CN111803454B - Support material, preparation method and application thereof - Google Patents

Abstract

The invention provides a stent material, which is obtained by crosslinking multi-arm amino polyethylene glycol and multi-aldehyde dextran. Compared with the prior art, the cross-linked grid is formed by the Schiff base action of aldehyde group and amino group, the medicine can be encapsulated in the stent when the medicine is carried, the aldehyde group rich in the material can be coupled with the medicine containing amino group, so that the medicine can be effectively retained in the cross-linked grid, the medicine can be locally and slowly released at the focus part, the problems of quick in-vivo metabolism and low utilization rate of the medicine are effectively solved, the wide development prospect is achieved in the application aspects of maintaining in-vivo medicine concentration, reducing administration dosage, improving medicine utilization rate, avoiding medicine resistance and the like, the preparation of the stent material is simple and mild, no selectivity is provided for the carried medicine type, the application range is wide, and the biocompatibility is good.

Description

Support material, preparation method and application thereof

Technical Field

The invention belongs to the technical field of sustained-release preparations, and particularly relates to a stent material, and a preparation method and application thereof.

Background

Surgical removal of tumors remains the first choice for tumor therapy, however, postoperative recurrence and metastasis become critical issues that limit the success of surgical therapy. Taking colon cancer as an example, the 5-year survival rate of early-stage colon cancer is as high as 85% when the colon cancer is completely resected, while the 5-year survival rate of middle-and late-stage colon cancer is suddenly reduced to 17%. One important reason behind this is that the infiltration of mid-and late-stage colon cancer tumors is extensive, the surgical resection is not clean, or metastasis has already occurred at the time of surgery. In addition, peritoneal metastases formed after some tumors such as ovarian cancer and colon cancer in middle and late stages invade the abdominal cavity grow dispersedly, and the tumors cannot be effectively excised in an operation, so that the 5-year survival rate after the operation is extremely low.

Postoperative chemotherapy is a major adjuvant approach after middle and late stage tumor surgery. Appropriate postoperative chemotherapy can remove tiny residual focus and prevent metastasis and tumor recurrence. However, due to the occurrence of the operation wound, the chemotherapy is generally started after 2-3 weeks of the operation, and the gap creates an early condition for the recurrence of the tumor. In addition, systemic high dose administration also causes strong side effects to patients, great influence to the immune system, and is not beneficial to long-term control of tumors, resulting in general treatment effect.

Compared with postoperative chemotherapy, the carrier material local slow-release drug has obvious practical significance for implementing postoperative adjuvant therapy of middle and late stage tumors. By means of the operation opportunity of a surgeon, the slow-release material can be arranged near the tumor to locally and continuously release the medicine, so that the occurrence of a treatment idle period can be avoided, and the strong toxic and side effects of high-concentration medicine can be avoided.

Based on such idea, Amiji in 2019 reported that a degradable braided fabric implant material prepared from Polydioxanone (PDS) slowly releases paclitaxel intraperitoneally for the treatment of metastatic ovarian cancer. Due to the slow degradation characteristic of PDS, the implant material can continuously and slowly release paclitaxel in the abdominal cavity for more than 60 days, and has obvious treatment advantages compared with the abdominal cavity infusion treatment of free paclitaxel. Although this PDS-based implant braid has a very long sustained-release time, a too long residence time of the foreign body implanted in the abdominal cavity may cause inflammatory reactions, forming adhesions and even ileus.

The fluxan (a fluorouracil implant carried by polylactic-co-glycolic acid (PLGA)) developed by WUKUNZHOUYIZHONGYAO (medicine industry Co., Ltd.) is an implant which is effectively used for postoperative chemotherapy of esophageal cancer, colon cancer, rectal cancer, gastric cancer and the like, and is currently on the market. However, since PLGA used to construct implants has a loading capacity only for small-molecule chemotherapeutic drugs, it is difficult to achieve effective sustained release at the implantation site for some conventional proteins, polypeptides, and nucleic acids, and since implants are difficult to fix at the post-operative site, intestinal adhesion and intestinal blockage are also easily induced.

Gliadel Wafer (carmustine sustained release membrane) developed by MGI Pharma in the united states is a patent drug for brain cancer treatment, and when the application method is to remove brain tumor by operation, PLGA membrane loaded with drug is implanted in the cavity created by operation, and the sustained release membrane also has the problems of limited drug-carrying types and limited application range.

There is therefore a great need to develop a new implant material for use in post-operative chemotherapy of cancer. The hydrogel material has good biocompatibility, adjustable mechanical property and various types of supported drugs, and is a promising local sustained-release drug carrier form. In particular, the hydrogel is used for drug loading with almost no limitation, and can be used not only for loading of small molecule drugs but also for loading of protein drugs due to its aqueous structure, and thus, the hydrogel has been widely used for local drug sustained release. The hydrogel can be used in the form of in-situ gel after local injection, and can also be prepared into a scaffold material by freeze-drying and implemented in an implantation mode. The latter may be more convenient for the surgeon to use.

Currently, various types of hydrogels have been widely used for local drug release. Xiao et al, using the NCA ring-opening polymerization method, grafted polyglutamic acid to the end of 4-arm PEG, constructed a physically cross-linked gel through the beta-sheet of polyglutamic acid, which can effectively carry and slowly release polypeptide insulin and bovine serum albumin, but the hydrogel obtained by the physical cross-linking method has weak strength and short retention time in vivo, and is difficult to apply clinically. Federac Corrende et al used a method of forming a gel by ultraviolet irradiation and prepared an injectable hydrogel using dextran, methacrylate-synthesized material (DEX-MA) and scleroglucan (Scl) as raw materials with the help of a photoinitiator. Compared with physical crosslinking hydrogel, the mechanical property of the hydrogel is obviously improved. Pacelli S and the like also adopt a similar method to successfully prepare hydrogel with good mechanical property, and the raw materials are polyethylene glycol dimethacrylate (PEG-DMA) and gellan gum modified by methacrylic acid. Although this method can effectively form hydrogel with higher strength, the crosslinking method by ultraviolet light destroys some protein or photosensitive drug activity, so there are many limitations to this crosslinking method. In addition, the gel formation process requires time and is inconvenient to store, which is not easy to be mastered by surgeons, and also limits the popularization of such materials to clinical application.

Disclosure of Invention

In view of the above, the technical problem to be solved by the present invention is to provide a scaffold material with mild preparation conditions and good compatibility, and a preparation method and an application thereof.

The invention provides a stent material, which is obtained by crosslinking multi-arm amino polyethylene glycol and multi-aldehyde dextran.

Preferably, the multi-arm aminopolyethylene glycol is selected from 2-8-arm aminopolyethylene glycol.

Preferably, the multi-arm aminopolyethylene glycol is selected from one or more of formulas (I) to (III):

wherein n and m are polymerization degrees, and m is more than or equal to 1 and less than or equal to 500; n is more than or equal to 1 and less than or equal to 500; p is more than or equal to 1 and less than or equal to 200

Wherein R is a group of tripentaerythritol with 8 hydroxyl groups removed.

Preferably, the polyformaldehyde group glucan is represented by formula (IV):

wherein q and k are polymerization degrees, q is more than or equal to 10 and less than or equal to 500, and k is more than or equal to 10 and less than or equal to 500.

Preferably, the mass ratio of the multi-arm aminopolyethylene glycol to the polyaldehyde dextran is 1: (0.05-10).

Preferably, the size of the bracket material is 0.1-20 cm.

The invention also provides a preparation method of the stent material, which comprises the following steps:

s) reacting multi-arm amino polyethylene glycol with polyaldehyde dextran in an aqueous solution to obtain the scaffold material.

Preferably, S) is specifically:

mixing the multi-arm amino polyethylene glycol aqueous solution with the polyaldehyde dextran aqueous solution for reaction to obtain a stent material;

the concentration of the amino compound in the multi-arm amino polyethylene glycol aqueous solution is 1 mg/mL-300 mg/mL;

the concentration of the aldehyde compound in the aqueous solution of the multi-aldehyde dextran is 1 mg/mL-300 mg/mL.

The invention also provides application of the stent material in drug loading.

The invention also provides application of the stent material in preparation of antitumor drugs.

The invention provides a stent material, which is obtained by crosslinking multi-arm amino polyethylene glycol and multi-aldehyde dextran. Compared with the prior art, the cross-linked grid is formed by the Schiff base action of aldehyde group and amino group, the medicine can be encapsulated in the stent when the medicine is carried, the aldehyde group rich in the material can be coupled with the medicine containing amino group, so that the medicine can be effectively retained in the cross-linked grid, the medicine can be locally and slowly released at the focus part, the problems of quick in-vivo metabolism and low utilization rate of the medicine are effectively solved, the wide development prospect is achieved in the application aspects of maintaining in-vivo medicine concentration, reducing administration dosage, improving medicine utilization rate, avoiding medicine resistance and the like, the preparation of the stent material is simple and mild, no selectivity is provided for the carried medicine type, the application range is wide, and the biocompatibility is good.

Drawings

FIG. 1 shows the preparation of polyaldehyde dextran obtained in example 1 of the present invention¹H NMR chart;

FIG. 2 is a scanning electron microscope image of an appearance morphology photograph and a stent material of a DOX-loaded stent material obtained in example 4 of the present invention;

FIG. 3 is a graph of the in vitro release of DOX from DOX-loaded stent material obtained in example 4 of the present invention;

FIG. 4 is a graph showing in vitro release of IgG from an IgG-loaded scaffold material obtained in example 5 of the present invention;

FIG. 5 shows the therapeutic effect of the stent material prepared in example 13 of the present invention in an abdominal metastasis model of colon cancer (blank control, stent supporting aPD-1 group BI @ aPD-1, stent supporting DOX group BI @ DOX, stent co-supporting DOX and aPD-1 group BI @ aPD-1+ DOX);

fig. 6 shows the therapeutic effect of the scaffold material prepared in example 14 of the present invention for a postoperative recurrence model of colon cancer (blank control group, blank scaffold group BI, scaffold-supported raquinmod group BI @ R848, scaffold-supported anti-OX 40 antibody group BI @ aOX40, pure drug raquinmod and anti-OX 40 antibody group freeR848+ aOX40, scaffold-supported raquinmod and anti-OX 40 antibody group BI @ R848+ aOX 40).

Detailed Description

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

The invention provides a stent material, which is obtained by crosslinking multi-arm amino polyethylene glycol and multi-aldehyde dextran.

In the invention, the multi-arm aminopolyethylene glycol is preferably 2-8-arm aminopolyethylene glycol, more preferably one or more of the following formulas (I) to (III), and further preferably eight-arm aminopolyethylene glycol:

wherein m, n and p are the polymerization degrees,

m is more than or equal to 1 and less than or equal to 500; n is more than or equal to 1 and less than or equal to 500; p is more than or equal to 1 and less than or equal to 200, wherein R is a group of tripentaerythritol with 8 hydroxyl groups removed.

The aldehydic dextran is preferably represented by formula (IV):

wherein n and p are polymerization degrees, q is more than or equal to 10 and less than or equal to 500, and k is more than or equal to 10 and less than or equal to 500.

The mass ratio of the multi-arm aminopolyethylene glycol to the polyaldehyde dextran is preferably 1: (0.05-10), more preferably 1: (0.1 to 5), and more preferably 1: (0.15 to 5), and most preferably 1: (0.2-2); in some embodiments provided herein, the mass ratio of the multi-arm aminopolyethylene glycol to polyaldehyde dextran is preferably 1: 1.

the scaffold material provided by the invention is preferably a gel material or a freeze-dried material, so that the scaffold material is convenient to store and clinically use; the size of the support material is preferably 0.1-20 cm.

The cross-linked grid is formed by the Schiff base action of aldehyde group and amino group, the medicine can be encapsulated in the stent when the medicine is carried, the aldehyde group rich in the material can be coupled with the medicine containing amino group, so that the medicine can be effectively retained in the cross-linked grid, the medicine can be locally and slowly released at the focus part, the problems of fast in-vivo metabolism and low utilization rate of the medicine are effectively solved, the wide development prospect is achieved in the application aspects of maintaining in-vivo medicine concentration, reducing administration dosage, improving medicine utilization rate, avoiding medicine resistance and the like, the preparation of the stent material is simple and mild, no selectivity is provided for the kind of the carried medicine, the application range is wide, and the biocompatibility is good.

The invention also provides a preparation method of the bracket material, which comprises the following steps: s) reacting multi-arm amino polyethylene glycol with polyaldehyde dextran in an aqueous solution to obtain the scaffold material.

Wherein, the sources of all raw materials are not specially limited and can be sold in the market; the multi-arm aminopolyethylene glycol and the multi-aldehyde dextran are the same as those described above, and are not described in detail herein.

In the invention, the multi-arm aminopolyethylene glycol aqueous solution and the polyaldehyde dextran aqueous solution are preferably mixed and reacted; the concentration of the multi-arm aminopolyethylene glycol in the multi-arm aminopolyethylene glycol aqueous solution is preferably 1 mg/mL-300 mg/mL, more preferably 10 mg/mL-250 mg/mL, still more preferably 30 mg/mL-220 mg/mL, and most preferably 50 mg/mL-200 mg/mL; in some embodiments provided herein, the concentration of the multi-arm aminopolyethylene glycol in the aqueous solution of multi-arm aminopolyethylene glycol is preferably 100 mg/ml; the multi-arm aminopolyethylene glycol aqueous solution is preferably a phosphate buffer solution of multi-arm aminopolyethylene glycol; the pH value of the multi-arm aminopolyethylene glycol aqueous solution is preferably 7-7.5, more preferably 7.2-7.5, and still more preferably 7.4; the concentration of the polyaldehyde group glucan in the aqueous solution of the polyaldehyde group glucan is preferably 1 mg/mL-300 mg/mL, more preferably 10 mg/mL-250 mg/mL, still more preferably 30 mg/mL-220 mg/mL, and most preferably 50 mg/mL-200 mg/mL; in some embodiments provided herein, the concentration of the polyaldehyde dextran in the aqueous solution of polyaldehyde dextran is preferably 100 mg/ml; the aqueous solution of the aldehydic glucan is preferably phosphate buffer solution of aldehydic glucan; the pH value of the aqueous solution of the aldehydic glucan is preferably 7-7.5, more preferably 7.2-7.5, and still more preferably 7.4; the mass ratio of the multi-arm aminopolyethylene glycol aqueous solution to the multi-aldehyde dextran aqueous solution is preferably 1: (0.05-10), more preferably 1: (0.1 to 5), and more preferably 1: (0.15-5), and more preferably 1: (0.2-2), and more preferably 1: (0.5 to 1.5), most preferably 1: 1.

after mixing and reacting, obtaining a liquid gel scaffold material; or after mixing reaction, preferably carrying out freeze drying to obtain a solid freeze-dried scaffold material; the temperature of the freeze drying is preferably-80 ℃; the freeze drying is preferably performed for 10-14 h, more preferably 12h, and then performed for 20-26 h, more preferably 22-26 h, and more preferably 24 h.

The shape and size of the stent material can be set according to the application.

The preparation method provided by the invention is simple, wide in raw material source and good in biocompatibility, can realize batch production, and can realize industrialization.

The invention also provides an application of the stent material in drug loading.

The stent material provided by the invention can be realized in a mild aqueous solution, so that the supported drugs are not selective, and the easily-deteriorated and inactivated drugs (such as proteins and acids) can be effectively protected to realize local slow release of the drugs; the drug carried by the invention can be a micromolecular drug or a macromolecular drug, and has no special limitation and wide application range.

The stent material can be used for carrying the drugs by dissolving one or more drugs in a mixed solution of an amino compound and an aldehyde compound before forming the stent material; alternatively, after the stent material is formed, the drug may be loaded by dropping the drug into the stent material or by immersing the stent material in a drug solution.

In the invention, the medicament is preferably one or more of chemotherapy medicament, immune agonist and antibody medicament, more preferably small molecule medicament such as adriamycin (DOX), raquintocet (R848) and the like, polypeptide polymyxin B, capecitabine and the like, protein medicament PD-1 antibody, anti-OX 40 antibody (aOX40) and the like.

The mass ratio of the drug, the multi-arm aminopolyethylene glycol and the polyaldehyde dextran is preferably 1: (0.01-1000): (0.01 to 1000), more preferably 1: (1-500): (1-500), and more preferably 1: (50-200): (50-200).

The invention also provides an application of the stent material in preparing anti-tumor drugs; the drug-loaded stent material may be surgically fixed near the mid-tumor, surgically fixed near the intra-abdominal tumor, or surgically implanted near the site of resection of the primary tumor.

In order to further illustrate the present invention, the following detailed description will be made of a stent material, a preparation method and applications thereof.

The reagents used in the following examples are all commercially available.

Example 1

20g (0.50mmol) of dextran (DEX, molecular weight 40000Da) was dissolved in 300mL of water, stirred to dissolve, 8.6g (0.15mmol solution) of sodium periodate was added, sealed, and stirred at 25 ℃ for 24 hours. And (3) dialyzing for 3 days by using deionized water after the reaction is finished, and freeze-drying to obtain the polyaldehyde dextran with the structure of the formula (IV).

The polyaldehyde dextran obtained in example 1 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in fig. 1. FIG. 1 shows the preparation of the resulting polyaldehyde dextran¹H NMR chart.

Example 2

Preparation of blank gel scaffold Material

Adding 4-arm PEG-NH with molecular weight of 10000₂And the polyaldehyde dextran (ODEX) obtained in example 1 were dissolved in PBS (pH 7.4) at a concentration of 100mg/mL for each. Then 250. mu.L of 4-arm PEG-NH was added₂The solution was mixed with 250. mu.L of ODEX solution (PEG-NH)₂Mass ratio to ODEX 1:1), after vortexing for 10s, the mixture was placed in a mold to give a blank gel scaffold material.

Example 3

Preparation of blank scaffold Material

Adding 4-arm PEG-NH with molecular weight of 10000₂And the polyaldehyde dextran (ODEX) obtained in example 1 were dissolved in PBS (pH 7.4) at a concentration of 100mg/mL for each. Then 250. mu.L of 4-arm PEG-NH was added₂The solution was mixed with 250. mu.L of ODEX solution (PEG-NH)₂Mass ratio to ODEX 1:1), vortexed for 10s, and the mixture was placed in a mold, then frozen at-80 ℃ for 12h, and then lyophilized for 24h to give a lyophilized blank scaffold material.

Example 4

Preparation of DOX-loaded stent material

Adding 4-arm PEG-NH with molecular weight of 10000₂And the polyaldehyde dextran (ODEX) obtained in example 1 were dissolved in PBS (pH 7.4) at a concentration of 100mg/mL for each. Then 300. mu.g DOX was added to 250. mu.L of 4-arm PEG-NH₂In solution, then mixed with 250. mu.L of ODEX solution (PEG-NH)₂Mass ratio to ODEX 1:1), vortex for 10s, mixThe material was placed in a mold, then frozen at-80 ℃ for 12h, and then lyophilized for 24h to give DOX-loaded scaffold material.

FIG. 2 is a photograph of the appearance and morphology of the DOX-loaded stent material obtained in example 4 and a scanning electron micrograph of the stent material, from which microscopic internal crosslinked structures can be observed.

Example 5

Preparation of IgG-loaded scaffold material

Adding 4-arm PEG-NH with molecular weight of 10000₂And ODEX obtained in example 1 were dissolved in PBS (pH 7.4) at a concentration of 100mg/mL for each, and 150 μ g of IgG and 250 μ L of the dissolved 4-arm PEG-NH were mixed with each other₂Vortex with 250. mu.L of dissolved ODEX mix (PEG-NH)₂The mass ratio of the IgG to the ODEX is 1:1), after 10s, the mixture is placed in a mold and stands to obtain the IgG-loaded gel scaffold material.

Example 6

Preparation of aPD-1-loaded scaffold Material

Adding 4-arm PEG-NH with molecular weight of 10000₂And ODEX obtained in example 1 were dissolved in PBS (pH 7.4) at a concentration of 100mg/mL, respectively, and 250 μ L of the dissolved 4-arm PEG-NH was added₂Mixing with 250. mu.L of dissolved ODEX (PEG-NH)₂Mass ratio to ODEX 1:1), vortexing for 10s, placing the mixture in a mold, freezing at-80 ℃ for 12h, lyophilizing for 24h, and adding 150 μ g of aPD-1 antibody solution to the lyophilized scaffold to obtain aPD-1-loaded scaffold material.

Example 7

Preparation of DOX and aPD-1-loaded scaffold material

Adding 4-arm PEG-NH with molecular weight of 10000₂And ODEX obtained in example 1 were dissolved in PBS (pH 7.4) at a concentration of 100mg/mL for each, and 250 μ L of 4-arm PEG-NH was dissolved₂And 250 μ L of ODEX mixed with 300 μ g of DOX vortexed (PEG-NH)₂The mass ratio of the antibody to ODEX is 1:1), after 10s, the mixture is placed in a mould, then frozen at-80 ℃ for 12h, after 24h of freeze-drying, 150 mug of aPD-1 antibody is added into the freeze-dried stent, and the implantable co-carrier is obtainedDOX and aPD-1.

Example 8

Preparation of loaded R848 stent material

Adding 4-arm PEG-NH with molecular weight of 10000₂And ODEX obtained in example 1 were dissolved in PBS (pH 7.4) at a concentration of 100mg/mL, and 250 μ L of 4-arm PEG-NH was dissolved₂And 250 μ L of ODEX mixed with 150 μ g R848 vortexing (PEG-NH)₂The mass ratio of the material to ODEX is 1:1), after 10s, the mixture is placed in a mould, then frozen at-80 ℃ for 12h, and after 24h of freeze-drying, the implantable R848-loaded stent material is obtained.

Example 9

Preparation of aOX 40-loaded antibody scaffold material

Adding 4-arm PEG-NH with molecular weight of 10000₂And ODEX obtained in example 1 were dissolved in PBS (pH 7.4) at a concentration of 100mg/mL for each, and 250 μ L of 4-arm PEG-NH was dissolved₂And 250. mu.L of ODEX Mixed vortex (PEG-NH)₂Mass ratio to ODEX 1:1), 10s later, the mixture was placed in a mold, then frozen at-80 ℃ for 12h, and after 24h of lyophilization, 15 μ g of aOX40 antibody was added to the lyophilized scaffold to give an implantable aOX 40-loaded scaffold material.

Example 10

Preparation of support material loaded with R848 and aOX40 antibodies

Adding 4-arm PEG-NH with molecular weight of 10000₂And ODEX obtained in example 1 were dissolved in PBS (pH 7.4) at a concentration of 100mg/mL, respectively, and 150 μ g R848 was added to 4-arm PEG-NH₂In solution. 250 μ L of 4-arm PEG-NH₂Mixing with 250. mu.L of ODEX (PEG-NH)₂Mass ratio to ODEX 1:1), vortexing for 10s, placing the mixture in a mold, freezing at-80 ℃ for 12h, lyophilizing for 24h, and adding 15 μ g of aOX40 antibody to the lyophilized scaffold to obtain implantable scaffolds loaded with R848 and aOX40 antibodies.

Example 11

In vitro release of small molecule drug DOX

The DOX-loaded stent material obtained in example 2 was placed in a release bottle, 2.0mL of phosphate buffer solution with pH 7.4 or pH 6.5 was added to the stent, the sample was then incubated in a 37 ℃ shaking chamber for 12h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 1mL of release solution coated on the stent was taken for detection, 1mL of new buffer solution was added, and the drug concentration was quantified by a fluorescence spectrophotometer (excitation wavelength of DOX is 480nm, emission wavelength is 560nm) to obtain the release curve of DOX, as shown in FIG. 3.

Example 12

In vitro release of the macromolecular drug IgG (protein pre-labeled with Cy 5)

The IgG-loaded scaffold obtained in example 3 was placed in a release flask, 2.0mL of phosphate buffer solution with pH 7.4 or pH 6.5 was added to the scaffold, the sample was incubated in a 37 ℃ shaking chamber for 12h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 1mL of release solution coated on the scaffold was taken for detection, 1mL of new buffer solution was added, and the drug concentration was quantified by a fluorescence spectrophotometer (excitation wavelength of IgG-Cy5 is 649nm, emission wavelength is 670nm) to obtain the release curve of IgG, as shown in FIG. 4.

Example 13

Implanted stent loaded with DOX and aPD-1 antibodies for treatment of abdominal cavity metastatic tumor model of colon cancer

35 Bablc mice (weighing about 16-18 g) were divided into five groups at random, namely, a blank control group, a DOX-loaded stent treatment group obtained in example 2, a aPD-1-loaded stent treatment group obtained in example 4, a DOX and aPD-1-loaded stent treatment group obtained in example 5, and a free DOX and aPD-1 treatment group (the dose of implanted DOX was 15mg/kg, and the dose of implanted aPD-1 was 150. mu.g/mouse). After injecting 500 ten thousand CT26 cells into the abdominal cavity for one week, implanting the stent into the abdominal cavity by operation, observing for one week, euthanizing the mouse, taking out the tumor in the abdominal cavity, photographing and weighing to obtain the treatment effect as shown in figure 5.

Example 14

Scaffold materials loaded with R848 and anti-OX 40 antibody (aOX40) for treatment of postoperative relapse models of colon cancer

60 Bablc mice (weighing about 16-18 g) were divided into six groups at random, namely a blank control group, a blank stent group (prepared according to the method of example 6 except that no load R848 was added), a stent treatment group loaded with R848 obtained in example 6, a stent treatment group loaded with aOX40 obtained in example 7, a stent treatment group loaded with R848 and aOX40 obtained in example 8, and a free R848 and aOX40 treatment group (the dose of R848 was 150. mu.g/mouse, and the dose of aOX40 was 15. mu.g/mouse). Injecting 150 ten thousand CT26 cells into a mouse subcutaneously until the tumor volume reaches 200-300 mm³Thereafter, the tumor was surgically removed by 90%, and then a stent was implanted on the remaining tumor, and the tumor volume was continuously observed, and the therapeutic effect was obtained as shown in fig. 6.

Claims (4)

1. A drug-loaded stent material is characterized in that the drug-loaded stent material is obtained by crosslinking multi-arm amino polyethylene glycol and polyaldehyde dextran;

the aldehydic dextran is represented by formula (IV):

wherein q and k are polymerization degrees, q is more than or equal to 10 and less than or equal to 500, and k is more than or equal to 10 and less than or equal to 500;

the multi-arm amino polyethylene glycol is selected from the group shown in formula (II):

wherein n and m are polymerization degrees, and m is more than or equal to 1 and less than or equal to 500; n is more than or equal to 1 and less than or equal to 500; p is more than or equal to 1 and less than or equal to 200;

the mass ratio of the multi-arm amino polyethylene glycol to the polyaldehyde dextran is 1: (0.05-10).

2. A method of making the drug-loaded stent material of claim 1, comprising:

s) reacting multi-arm amino polyethylene glycol with polyaldehyde dextran in an aqueous solution to obtain the scaffold material.

3. The preparation method according to claim 2, wherein S) is in particular:

mixing the multi-arm amino polyethylene glycol aqueous solution with the polyaldehyde dextran aqueous solution for reaction to obtain a stent material;

the concentration of the amino compound in the multi-arm amino polyethylene glycol aqueous solution is 1 mg/mL-300 mg/mL;

the concentration of the aldehyde compound in the aqueous solution of the multi-aldehyde dextran is 1 mg/mL-300 mg/mL.

4. Use of the drug-loaded scaffold material of claim 1 or the drug-loaded scaffold material prepared by the preparation method of any one of claims 2 to 3 in the preparation of an anti-tumor drug.

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