3-methylimidazolium bromide ionic liquid ([EMIM][Br]), 1-ethyl-3-methylimidazolium formate ionic liquid ([EMIM][HCOO]), 1-ethyl-3-methylimidazolium acetate ionic liquid ([EMIM][Ac]), 1-ethyl-3-methylimidazolium octanoate ionic liquid ([EMIM][Oct]), 1-ethyl-3-methylimidazolium methyl phosphate ionic liquid ([EMIM][MP]), 1-ethyl-3-methylimidazolium dimethyl phosphate ionic liquid ([EMIM][MP]), 1-ethyl-3-methylimidazolium ... methyl phosphate ionic liquid ([EMIM][Ac]), 1-ethyl-3-methylimidazolium methyl phosphate ionic liquid ([EMIM][MP]), 1-ethyl-3-methylimidazol ionic liquids ([EMIM][DMP]), 1-ethyl-3-methylimidazolium diethyl phosphate ionic liquid ([EMIM][DEP]), 1-ethyl-3-methylimidazolium propionate ionic liquid ([EMIM][OPr]), 1-ethyl-3-methylimidazolium top ionic liquid ([EMIM][OBu]), 1-ethyl-3-methylimidazolium glycinate ionic liquid ([EMIM][Gly]), 1-ethyl-3-methylimidazolium lysine ionic liquid ([EMIM][Lys]), 1-allyl-3-methylimidazolium chloride ionic liquid ([AMIM][Cl]), 1-allyl-3-methylimidazolium bromide ionic liquid ([AMIM][Br]), 1-allyl-3-methylimidazolium formate ionic liquid ([AMIM][HCOO]), 1-allyl-3-methylimidazolium acetate ionic liquid ([AMIM][Ac]), 1-butyl-3-methylimidazolium chloride ionic liquid ([BMIM][Cl]), 1-butyl-3-methylimidazolium bromide ionic liquid ([BMIM][Br]), 1-butyl-3-methylimidazolium formate ionic liquid ([BMIM][HCOO]), 1-butyl-3-methylimidazolium acetate ionic liquid ([BMIM][Ac]), 1-butyl-3-methylimidazolium glycolate ionic liquid ([BMIM][HOCH2COO]), 1-butyl-3-methylimidazolium propionate ionic liquid Liquid ([BMIM][CH3CH2COO]), 1-butyl-3-methylimidazolium lactate ionic liquid [BMIM][Lac], 1-butyl-3-methylimidazolium butyrate ionic liquid ([BMIM][CH3CH2CH2COO]), 1-butyl-3-methylimidazolium benzoate ionic liquid ([BMIM][C6H5COO]), 1-butyl-3-methylimidazolium glycine salt ionic liquid ([BMIM][H2NCH2COO]), 1-butyl-3-methylimidazolium dicyanamide ionic liquid ([BMIM][N(CN)2]), 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquid ([BMIM][Tf2N]),1-Butyl-3-methylimidazolium hexafluorophosphate ionic liquid ([BMIM][PF6]), 1-Butyl-3-methylimidazolium tetrafluoroborate ionic liquid ([BMIM][BF4]), 1-Butyl-3-methylimidazolium methanesulfonate ionic liquid ([BMIM][MeOSO3]), 1-Butyl-3-methylimidazolium trifluoromethylsulfonate ionic liquid ([BMIM][CF3SO3]), 1-Butyl-2,3-dimethylimidazolium tetrafluoroborate ionic liquid ([BMMIM][BF4]), 3-Methylimidazolium formate ionic liquid ([MIM][HCOO]), 1,3-Dimethylimidazolium chloride ionic liquid ([MMIM][Cl]), 1,3-Dimethyl 1-(2-hydroxyethyl)-3-methylimidazolium chloride ionic liquid ([HOEMIM][Cl]), 1-methoxymethyl-3-methylimidazolium bromide ionic liquid ([MeOMMIM][Br]), 1-methoxyethyl-3-methylimidazolium chloride ionic liquid ([HMIM][Cl]), 1-hydroxy-3-methylimidazolium trifluoromethylsulfonate ionic liquid ([HMIM][CF3SO3]), 1-(2-hydroxyethyl)-3-methylimidazolium chloride ionic liquid ([HOEMIM][Cl]), 1-methoxymethyl-3-methylimidazolium bromide ionic liquid ([MeOMMIM][Br]), 1-methoxyethyl-3-methylimidazolium chloride ionic liquid ([HMIM][Cl]), 1-methoxyethyl ...methoxyethyl-3-methylimidazolium chloride 3-Methylimidazolium bromide ionic liquid ([MeOEMIM][Br]), N-ethylpyridinium chloride ionic liquid ([EPyr][Cl]), N-ethylpyridinium bromide ionic liquid ([EPyr][Br]), N-methylpicolinate ionic liquid ([MPyr][HCOO]), tris(2-hydroxyethyl)methylamine acetate ionic liquid ([THEMA][Ac]), tris(2-hydroxyethyl)methylamine methanesulfonate ionic liquid ([THEMA][MeOSO3]), tris(2-hydroxyethyl)methylamine trifluoromethanesulfonate ionic liquid [THEMA][CF3SO3], tetrabutylphosphine valine ionic liquid [PBu4][Val], tetrabutylphosphine lysate Amine salt ionic liquid [PBu4][Lys], tetrabutylphosphine glycinate ionic liquid [PBu4][Gly], 1-benzyl-3-methylimidazolium chloride ionic liquid ([BzMIM][Cl]), 1-benzyl-3-methylimidazolium dicyanamide ionic liquid ([BzMIM][DCA]), 1-m-methylbenzyl-3-methylimidazolium chloride ionic liquid ([MeBzMIM][Cl]), 1-m-methoxybenzyl-3-methylimidazolium chloride ionic liquid ([MeOBzMIM][Cl]), choline chloride ionic liquid ([Ch][Cl]), choline bromide ionic liquid (Ch][Br]), choline acetate ionic liquid ([Ch][CH3COO]),Ionic liquids include choline propionate ionic liquid ([Ch][CH3CH2COO]), choline butyrate ionic liquid ([Ch][CH3CH2CH2COO]), glycine hydrochloride ionic liquid ([Gly][Cl]), 1,5-diazabicyclo[4.3.0]keto-5-ene acetate ionic liquid ([DBNH][Ac]), etc.

[0041] Preferably, the choline-type deep eutectic solvent system is selected from one or more of [Ch][Cl] / urea, [Ch][Br] / urea, [Ch][Cl] / thio-urea, [Ch][Cl] / glycerol, and [Ch][Cl] / lactic acid.

[0042] Preferably, the solvent system for dissolving cellulose is selected from the ionic liquid and / or NaOH / Urea system; more preferably, the cellulose-dissolving ionic liquid is selected from one or more of [AMIM][Cl], [BMIM][Cl], [EMIM][Ac], and [BMIM][Ac].

[0043] According to an embodiment of the present invention, in step 1), the cellulose derivative includes cellulose ester, cellulose ether, cationized cellulose, anionized cellulose or oxidized cellulose.

[0044] According to an embodiment of the present invention, in step 2), the solvent that can be used in the coagulation bath includes water, ethanol, acetone or ethylene glycol.

[0045] According to an embodiment of the present invention, the solid content of the cellulose matrix glue is 0.1-3.0 wt%, for example, 0.1 wt%, 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt% or 3.0 wt%.

[0046] According to an embodiment of the present invention, in step 2), the obtained cellulose matrix glue is further pulverized using a grinder, a colloid mill, a high-pressure homogenizer, or the like. Specifically, the pulverization is performed to a particle size of the matrix of 1 μm to 50 μm, for example, 1 μm, 5 μm, 8 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, or 50 μm.

[0047] According to an embodiment of the present invention, in step 2), after the crushing, a high-pressure sterilization step is further included, and then the cellulose matrix glue formed by the cellulose copolymer, cellulose derivative copolymer or a blend thereof is obtained for constructing a tumor CDX or PDX model.

[0048] The present invention also provides a method for constructing a tumor CDX or PDX model using the cellulose matrix glue.

[0049] The present invention also provides a tumor CDX or PDX model obtained according to the method.

[0050] The present invention also provides an application of the tumor CDX or PDX model in personalized precision diagnosis and treatment, preclinical drug screening of new anticancer drugs, and tumor disease research.

[0051] According to an embodiment of the present invention, the tumor is preferably a human gastric cancer tumor, a human intestinal cancer tumor, a human lung cancer tumor, a human pancreatic cancer tumor, a human breast cancer tumor, or a human colon cancer tumor.

[0052] According to an embodiment of the present invention, the method for constructing the tumor CDX model comprises the following steps:

[0053] a) Tumor cell preparation;

[0054] b) Tumor cell mixing: Tumor cells are mixed in the cellulose matrix gel;

[0055] c) transplanting the tumor cells mixed with the cellulose matrix gel into mice.

[0056] According to an embodiment of the present invention, preferably, the cellulose matrix glue and the cell suspension are evenly mixed in a ratio of 1:1.

[0057] According to an embodiment of the present invention, the method for constructing the tumor PDX model comprises the following steps:

[0058] a) Tumor tissue preparation;

[0059] b) mixing the tumor tissue with the cellulose matrix gel;

[0060] c) transplanting the tumor group mixed with the cellulose matrix gel into mice.

[0061] Beneficial effects of the present invention:

[0062] 1) The present invention uses cellulose copolymers, cellulose derivative copolymers, and blends thereof as raw materials to prepare Matrigel, which has incomparable advantages over animal-derived Matrigel in terms of performance, ease of use, batch-to-batch stability, process amplification stability, and automation compatibility.

[0063] 2) The present invention provides a method for constructing a tumor CDX or PDX model, which constructs an efficient and stable tumor CDX or PDX model, overcomes the difficulties of limited animal models in clinical tumor research and treatment, has a high similarity with clinical tumors, has a high tumor formation rate after tumor cell transplantation, and retains the original microenvironment of the tumor tissue. The construction method is simple and the cost is low. It can be widely used in personalized precision diagnosis and treatment, preclinical drug screening of new anti-cancer drugs and tumor disease research.

[0064] The present invention proposes a matrix gel based on cellulose copolymers, cellulose derivative copolymers, or blends thereof, which can be used to construct tumor CDX or PDX models to form a favorable microenvironment for tumor growth. The advantages are as follows:

[0065] 1) Non-animal origin, with clear ingredients, and potential applications in clinical, pharmaceutical, cell, and stem cell industrial scenarios and research;

[0066] 2) Batch stability: standardized production and strict quality control can ensure batch stability;

[0067] 3) Ready-to-use, stored at room temperature, ready for use at any time, no gel preparation steps required, just mix with cells;

[0068] 4) One-step cell recovery: a gentle one-step enzymatic process is used to recover organoids without any impact on the organoids;

[0069] 5) The expression of proteins and gene mutations in tissues / organs in vivo can be preserved;

[0070] 6) Can be cultured to form tissue-like and organoid functions similar to those in vivo;

[0071] 7) The tumor organoid structures formed in culture are non-vacuolated and mostly solid;

[0072] 8) Can be vascularized, immune co-cultured, etc.

[0073] 9) Provide a standard and effective 3D platform for organoid research and industrialization.

[0074] The cellulose matrix gel formed by the cellulose copolymer, cellulose derivative copolymer or their blends of the present invention is a ready-to-use hydrogel that does not contain animal-derived components. It can be used to construct efficient and stable tumor CDX or PDX models. It is simple to operate and has a high similarity with clinical tumors, providing a solution for the prediction of clinical efficacy and preclinical research. DETAILED DESCRIPTION

[0075] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0076] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0077] In the present invention, "cellulose copolymer-based hydrogel" may have the same meaning as "cellulose copolymer matrix gel", "cellulose matrix gel formed by cellulose copolymer, cellulose derivative copolymer or a blend thereof".

[0078] The present invention provides a method for constructing a tumor CDX or PDX model using a cellulose matrix glue formed by a cellulose copolymer, a cellulose derivative copolymer or a blend thereof, thereby constructing a human tumor xenograft model.

[0079] The present invention will be further described below by means of specific embodiments:

[0080] I. Preparation Example 1: Preparation of Cellulose Derivative Copolymer Matrix Gel

[0081] (1) Preparation of matrix glue of cellulose ester grafted polylactic acid

[0082] 15g of cellulose is added to 300g of the ionic liquid 1-allyl-3-methylimidazolium chloride (AmimCl) and mechanically stirred at 80°C for 2h to dissolve the cellulose. The cellulose can be microcrystalline cellulose, refined cotton, cotton pulp, or wood pulp. A certain amount of anhydride (at a 1:1 molar ratio with the cellulose) is then added. The anhydride can be acetic anhydride, propionic anhydride, butyric anhydride, or maleic anhydride, and the mixture is allowed to react at 80°C for 2h. Next, 11.3g of DMAP (at a 1:1 molar ratio with the cellulose) and 80g of lactide (at a 2:1 molar ratio with the hydroxyl groups in the cellulose) are added. The mixture is allowed to react at 80°C for 5h under vacuum. After the reaction is complete, the reaction solution is poured into water and stirred to precipitate the product. The product is then filtered and washed 6-8 times with a solution such as water, ethanol, acetone, or ethylene glycol to remove any remaining impurities. The washed product is dispersed in pure water with a mass ratio of water to product of 9:1, and then the product is crushed and crushed using a colloid mill, a high-pressure homogenizer, etc. to a particle size of 1-50 μm and a solid content of 0.1-3.0 wt%. After high-pressure sterilization, a cellulose ester grafted polylactic acid matrix glue is obtained.

[0083] (2) Preparation of Cellulose Acetate Grafted Polycaprolactone Matrix Glue

[0084] 6 g of wood pulp cellulose is added to 120 g of ionic liquid 1-allyl-3-methylimidazolium chloride (AmimCl), and the mixture is mechanically stirred at 80°C for 2 hours to dissolve the cellulose. Then, 14 ml of acetic anhydride (at a molar ratio of 4:3 to the hydroxyl groups in the cellulose) is added, and the reaction is continued at 40°C with stirring for 1 hour. Then, 2.06 g of PPY (at a molar ratio of 1:8 to the hydroxyl groups in the cellulose) and 12.7 g of ε-caprolactone (at a molar ratio of 1:1 to the hydroxyl groups in the cellulose) are added, and the temperature is raised to 90°C. The grafting reaction is carried out under nitrogen protection for 4 hours. After the reaction is completed, the reaction solution is poured into water, stirred to precipitate the product, filtered, and the product is washed 6-8 times with a solution to remove residual impurities. The solution that can be used includes water, ethanol, acetone, and ethylene glycol. The washed product is dispersed in pure water with a mass ratio of water to product of 9:1. The product is then crushed and pulverized using a colloid mill, a high-pressure homogenizer, or the like to a particle size of 1-50 μm and a solid content of 0.1-3.0 wt%. After high-pressure sterilization, a cellulose acetate grafted polycaprolactone matrix adhesive is obtained.

[0085] (3) Preparation of Cellulose Propionate Grafted Polyethylene Carbonate Matrix Glue

[0086] 24g of cotton pulp was added to 300g of ionic liquid BMIMCl and mechanically stirred at 80°C for 3h to dissolve the cellulose. 38.2ml of propionic anhydride (at a molar ratio of 2:3 to the hydroxyl groups in the cellulose) was then added and the mixture was allowed to react at 80°C for 2h. 18.1g of DMAP (at a molar ratio of 1:3 to the hydroxyl groups in the cellulose) and 117.4g of ethylene carbonate (at a molar ratio of 3:1 to the hydroxyl groups in the cellulose) were then added and the mixture was allowed to react at 80°C for 9h under vacuum. After the reaction, the reaction mixture was poured into water, stirred to precipitate the product, filtered, and washed 6-8 times with a solution such as water, ethanol, acetone, or ethylene glycol to remove any residual impurities. The washed product was dispersed in pure water at a water:product ratio of 9:1 by mass. The product was then pulverized and ground using a colloid mill or high-pressure homogenizer to a particle size of 1-50μm and a solids content of 0.1-3.0wt%. The product was then sterilized by autoclave to obtain a cellulose propionate-grafted polyethylene carbonate matrix adhesive.

[0087] (4) Preparation of Cellulose Butyrate Grafted Polypropylene Carbonate Matrix Glue

[0088] 9 g of cotton pulp was added to 200 g of the ionic liquid AMIMCl and mechanically stirred at 80° C. for 3 h to dissolve the cellulose. 45 ml of butyric anhydride (at a molar ratio of 5:3 to the hydroxyl groups in the cellulose) was then added and stirred at 90° C. for 3 h. 6.75 g of stannous octoate (at a molar ratio of 1:10 to the hydroxyl groups in the cellulose) and 34.0 g of propylene carbonate (at a molar ratio of 2:1 to the hydroxyl groups in the cellulose) were then added and the grafting reaction was carried out at 120° C. under nitrogen atmosphere for 10 h. The product was precipitated with water, filtered, and washed 6-8 times with a solution such as water, ethanol, acetone, or ethylene glycol to remove residual impurities. The washed product was dispersed in pure water at a water-to-product mass ratio of 9:1. The product was then crushed and pulverized using a colloid mill, a high-pressure homogenizer, or the like to a particle size of 1-50 μm and a solid content of 0.1-3.0 wt%. After autoclaving, the cellulose butyrate grafted polypropylene carbonate matrix adhesive was obtained.

[0089] (5) Preparation of Cellulose Acetate Grafted Polydioxanone Matrix Glue

[0090] 5g of cotton pulp was added to 100g of the ionic liquid EMIMAc and mechanically stirred at 80°C for 3h to dissolve the cellulose. The mixture was then cooled to 40°C and 8.8ml of acetic anhydride (at a 1:1 molar ratio of hydroxyl groups to cellulose) was added, followed by stirring for 0.5h. 1.41g of DMAP (at a 1:8 molar ratio of hydroxyl groups to cellulose) and 18.9g of dioxanone (at a 2:1 molar ratio of hydroxyl groups to cellulose) were then added. The mixture was heated to 85°C and nitrogen was introduced for grafting reaction for 4h. The product was precipitated with water, filtered, and washed 6-8 times with a solution (e.g., water, ethanol, acetone, or ethylene glycol) to remove residual impurities. The washed product was dispersed in pure water at a water:product mass ratio of 9:1. The product was then pulverized and ground using a colloid mill or high-pressure homogenizer to a particle size of 1-50μm and a solid content of 0.1-3.0wt%. After autoclaving, the cellulose acetate grafted polydioxanone matrix glue was obtained.

[0091] 2. Construction of CDX Xenograft Model:

[0092] (1) CDX xenograft model establishment method

[0093] 1. Select cells that are in good growth condition and exhibiting logarithmic growth. The recommended inoculation dose is: 5×10^6 cells / 100μl / cell and 100μl of Matrigel / cell, i.e., the ratio of cell suspension to Matrigel is 1:1.

[0094] 2. Mix the matrix gel and cell suspension at a ratio of 1:1.

[0095] 3. Use a syringe and needle to draw up the matrix gel cell suspension to be inoculated.

[0096] 4. Inoculation: 200 μl / mouse.

[0097] (II) CDX xenograft model

[0098] 1. Construction of a tumorigenic model of HCT116 subcutaneously transplanted into nude mice using cellulose ester grafted polylactic acid matrix glue of the present invention

[0099] BALB / c-Nude mice were subcutaneously inoculated with HCT116-Luc cells. HCT116-Luc cells were cultured and recovered, and the number of recovered progeny was recorded. HCT116-Luc cells were harvested during the logarithmic growth phase, the culture medium was removed, and cells were washed with DPBS before inoculation (cell survival was measured before and after tumor inoculation). The inoculation volume was 5×106 / mouse / 100 μL / mouse (with Matrigel in a 1:1 ratio) and the inoculation site was the right hind limb.

[0100] The formula for calculating tumor volume is: tumor volume (mm 3 ) = 0.5 × tumor long diameter × tumor short diameter 2 .

[0101] 2. Construction of a tumorigenic model of HCT116 subcutaneously transplanted into nude mice using animal-derived matrix gel (Corning, 356234)

[0102] The specific method for model construction is the same as the method for constructing a tumorigenic model of HCT116 subcutaneously transplanted into Nude mice using cellulose ester grafted polylactic acid matrix glue of the present invention. The only difference is that the matrix glue in this part uses known animal-derived matrix glue (Corning, 356234) instead of the cellulose ester grafted polylactic acid matrix glue of the present invention.

[0103] Table 1 Comparative effect of constructing CDX xenograft model using cellulose ester grafted polylactic acid matrix glue and animal-derived matrix glue (Corning, 356234)

[0104]

[0105] The results in Table 1 show that compared with traditional animal-derived matrix glue, the cellulose ester grafted polylactic acid matrix glue of the present invention forms tumors faster and has a larger volume.

[0106] 3. Construction of PDX Xenograft Models:

[0107] (1) PDX xenograft model construction method

[0108] 1. Mouse preparation: Anesthetize and disinfect the mice according to experimental requirements.

[0109] 2. Preparation of the transplant site: Common transplant sites are subcutaneous or in situ (such as under the renal capsule). A small incision is made at the transplant site.

[0110] 3. Tumor tissue preparation: After receiving fresh tumor tissue, store it at 4°C for transportation and begin modeling within 2 hours. During modeling, remove any necrotic tumor tissue and cut the tumor into 3 x 3 x 3 mm pieces. Each piece should be embedded in Matrigel.

[0111] 4. Transplantation: Use sterile surgical instruments to implant the tumor tissue mixed with matrix gel into the transplantation site of the mouse. Ensure that the transplant is placed stably to avoid displacement or falling off.

[0112] 5. Postoperative monitoring: After the incision is sutured, the tumor formation of the animals is observed every day.

[0113] (II) PDX xenograft model

[0114] 1. Construction of a tumorigenic model of NCG mice subcutaneously inoculated with lung cancer using the cellulose butyrate grafted polypropylene carbonate matrix glue of the present invention

[0115] Fresh tumor tissue was cleaned of necrotic parts and cut into small pieces of 3*3*3mm. The small pieces of tissue were then placed in biomass-based hydrogel. The NCG mice were anesthetized and disinfected. A small incision was made subcutaneously in the upper limbs. A small piece of tissue was transplanted into each mouse. The incision was sutured and the tumor formation was observed every day.

[0116] The formula for calculating tumor volume is: tumor volume (mm 3 ) = 0.5 × tumor long diameter × tumor short diameter 2 .

[0117] 2. Construction of a tumorigenic model of NCG mice subcutaneously inoculated with animal-derived matrix gel (Corning, 356234) for lung cancer

[0118] The specific method for model construction is the same as the method for constructing a tumorigenic model of lung cancer subcutaneously inoculated into NCG mice using the cellulose butyrate grafted polypropylene carbonate matrix glue of the present invention. The only difference is that the matrix glue in this part uses the known animal-derived matrix glue (Corning, 356234) instead of the cellulose butyrate grafted polypropylene carbonate matrix glue of the present invention.

[0119] Table 2 Comparative effects of constructing PDX xenograft models using cellulose butyrate grafted polypropylene carbonate matrix glue and animal-derived matrix glue (Corning, 356234)

[0120]

[0121] The results in Table 2 show that compared with traditional animal-derived matrix gel, the cellulose butyrate grafted polypropylene carbonate matrix gel of the present invention forms tumors faster and has a larger volume.

[0122] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A cellulose matrix adhesive formed by a cellulose copolymer, a cellulose derivative copolymer or a blend thereof, characterized in that: The matrix is ​​a cellulose copolymer, a cellulose derivative copolymer or a blend thereof. The cellulose matrix glue is composed of ultrafine fibers to form a network structure and has a highly ordered three-dimensional micro-nano structure.

2. The cellulose matrix adhesive according to claim 1, characterized in that The cellulose copolymer is a graft copolymer, which includes cellulose grafted onto biodegradable polyester (such as grafted polylactic acid, grafted polycaprolactone, grafted polyadipate, etc.), cellulose grafted onto polyethylene glycol, cellulose grafted onto polyurethane, cellulose grafted onto cyclodextrin, cellulose grafted onto monosaccharide / disaccharide / polysaccharide, cellulose grafted onto polyacrylamide, cellulose grafted onto poly(meth)acrylic acid, cellulose grafted onto polymethyl(meth)acrylate, cellulose grafted onto polystyrene or cellulose grafted onto polyester, etc.; the cellulose derivative copolymer is a graft copolymer of cellulose derivatives: for example, cellulose acetate grafted onto polylactic acid, cellulose acetate grafted onto polycaprolactone, cellulose propionate grafted onto polyethylene carbonate, cellulose butyrate grafted onto polypropylene carbonate or cellulose acetate grafted onto polydioxanone, etc.; the blend contains at least one of the above-mentioned cellulose copolymers and cellulose derivative copolymers.

3. The cellulose matrix adhesive according to claim 1 or 2, characterized in that The fiber has a diameter of 0.01 μm to 0.10 μm, for example, 0.01 μm, 0.02 μm, 0.03 μm, 0.04 μm, 0.05 μm, 0.06 μm, 0.07 μm, 0.08 μm, 0.09 μm or 0.10 μm.

4. The cellulose matrix adhesive according to any one of claims 1 to 3, characterized in that The particle size of the matrix in the matrix gel is 1 μm-50 μm, for example, 1 μm, 5 μm, 8 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm or 50 μm, and the solid content of the matrix gel is 0.1-3.0 wt%, for example, 0.1 wt%, 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt% or 3.0 wt%.

5. A method for preparing the cellulose matrix adhesive according to any one of claims 1 to 4, comprising the following steps: 1) preparing cellulose copolymers, cellulose derivative copolymers or blends thereof from cellulose or cellulose derivatives as raw materials, hereinafter referred to as products; 2) dispersing the product of step 1) in pure water, or pouring the product solution into a coagulation bath, and washing with pure water to obtain the cellulose matrix glue; in, In step 1), the cellulose includes microcrystalline cellulose, wood pulp cellulose, refined cotton, cotton pulp or wood pulp; Preferably, in step 1), the cellulose is dissolved in a cellulose solvent, and the cellulose solvent is any good solvent known in the art that can dissolve (the dissolving includes complete dissolution and partial dissolution) cellulose. Preferably, the cellulose solvent can be selected from one or more of the following systems: copper ammonia solution, copper ethylenediamine solution, organic solvent, ionic liquid, mixed solvent of ionic liquid and organic solvent, choline-type ionic liquid deep eutectic solvent system, organic solvent / salt system, amine oxide system (NMMO), carbamate system, alkali / water system, alkali / urea system, alkali / thiourea system, liquid ammonia / NH4SCN, organic acid, aqueous solution of metal salt, alcohol solution of metal salt hydrate, water-alcohol mixed solution of metal salt hydrate, and the like solvent system; The organic solvent may be selected from one or more of N,N-dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), N-methylimidazole, imidazole, pyridine, ethylenediamine, hexafluoroacetone, hexafluoroisopropanol, glycerol, methyl isobutyl ketone, tetrahydrofuran, dioxane, and γ-valerolactone (GVL); The organic solvent / salt system may be selected from one or more of N,N-dimethylacetamide / lithium chloride (DMAc / LiCl) system, N-methyl-2-pyrrolidone / NMP, and N,N-dimethyl sulfoxide / tetrabutylammonium fluoride system (DMSO / TBAF); Wherein, the alkali / water system can be selected from one or both of NaOH / H2O and KOH / H2O; Wherein, the alkali / urea system can be selected from NaOH / Urea; Wherein, the alkaline / thiourea system is selected from NaOH / thio-urea; The organic acid may be selected from one or more of formic acid, acetic acid, propionic acid, butyric acid, succinic acid, lactic acid, glutamic acid, glycine, dichloroacetic acid, trichloroacetic acid, and toluenesulfonic acid; Wherein, the aqueous solution of metal salt is preferably selected from aqueous solutions of metal salts such as CaCl2, ZnCl2, LiClO4, Ca(SCN)2, and LiSCN; Wherein, the alcohol solution of the metal salt hydrate can be selected from a methanol solution of CaBr2·H2O and a methanol solution of CaCl2·2H2O; Wherein, the water-alcohol mixed solution of the metal salt hydrate can be selected from a methanol aqueous solution of CaBr2·H2O and a methanol aqueous solution of CaCl2·2H2O; Wherein, the amine oxide system can be NMMO / H2O / DMSO system, NMMO / H2O / diethyltriamine, NMMO / H2O system; Wherein, the ionic liquid is selected from an organic molten salt formed by cations and anions with a melting point below 100°C, preferably an organic molten salt that can dissolve the biomass natural polymer; For example, the cation of the ionic liquid is selected from one or more substituted or unsubstituted imidazole, pyridine, pyrrole, amine, phosphine, choline, diazabicyclic, amino acid type cations; for example, the substituent can be C 1-6 Alkyl, C 1-6 One or more of alkenyl, phenyl or substituted phenyl; preferably one or more of methyl, ethyl, butyl and allyl; Preferably, the cation is selected from one or more of the following cations: 1-ethyl-3-methylimidazolium cation ([EMIM]), 3-methylimidazolium cation ([MIM]), 1-propyl-3-methylimidazolium cation ([PMIM]), 1-allyl-3-methylimidazolium cation ([AMIM]), 1-butyl-3-methylimidazolium cation ([BMIM]), 1-butyl-2,3-dimethylimidazolium cation ([BMMIM]), 1,3-dimethylimidazolium cation ([MMIM]), 1-methoxyethyl-3-methylimidazolium cation ([MeOEMIM]), 1-methoxymethyl-3-methylimidazolium cation ([MeOMMIM]), 1-hydroxy-3-methylimidazolium cation ([HMIM]), 1-(2-hydroxyethyl)-3-methylimidazolium cation ([HOEMIM]), 1-methyl-3-benzylimidazolium cation ([MBzIM]), 1 cations such as 1-pentyl-3-methylimidazolium cation ([PeMIM]), 1-benzyl-3-methylimidazolium cation ([BzMIM]), 1-m-methoxybenzyl-3-methylimidazolium cation ([MeOBzMIM]), 1-m-methylbenzyl-3-methylimidazolium cation ([MeBzMIM]), N-methylpyridinium cation ([MPyr]), N-ethylpyridinium cation ([EPyr]), N-butylpyridinium cation ([BPyr]), N-n-hexylpyridinium cation ([HPyr]), 1-butyl-3-methylpyrrolidinium ion ([BMPyrr]), tris(2-hydroxyethyl)methylamine ([THEMA]), tetrabutylamine ([TBA]), tetrabutylphosphine ([PBu4]), glycine cation ([Gly]), choline cation ([Ch]), and 1,5-diazabicyclo[4.3.0]one-5-ene ([DBNH]); More preferably, the cation is selected from one or more of the following cations: 1-ethyl-3-methylimidazolium cation ([EMIM]), 1-allyl-3-methylimidazolium cation ([AMIM]), 1-butyl-3-methylimidazolium cation ([BMIM]), choline cation ([Ch]); For example, the anion is selected from one or more of halogen anions, organic acid radical ions, organic acid ester anions, amino acid type anions, etc.; Preferably, the anion is selected from one or more of the following anions: chloride ([Cl]), bromide ([Br]), fluoride ([F]), formate ([HCOO]), acetate ([CH3COO] or [Ac]), glycolate ([HOCH2COO]), propionate ([CH3CH2COO] or [OPr]), butyrate ([CH3CH2CH2COO] or [OBu]), octanoate ([Oct]), benzoate ([C6H5COO] or [PhCOO]), lactate ([CH3CH(OH)COO] or [Lac]), thioglycolate ([HSCH2COO]) , hexafluorophosphate ion ([PF6]), trifluoroborate ([BF3]), methyl phosphate ion ([(MeO)HPO2] or [MP]), dimethyl phosphate ion ([(MeO)2PO2] or [DMP]), diethyl phosphate ion ([(EtO)2PO2] or [DEP]), methyl sulfonate anion ([MeOSO3]), trifluoromethylsulfonate anion ([CF3SO3]), glycine anion ([Gly]), lysine anion ([Lys]), valine anion ([Val]), dicyanamide anion ([N(CN)2] or [DCA]), bistrifluoromethylsulfonimide ([Tf2N]), and the like; More preferably, the anion is selected from one or more of the following anions: chloride ion ([Cl]), formate ion ([HCOO]), acetate ion ([Ac]), methyl phosphate ion ([(MeO)HPO2] or [MP]), dimethyl phosphate ion ([(MeO)2PO2] or [DMP]) and dicyanamide anion ([N(CN)2] or [DCA]); Further preferably, the ionic liquid can be selected from one or more of the following ionic liquids: 1-ethyl-3-methylimidazolium chloride ionic liquid ([EMIM][Cl]), 1-ethyl-3-methylimidazolium bromide ionic liquid ([EMIM][Br]), 1-ethyl-3-methylimidazolium formate ionic liquid ([EMIM][HCOO]), 1-ethyl-3-methylimidazolium acetate ionic liquid ([EMIM][Ac]), 1-ethyl-3-methylimidazolium octanoate ionic liquid ([EMIM][Oct]), 1-ethyl-3-methylimidazolium methyl phosphate ionic liquid ([EMIM][MP]), 1-ethyl-3-methylimidazolium dimethyl phosphate ionic liquid ([EMIM][MP]), [EMIM][DMP]), 1-ethyl-3-methylimidazolium diethyl phosphate ionic liquid ([EMIM][DEP]), 1-ethyl-3-methylimidazolium propionate ionic liquid ([EMIM][OPr]), 1-ethyl-3-methylimidazolium top ionic liquid ([EMIM][OBu]), 1-ethyl-3-methylimidazolium glycinate ionic liquid ([EMIM][Gly]), 1-ethyl-3-methylimidazolium lysine ionic liquid ([EMIM][Lys]), 1-allyl-3-methylimidazolium chloride ionic liquid ([AMIM][Cl]), 1-allyl-3-methylimidazolium bromide ionic liquid ([AMIM][Br]), 1-ethyl-3-methylimidazolium octanoate ionic liquid ([EMIM][C1]), 1-ethyl-3-methylimidazolium lysine ionic liquid ([EMIM][C2]), 1-ethyl-3-methylimidazolium chloride ionic liquid ([AMIM][Cl]), 1-ethyl-3-methylimidazolium bromide ionic liquid ([AMIM][Br]), 1-ethyl-3-methylimidazolium octanoate ionic liquid ([EMIM][C3]), 1-ethyl-3-methylimidazolium chloride ionic liquid ([EMIM][C4]), 1-ethyl-3-methylimidazolium chloride ionic liquid ([EMIM][C5]), 1-ethyl-3-methylimidazolium chloride ionic liquid ([EMIM][C6]), 1-ethyl-3-methylimidazolium chloride ionic liquid ([EMIM][C7]), 1-ethyl-3-methylimidazolium chloride ionic liquid ([EMIM][C8]), 1-ethyl-3-methylimidazolium chloride ionic liquid ([EMIM][ Propyl-3-methylimidazolium formate ionic liquid ([AMIM][HCOO]), 1-allyl-3-methylimidazolium acetate ionic liquid ([AMIM][Ac]), 1-butyl-3-methylimidazolium chloride ionic liquid ([BMIM][Cl]), 1-butyl-3-methylimidazolium bromide ionic liquid ([BMIM][Br]), 1-butyl-3-methylimidazolium formate ionic liquid ([BMIM][HCOO]), 1-butyl-3-methylimidazolium acetate ionic liquid ([BMIM][Ac]), 1-butyl-3-methylimidazolium hydroxyacetate ionic liquid ([BMIM][HOCH2COO]), 1-butyl-3-methylimidazolium propionate ionic liquid 1-Butyl-3-methylimidazolium lactate ionic liquid [BMIM][Lac], 1-Butyl-3-methylimidazolium butyrate ionic liquid ([BMIM][CH3CH2CH2COO]), 1-Butyl-3-methylimidazolium benzoate ionic liquid ([BMIM][C6H5COO]), 1-Butyl-3-methylimidazolium glycinate ionic liquid ([BMIM][H2NCH2COO]), 1-Butyl-3-methylimidazolium dicyanamide ionic liquid ([BMIM][N(CN)2]), 1-Butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquid ([BMIM][Tf2N]),1-Butyl-3-methylimidazolium hexafluorophosphate ionic liquid ([BMIM][PF6]), 1-Butyl-3-methylimidazolium tetrafluoroborate ionic liquid ([BMIM][BF4]), 1-Butyl-3-methylimidazolium methanesulfonate ionic liquid ([BMIM][MeOSO3]), 1-Butyl-3-methylimidazolium trifluoromethylsulfonate ionic liquid ([BMIM][CF3SO3]), 1-Butyl-2,3-dimethylimidazolium tetrafluoroborate ionic liquid ([BMMIM][BF4]), 3-Methylimidazolium formate ionic liquid ([MIM][HCOO]), 1,3-Dimethylimidazolium chloride ionic liquid ([MMIM][Cl]), 1,3-Dimethyl 1-(2-hydroxyethyl)-3-methylimidazolium chloride ionic liquid ([HOEMIM][Cl]), 1-methoxymethyl-3-methylimidazolium bromide ionic liquid ([MeOMMIM][Br]), 1-methoxyethyl-3-methylimidazolium chloride ionic liquid ([HMIM][Cl]), 1-hydroxy-3-methylimidazolium trifluoromethylsulfonate ionic liquid ([HMIM][CF3SO3]), 1-(2-hydroxyethyl)-3-methylimidazolium chloride ionic liquid ([HOEMIM][Cl]), 1-methoxymethyl-3-methylimidazolium bromide ionic liquid ([MeOMMIM][Br]), 1-methoxyethyl-3-methylimidazolium chloride ionic liquid ([HMIM][Cl]), 1-methoxyethyl ...methoxyethyl-3-methylimidazolium chloride 3-Methylimidazolium bromide ionic liquid ([MeOEMIM][Br]), N-ethylpyridinium chloride ionic liquid ([EPyr][Cl]), N-ethylpyridinium bromide ionic liquid ([EPyr][Br]), N-methylpicolinate ionic liquid ([MPyr][HCOO]), tris(2-hydroxyethyl)methylamine acetate ionic liquid ([THEMA][Ac]), tris(2-hydroxyethyl)methylamine methanesulfonate ionic liquid ([THEMA][MeOSO3]), tris(2-hydroxyethyl)methylamine trifluoromethanesulfonate ionic liquid [THEMA][CF3SO3], tetrabutylphosphine valine ionic liquid [PBu4][Val], tetrabutylphosphine lysate Amine salt ionic liquid [PBu4][Lys], tetrabutylphosphine glycinate ionic liquid [PBu4][Gly], 1-benzyl-3-methylimidazolium chloride ionic liquid ([BzMIM][Cl]), 1-benzyl-3-methylimidazolium dicyanamide ionic liquid ([BzMIM][DCA]), 1-m-methylbenzyl-3-methylimidazolium chloride ionic liquid ([MeBzMIM][Cl]), 1-m-methoxybenzyl-3-methylimidazolium chloride ionic liquid ([MeOBzMIM][Cl]), choline chloride ionic liquid ([Ch][Cl]), choline bromide ionic liquid (Ch][Br]), choline acetate ionic liquid ([Ch][CH3COO]),Ionic liquids such as choline propionate ionic liquid ([Ch][CH3CH2COO]), choline butyrate ionic liquid ([Ch][CH3CH2CH2COO]), glycine hydrochloride ionic liquid ([Gly][Cl]), and 1,5-diazabicyclo[4.3.0]keto-5-ene acetate ionic liquid ([DBNH][Ac]); Preferably, the choline-type deep eutectic solvent system is selected from one or more of [Ch][Cl] / urea, [Ch][Br] / urea, [Ch][Cl] / thio-urea, [Ch][Cl] / glycerol, and [Ch][Cl] / lactic acid; Preferably, the solvent system for dissolving cellulose is selected from the ionic liquid and / or NaOH / Urea system; more preferably, the cellulose-dissolving ionic liquid is selected from one or more of [AMIM][Cl], [BMIM][Cl], [EMIM][Ac], and [BMIM][Ac]; Wherein, in step 1), the cellulose derivative includes cellulose ester, cellulose ether, cationized cellulose, anionized cellulose or oxidized cellulose; In step 2), the solvent that can be used in the coagulation bath includes water, ethanol, acetone or ethylene glycol.

6. The method according to claim 5, characterized in that In step 2), the obtained cellulose matrix glue is further crushed using a grinder, a colloid mill, a high-pressure homogenizer, etc. Specifically, the crushing is performed to a particle size of the matrix of 1 μm-50 μm, for example, 1 μm, 5 μm, 8 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm or 50 μm. After the crushing, a high-pressure sterilization step is also included, and then the cellulose matrix glue formed by the cellulose copolymer, cellulose derivative copolymer or a blend thereof is obtained for constructing a tumor CDX or PDX model.

7. The cellulose matrix adhesive according to claim 1, characterized in that The solid content of the cellulose matrix glue is 0.1-3.0 wt %, for example, 0.1 wt %, 0.5 wt %, 1 wt %, 1.5 wt %, 2 wt %, 2.5 wt % or 3.0 wt %.

8. A method for constructing a tumor CDX or PDX model using the cellulose matrix gel according to claim 1, characterized in that: The tumor is preferably a human gastric cancer tumor, a human intestinal cancer tumor, a human lung cancer tumor, a human pancreatic cancer tumor, a human breast cancer tumor, or a human colorectal cancer tumor.

9. A tumor CDX or PDX model obtained according to the method of claim 8.

10. Use of the tumor CDX or PDX model according to claim 8 in personalized precision diagnosis and treatment, preclinical drug screening of new anticancer drugs, and tumor disease research.

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