CN115124711A - Hypoxic sensitive nano material and preparation method and application thereof - Google Patents

Hypoxic sensitive nano material and preparation method and application thereof Download PDF

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CN115124711A
CN115124711A CN202210667143.2A CN202210667143A CN115124711A CN 115124711 A CN115124711 A CN 115124711A CN 202210667143 A CN202210667143 A CN 202210667143A CN 115124711 A CN115124711 A CN 115124711A
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段晓品
蔡程远
肖计生
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Southern Medical University
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Abstract

The invention discloses a hypoxic sensitive nano material, a preparation method and an application thereof, wherein the nano material is obtained by reacting a raw material containing azophenyl, a soluble skeleton polymer and a polyphenol compound in a solvent. The azobenzene-containing compoundThe raw material of the base comprises any one of 4,4 '-dicarboxylic acid azobenzene, 4-carboxyl-4' -amino azobenzene and 3,3 ', 5, 5' -tetracarboxylic acid azobenzene; the soluble skeleton polymer comprises mPEG-NH 2 Any one of mPEG-COOH; the polyphenol compound comprises any one of dopamine and 6-hydroxy dopamine. The nitrogen-nitrogen double bond in the azo group in the nano material can be broken under the condition of oxygen deficiency, so that the nano material loaded with the drug can be dissociated when reaching the tumor, thereby releasing the drug, improving the concentration of the drug in the deep part of the tumor, further effectively killing tumor cells and achieving the effect of treatment.

Description

Nano material sensitive to hypoxic and preparation method and application thereof
Technical Field
The invention belongs to the technical field of polymer drug carriers, and particularly relates to a hypoxic sensitive nano material, and a preparation method and application thereof.
Background
The tumor microenvironment has the characteristics of hypoxia, low pH, inflammatory reaction and immunosuppression. Wherein, hypoxia is the common property of all solid tumors, and the degree of hypoxia gradually weakens from the center of the tumor to the outside. Intratumoral hypoxia has been shown to produce subsequent biological responses primarily through the hypoxia inducible factor (HIF-1 α) signaling pathway. Hypoxia induces HIF-1 alpha high expression, and is combined with HRE of programmed death ligand (PD-L1) promoter to up-regulate the expression of PD-L1 on the surface of marrow-derived immunosuppressive cells (MDSC), thereby causing the abnormality of tumor microenvironment, influencing the anti-tumor immune response of organisms and finally being difficult to effectively kill tumor cells.
At present, many drugs are available for killing tumor cells, but the existing drugs can also damage normal cells, thereby causing serious side effects. The nano targeting drug-loaded system has the characteristics of small size effect, surface effect and the like, and can deliver the drug to a tumor part in a targeting way through the high permeability and retention effect (EPR effect) of solid tumor, so that the concentration of the drug at a pathological change part is further improved, the toxic and side effect of the drug on normal tissues is reduced, and the application advantage of the nano targeting drug-loaded system is larger than that of a free drug. The liposome material which is clinically used at present wraps the corresponding medicine in the liposome through the principle of hydrophilicity and hydrophobicity, and aims to improve the stability and the in-vivo bioavailability of the medicine. However, the traditional liposome formulation still has the disadvantages of low encapsulation efficiency, poor stability and low utilization rate, thereby limiting the drug effect. On the other hand, the high heterogeneity and complex physiological barrier of tumor tissues severely limit the depth of the nanometer materials entering the tumor, so that the deep tumor cannot be killed, and the treatment effect is further influenced.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. According to the invention, azobenzene, mPEG and dopamine are connected through an amide reaction to prepare the nano material, phenolic hydroxyl in the dopamine in the nano material can be connected with a medicament containing carboxyl or phenolic hydroxyl through metal ions with coordination capacity, and the mPEG can increase the water solubility of the nano material and prolong the circulation time of the nano material in vivo; the nitrogen-nitrogen double bond in the azo group can be broken under the condition of oxygen deficiency, so that the drug-loaded nano material is dissociated when reaching the deep part of the tumor, the drug is released, the concentration of the drug at the deep part of the tumor is improved, the tumor cells are effectively killed, and the treatment effect is achieved.
In a first aspect of the present invention, a method for preparing a nanomaterial is provided, wherein the nanomaterial is obtained by reacting a raw material containing an azophenyl group, a soluble skeleton polymer, and a polyphenol compound in a solvent.
In some preferred embodiments of the present invention, the raw material containing an azophenyl group includes any one of 4,4 '-dicarboxylic acid azobenzene, 4-carboxy-4' -aminoazobenzene, and 3,3 ', 5' -tetracarboxylic acid azobenzene.
In some preferred embodiments of the invention, the soluble backbone polymer comprises mPEG-NH 2 And mPEG-COOH.
In some preferred embodiments of the invention, the polyphenol compound comprises any one of dopamine, 6-hydroxydopamine.
In some preferred embodiments of the present invention, the solvent comprises any one of pyridine, chloroform, and dimethylsulfoxide.
In some preferred embodiments of the present invention, the raw material containing an azophenyl group is subjected to catalyst activation.
In some more preferred embodiments of the present invention, the activating is performed by mixing the raw material containing the azophenyl group and the catalyst in a solvent.
In some preferred embodiments of the invention, the catalyst comprises N-hydroxysuccinimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine.
In some preferred embodiments of the present invention, the raw material containing an azophenyl group and the soluble backbone polymer and polyphenol compound are subjected to purification after reaction in a solvent.
In some preferred embodiments of the invention, the method of purification comprises dialysis purification.
In some more preferred embodiments of the invention, the dialysis purification uses a dialysis bag of 1500Da to 2500 Da.
In some preferred embodiments of the present invention, the raw material containing an azophenyl group, the soluble skeleton polymer, and the polyphenol compound are reacted in a solvent, and then dried.
In some preferred embodiments of the invention, the method of drying comprises freeze-drying.
In some more preferred embodiments of the invention, the temperature of the freeze-drying is from-40 ℃ to-70 ℃.
In some more preferred embodiments of the present invention, the freeze-drying time is 20 to 30 hours.
In a second aspect of the present invention, a nanomaterial prepared by the preparation method of the first aspect of the present invention is provided, and the particle size of the nanomaterial is 120 to 140 nm.
According to a second aspect of the invention, in some embodiments of the invention, the nanomaterial has a potential of-14 to-16 mV.
Azobenzene in the nano material has nitrogen-nitrogen double bonds which can be broken under the condition of oxygen deficiency, so the nano material prepared in the invention is an oxygen deficiency sensitive nano material. In addition, the nano material in the invention is provided with mPEG, the mPEG can increase the water solubility of the nano material and prolong the circulation time of the nano material in vivo, so that the circulation time of the drug in vivo is prolonged, the nitrogen-nitrogen double bond in the azo group can be broken under the condition of hypoxia, and the nitrogen-nitrogen double bond can be broken when the nano material loaded with the drug reaches the tumor, so that the drug is released, the concentration of the drug at the tumor is improved, the tumor cells can be effectively killed, and the treatment effect is achieved.
In the nano material, the coordination with metal ions can be realized through phenolic hydroxyl on dopamine, and the metal ions can be simultaneously coordinated with carboxyl or phenolic hydroxyl on a medicament, so that the medicament is loaded into the nano material, wherein the medicament is an anticancer medicament with phenolic hydroxyl or carboxyl, and comprises one or a combination of mitoxantrone, sulfasalazine, brequinar, catechin, epicatechin, gallocatechin, pemetrexed, indomethacin, adriamycin, paclitaxel and docetaxel.
In a third aspect of the present invention, there is provided a use of the nanomaterial of the second aspect of the present invention in a drug delivery vehicle.
According to the third aspect of the present invention, in some preferred embodiments of the present invention, the drug is an anti-tumor drug.
In some preferred embodiments of the invention, the drug comprises one or a combination of mitoxantrone, sulfasalazine, brequinar, catechin, epicatechin, gallocatechin, pemetrexed, indomethacin, doxorubicin, paclitaxel, docetaxel.
In a fourth aspect of the present invention, a pharmaceutical composition is provided, which comprises the nanomaterial of the second aspect of the present invention, a drug containing a phenolic hydroxyl group or a carboxyl group, and a metal ion having coordination ability.
According to a fourth aspect of the invention, in some embodiments of the invention, the drug is an anti-tumor drug.
In some preferred embodiments of the present invention, the drug is preferably one of mitoxantrone, sulfasalazine, brequinar, catechin, epicatechin, gallocatechin, pemetrexed, indomethacin, doxorubicin, paclitaxel, docetaxel, or a combination thereof.
In some more preferred embodiments of the invention, the drug is mitoxantrone, sulfasalazine.
Sulfasalazine can reduce the expression of cystine/glutamate reverse transporter (SLC7a11) on the surface of cell membrane, reduce glutathione in cell, thereby causing cell iron death, and metal ions with coordination ability (ferrous ion, ferric ion and cupric ion) can also cause cell iron death through fenton reaction. Mitoxantrone can block DNA replication and simultaneously can induce cells to undergo immunogenic death, the cells undergoing immunogenic death can induce dendritic cells (DC cells) to mature, so that T lymphocytes (T cells) are promoted to be activated and secrete INF-gamma, and the INF-gamma can further induce SCL7A11 on the surface of tumor cells to be reduced in expression, so that the tumor cells are induced to undergo iron death and are further killed.
In some preferred embodiments of the present invention, the metal ions with coordination ability include ferric ions, ferrous ions, cupric ions, divalent zinc ions, and trivalent chromium ions, and the drug is attached to the nanomaterial according to the second aspect of the present invention through a coordination bond formed by the metal ions and dopamine.
In some preferred embodiments of the present invention, the mass percentage of the substance that provides metal ions having a coordinating ability is 10 to 15%.
In some preferred embodiments of the present invention, the drug loading of the nanomaterial according to the second aspect of the present invention is 0.1 to 0.3mg/mg, that is, 0.1 to 0.3mg of drug can be loaded per mg of nanomaterial.
In some preferred embodiments of the present invention, the drug comprises one drug, two drugs, or a plurality of drugs.
In a fifth aspect of the present invention, there is provided a process for preparing a composition according to the fourth aspect of the present invention, the process comprising the steps of: mixing and coordinating the nano material, the medicine containing phenolic hydroxyl or carboxyl and the metal ions with coordination capacity.
According to the content of the fifth aspect of the present invention, in some embodiments of the present invention, the nanomaterial of the second aspect of the present invention, the drug containing phenolic hydroxyl or carboxyl, and the metal ion with coordination capability need to be purified after mixed coordination.
In some more preferred embodiments of the invention, the method of purification comprises dialysis purification.
In some further embodiments of the present invention, the dialysis purification uses a 400-6000 KDa dialysis bag.
In some further embodiments of the present invention, the dialysis purification time is 2-5 hours.
In a sixth aspect, the invention provides a use of the composition of the fourth aspect in the preparation of an anti-tumor medicament.
According to a sixth aspect of the invention, in some embodiments of the invention, the tumor comprises a mouse colon cancer tumor, a mouse liver cancer tumor, a breast cancer tumor, a melanoma.
The invention has the beneficial effects that:
(1) according to the invention, azo groups, mPEG and dopamine are connected through an amide reaction to prepare a nano material, phenolic hydroxyl groups in the dopamine in the nano material can be coordinated with metal ions with coordination capacity, and meanwhile, the metal ions with coordination capacity can also be coordinated with a drug with phenolic hydroxyl groups or carboxyl groups, so that the nano material and the drug are connected; the mPEG can increase the water solubility of the nano material and the effective drug concentration of the nano material connected with the drug in vivo, and can kill the tumor more effectively; in addition, the nitrogen-nitrogen double bond in the azo group in the nano material can be broken under the condition of hypoxia, so that the nano material loaded with the drug can be dissociated when reaching the tumor, thereby releasing the drug, improving the concentration of the drug in the deep part of the tumor, further effectively killing tumor cells and achieving the effect of treatment.
(2) The nano material loaded with the drug can improve the uptake capacity of tumor cells to the drug, prolong the effective uptake time of the tumor cells to the drug, effectively enrich the drug to the tumor part and improve the retention time of the drug at the tumor part.
(3) The nano material loaded with the drug can effectively reduce the survival rate of tumor cells, can reduce the toxicity of the drug and has better biological safety.
Drawings
FIG. 1 is a schematic illustration of a drug loaded nanomaterial in an embodiment of the present invention;
FIG. 2 is a particle size diagram of the drug-loaded hypoxic sensitive nanomaterial PAD @ MS in an embodiment of the present invention;
FIG. 3 is a potential diagram of the drug-loaded hypoxic sensitive nanomaterial PAD @ MS in an embodiment of the present invention;
FIG. 4 is a dispersion condition of a hypoxic sensitive nanomaterial PAD @ MS loaded with a drug in water under an normoxic condition;
FIG. 5 is a dispersion of a hypoxic sensitive nanomaterial PAD @ MS loaded with a drug under a hypoxic condition in water;
FIG. 6 shows drug uptake by mouse colon cancer MC38 cells in different groups after incubation for 4h and 8h under normoxic and hypoxic conditions, respectively;
FIG. 7 shows the drug uptake by cells in different groups imaged by confocal laser scanning microscopy after incubation of MC38 cells from mouse colon cancer for 4 h;
FIG. 8 shows the drug uptake by cells in different groups imaged by confocal laser scanning microscopy after incubation of mouse colon cancer MC38 cells for 8 h;
FIG. 9 is a graph of the biodistribution of MTX in mice at different times following administration of MTX + SAS;
FIG. 10 is the biological distribution of MTX in mice at different times after administration of the drug-loaded hypoxic sensitive nanomaterial PAD @ MS;
FIG. 11 shows the body weight changes of C57BL/6 mice in MTX + SAS dosed group and PAD @ MS dosed group and PBS group;
FIG. 12 shows the body weight changes of BALB/c mice in MTX + SAS dosed group and PAD @ MS dosed group and PBS group;
FIG. 13 shows the change in body weight of C57BL/6 mice following increased PAD @ MS dosing;
FIG. 14 shows the glutamic-pyruvic transaminase content in the serum of mice in MTX + SAS administered group, PAD @ MS administered group, and PBS group;
FIG. 15 shows the serum contents of glutamic-oxaloacetic transaminase, in MTX + SAS administered group, PAD @ MS administered group, and PBS group;
FIG. 16 shows the serum alkaline phosphatase levels of mice in MTX + SAS-administered group, PAD @ MS-administered group, and PBS-administered group;
FIG. 17 shows H & E section results of heart, liver, spleen, lung and kidney of C57BL/6 mice in MTX + SAS administration group, PAD @ MS administration group and PBS group;
FIG. 18 is a graph showing the change of MTX concentration in plasma in rats in vivo with time in the MTX + SAS dosed group, PAD @ MS dosed group and PD @ MS dosed group;
FIG. 19 shows the change of plasma SAS concentration in rats over time in MTX + SAS dosed group, PAD @ MS dosed group, and PD @ MS dosed group;
FIG. 20 is a graph showing statistics of mouse colon cancer MC38 cell viability as a function of MTX concentration for PAD @ MS dosing and PD @ MS dosing groups under normoxic conditions;
FIG. 21 is a graph of the survival of mouse colon carcinoma MC38 cells in PAD @ MS dosed and PD @ MS dosed groups as a function of MTX concentration under hypoxic conditions.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Test materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
The preparation process of the hypoxic sensitive nanomaterial in example 1 is as follows:
(1) 24mg of 4,4' -dicarboxylic acid Azobenzene (AZO), 26mg of N-hydroxysuccinimide (NHS) and 36mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are weighed and dissolved in 12mL of pyridine, and the mixture is stirred at 30 ℃ for 1 hour to activate carboxyl groups;
(2) adding 20mg of dopamine into the step (1), and stirring for 24 hours at 30 ℃;
(3) to step (2) was added 84mg of aminopolyethylene glycol monomethyl ether (mPEG-NH) 2 ) Stirring at 30 ℃ for 16h, dialyzing and purifying by using a 2000Da dialysis bag for 2 days, and freezing and drying to obtain a sample called mPEG-AZO-dopamine (PAD), wherein the freezing temperature is-60 ℃ and the freezing time is 24 h; samples PAD were stored at-20 ℃.
Example 2
The drug loading method of the hypoxic sensitive nanomaterial in embodiment 1 comprises the following steps:
5mg of PAD prepared in example 1, 0.32mg of Mitoxantrone (MTX) were dissolved in 1mL of ddH 2 In O, 1.92mg of sulfasalazine (SAS) is dissolved in 20. mu.L of N, N-Dimethylformamide (DMF) solvent, the solution is mixed evenly at 25 ℃, and 1.2mg of FeCl is added 3 And continuously stirring for 40min at 25 ℃, and dialyzing for 3h by using a 500KDa dialysis bag to obtain the nanometer material loaded with the medicine, which is recorded as PAD @ MS.
In the embodiment of the invention, an antitumor drug with carboxyl or phenolic hydroxyl is coordinated and combined with a hypoxic sensitive nano material through a metal ion coordination bond, the combination principle is shown in figure 1, the drugs Mitoxantrone (MTX) and sulfasalazine (SAS) are directly mixed and stirred with the hypoxic sensitive nano material PAD in the embodiment 1, and then Fe is added into the mixed solution 3+ After stirring, Fe 3+ Can coordinate with phenolic hydroxyl in dopamine, and can coordinate with carboxyl or phenolic hydroxyl in the drug, thereby connecting the drug and the nano material in the embodiment of the invention.
Comparative example 1
The preparation process of the nanomaterial in comparative example 1 is as follows:
in contrast to example 1, in comparative example 1, 4' -dicarboxylic acid azobenzene was not added, and in comparative example 1 mPEG-COOH was directly reacted with azobenzene, i.e., the nanomaterial in comparative example 1 did not have oxygen deficiency sensitivity.
(1) 84mg of mPEG-COOH, 26mg of N-hydroxysuccinimide (NHS) and 36mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) were weighed out and dissolved in 12mL of pyridine, and stirred at 30 ℃ for 1 h;
(2) adding 20mg of dopamine into the step (1), stirring at 30 ℃ for 24h, dialyzing and purifying by using a 2000Da dialysis bag, wherein the dialysis time is 2 days, the sample obtained after freeze drying is recorded as PD, the freezing temperature is-60 ℃, and the freezing time is 24 h.
Comparative example 2
5mg of PD in comparative example 1, 0.32mg of Mitoxantrone (MTX) were dissolved in 1mL of ddH 2 Dissolving 1.92mg of sulfasalazine (SAS) in 20 μ L of DMF solvent in O, mixing the above solutions at 25 deg.C, adding 1.2mg of FeCl 3 And after stirring for 40min at 25 ℃, dialyzing for 3h by using a dialysis bag of 500KDa to obtain the drug-loaded nano material in the comparative example 2, which is marked as PD @ MS.
PAD @ MS characterization and performance testing
1. The particle size, dispersion index and Zeta potential of the PAD @ MS in example 2 were measured using a nano-particle size and Zeta potential analyzer, and the results are shown in fig. 2 and 3, fig. 2 is a graph of the particle size of the PAD @ MS in the example of the present invention measured using DLS, and fig. 3 is a graph of the potential of the PAD @ MS in the example of the present invention, in which the left bar graph represents the measurement result of the particle size and the right bar graph represents the measurement result of the potential.
2. And (3) hypoxic sensitivity test: adding 10mM Na into the nano material PAD @ MS 2 S 2 O 4 Solution of Na by 2 S 2 O 4 The reducibility of (a) cleaves the nitrogen-nitrogen double bond in azobenzene, resulting in the dissociation of PAD @ MS. Since PAD @ MS also undergoes dissociation under hypoxic conditions, Na is utilized 2 S 2 O 4 The hypoxic condition of the nano material PAD @ MS is simulated. The dispersion of PAD @ MS under normoxic and hypoxic conditions is observed under a transmission electron microscope, as shown in FIGS. 4 and 5, wherein FIG. 4 is normoxicThe dispersion of PAD @ MS in water under oxygen conditions is shown in FIG. 5, and the dispersion of PAD @ MS in water under oxygen-deficient conditions is shown in FIG. 4 and FIG. 5, and it can be seen that under oxygen-deficient conditions, the originally complete nanostructure of PAD @ MS in the embodiment of the invention is dispersed, which is caused by the breakage of the nitrogen-nitrogen double bond in azobenzene under oxygen-deficient conditions.
3. PAD @ MS drug loading effect test
(1) The uptake capacity of the cells at different time points for the drug was examined by flow cytometry and confocal laser scanning microscopy. Mouse colon cancer cell MC38 cells were seeded in 6-well plates at a density of 5X 10 4 Each cell/well, experiments were divided into 4 groups, MTX group (2 mL of DMEM medium containing MTX added to mouse colon cancer cell MC38 cells), MTX + SAS group (2 mL of DMEM medium containing MTX + SAS added to mouse colon cancer cell MC38 cells), PD @ MS group (2 mL of DMEM medium containing PD @ MS added to mouse colon cancer cell MC38 cells), PAD @ MS group (2 mL of DMEM medium containing PAD @ MS added to mouse colon cancer cell MC38 cells); MTX and MTX + SAS are respectively dissolved in dimethyl sulfoxide to prepare high-concentration mother liquor, then the mother liquor is added into a DMEM medium, PAD @ MS and PAD @ MS are respectively dissolved in deionized water to prepare solutions, and then the solutions are added into the DMEM medium, wherein the adding concentration of MTX is 1 mug/mL, and the adding amount of SAS is 6 mug/mL. Cells in different groups were separately treated in normoxia (5% CO) 2 And 95% air) and hypoxic oxygen (1% O) 2 ，5％CO 2 And balance N 2 ) Incubation was performed under conditions. After incubation for 4h and 8h, respectively, the cells were washed three times with Phosphate Buffered Saline (PBS) and analyzed for drug uptake by mouse colon cancer MC38 cells by imaging with flow cytometry and confocal laser scanning microscopy, and since MTX is self-fluorescent, drug uptake by mouse colon cancer MC38 cells was analyzed by detecting MTX fluorescence, and Hoechst fluorescent dye was used to stain the cell nuclei. The test results of flow cytometry are shown in FIG. 6, FIG. 6 shows the drug uptake of MC38 cells of mouse colon carcinoma in different groups (NC is blank control group) after incubation for 4h and 8h under normoxic and hypoxic conditions, respectively, and it can be seen from FIG. 6 that under normoxic conditions, the cells incubate with each otherThe increasing of the breeding time, the uptake capacity of the PAD @ MS group and the PD @ MS group to the medicine is relatively close, the difference between the two is not large, the uptake capacity of the cells in the PAD @ MS group to the medicine is remarkably higher than that of the PD @ MS group along with the increasing of the incubation time under the hypoxic condition, and the reason is that under the hypoxic condition, the nitrogen-nitrogen double bond in azobenzene in the PAD @ MS is broken to cause the dropping of mPEG, so that the cell uptake of the medicine is facilitated.
The results of the confocal tests are shown in fig. 7-8, fig. 7 shows the drug uptake condition of cells in different groups imaged by a laser confocal scanning microscope after the mouse colon cancer MC38 cells are incubated for 4h, fig. 8 shows the drug uptake condition of cells in different groups imaged by a laser confocal scanning microscope after the mouse colon cancer MC38 cells are incubated for 8h, and as can be seen from fig. 7 and 8, when the cells in the MTX group, the MTX + SAS group, the PD @ MS group and the PAD @ MS group are incubated for 4h under the normoxic condition and the hypoxic condition, the fluorescence of MTX is detected in the cells in the MTX group, the MTX + SAS group, the PD @ MS group and the PAD @ MS group, which indicates that the drugs enter the cells in the MTX group, the MTX + SAS group, the PD @ MS group and the PAD @ MS group. And the amount of the drugs entering the cells under the hypoxic condition is more, and when the incubation time reaches 8h, the distribution of the drugs in the PAD @ MS group cells is denser, which indicates that a large amount of the drugs enter the cell nucleus.
(2) Enrichment of PAD @ MS in tumor sites in mice purchased from southern university of medicine animal center, experimentally selected BALB/c mice (5-6 weeks, about 20g) containing 1X 10 s.c.injected subcutaneously on the right side of BALB/c mice was examined by in vivo imaging 6 Mouse colon cancer cells CT26 in PBS. When the tumor reaches about 100mm 3 When mice were randomly divided into 2 groups, namely, MTX + SAS group and PAD @ MS group, wherein 3 mice in each group were subjected to 100 muL of MTX + SAS (MTX + SAS was dissolved in PBS), 5mg/kg of MTX and 30mg/kg of SAS were administered, 100 muL of @ PAD MS (PAD @ MS was dissolved in PBS) was subjected to intraperitoneal injection of PAD, 5mg/kg of MTX and 30mg/kg of SAS were administered, and changes in near infrared fluorescence intensity of tumor sites of the mice were photographed by live imaging of the mice at 1, 3, 5, 8, 12, 24 and 48h after administration, as shown in FIGS. 9 and 10, as shown in FIG. 9, biodistribution of MTX in the mice at different times after administration of MTX + SAS, and as shown in FIG. 10, biological distribution of MTX in the mice at different times after administration of MTX + SAS was photographedAfter PAD @ MS, the biodistribution of MTX in mice at different times, as can be seen from FIGS. 9 and 10, PAD @ MS can be effectively enriched to tumor sites in mice and the retention time of the drug in tumors is prolonged compared to free MTX and SAS.
(3) And (3) toxicity testing: the PAD @ MS in the embodiment of the invention can also reduce the toxic effect of MTX and SAS on organisms, C57BL/6 mice and BALB/C mice are selected for experiments, MTX + SAS and PAD @ MS are selected for medicines, and 1 × 10 is injected subcutaneously on the right side of C57BL/6 mice 6 Mouse colon cancer cell MC38 PBS subcutaneous tumor was implanted, BALB/c mice right side subcutaneous injection containing 1X 10 6 Mouse colon cancer cells CT26 were seeded with PBS to obtain subcutaneous tumors and reached a tumor volume of 50mm 3 The mice of the MTX + SAS group are injected with 100 mu L of PBS containing MTX + SAS in the abdominal cavity, the PAD @ MS group is injected with 100 mu L of PBS containing PAD @ MS in the same volume, the administration mode is that the mice of the MTX + SAS group are injected with 5mg/kg of MTX and 30mg/kg of SAS once in the abdominal cavity every 2 days, a blank control group is arranged, the mice of the C57BL/6 are injected with PBS in the same volume, and the mice of the BALB/C group are injected with 10 times. FIG. 11 shows the body weight changes of C57BL/6 mice in MTX + SAS dosed group and PAD @ MS dosed group and PBS group, FIG. 12 shows the body weight changes of BALB/C mice in MTX + SAS dosed group and PAD @ MS dosed group and PBS group, and it can be seen from FIGS. 11-12 that the body weight of C57BL/6 mice and BALB/C mice in MTX + SAS dosed group is significantly reduced, while the body weight of C57BL/6 mice and BALB/C mice in PAD @ MS dosed group is not significantly changed. The PAD @ MS was further increased at 50mg/kg MTX and 300mg/kg SAS, subcutaneous tumor-implanted C57BL/6 mice were administered in the same manner, and the body weight of C57BL/6 mice was tested 5 times after administration, as shown in FIG. 13, which is a change in body weight of C57BL/6 mice after increasing the PAD @ MS administration, and the change in body weight of three C57BL/6 mice was recorded. As can be seen in fig. 13, even with the increased dose of PAD @ MS administered, there was no significant decrease in body weight in the mice.
Further comparing the contents of alanine Aminotransferase (ALT), aspartate Aminotransferase (AST) and alkaline phosphatase (AKP) in the serum of the C57BL/6 mouse after administration, wherein the contents of ALT, AST and AKP can reflect the liver function condition of the mouse and reflect the damage condition of drug toxicity to the liver, and the contents of ALT, AST and AKP are measured according to the instructions in corresponding kits which are all purchased from Nanjing construction reagent company. The measured results are shown in fig. 14-16, and it can be seen from the graphs that the contents of ALT, AST and AKP in the serum of the mice in the MTX + SAS administration group after administration are all obviously higher than those of the PAD @ MS administration group and the PBS group, indicating that the liver function of the mice in the MTX + SAS administration group is obviously impaired, while the contents of ALT, AST and AKP in the PAD @ MS administration group are lower than those of the PBS administration group, further indicating that the PAD @ MS in the practice of the present invention has lower toxicity.
Further, the H & E section results of the heart, liver, spleen, lung and kidney of the C57BL/6 mice after administration of the MTX + SAS group and the PAD @ MS group were investigated, and similarly, the C57BL/6 mice implanted with subcutaneous tumors were used, the mice of the MTX + SAS group were intraperitoneally injected with 100. mu.L of PBS containing MTX + SAS, the PAD @ MS group was injected with 100. mu.L of PBS containing PAD @ MS in equal volume, and the blank control group was injected with PBS in equal volume, and the mice were administered with 5mg/kg of MTX and 30mg/kg of SAS once every 2 days, 4 times, and the heart, liver, spleen, lung and kidney of the C57BL/6 mice were subjected to section analysis the next day after completion of administration, and the results are shown in FIG. 17, and it can be seen that the liver of the mice in the MTX + administration group had significant cavitation necrosis, while the liver of the mice in the PAD @ MS group and the PAD group had no significant change in PBS, compared with free MXT and SAS, PAD @ MS in the embodiment of the invention has lower toxicity and higher biological safety.
(4) Further comparing the in vivo circulation time of PAD @ MS, PD @ MS and free drugs MTX and SAS, SD rats are adopted in the experiment, are purchased from southern medical university animal center and are in SPF grade, the SD rats in the experiment are randomly divided into 3 groups, namely PAD @ MS group, PD @ MS group and MTX + SAS group, 3 rats are adopted in each group, the administration mode of the PAD @ MS group rats is that 500 mu L of PBS containing PAD @ MS is injected intraperitoneally, the administration mode of the PD @ MS group rats is that 500 mu L of PBS containing PD @ MS is injected intraperitoneally, the administration mode of the MTX + SAS group rats is that 500 mu L of PBS containing MTX + SAS is injected intraperitoneally, and the administration dosage of MTX containing 5mg/kg and SAS is 30 mg/kg. After administration, blood of SD rats was collected at 0.5, 1, 3, 5, 8, 12, 24, 48, 72, 96 and 120h, respectively, and immediately centrifuged at 2000rpm for 10min to harvest plasma, 150 μ L of methanol was added to 50 μ L of plasma to destroy the structure of PAD and PD and release the drug, precipitate protein and extract the drug from plasma. After centrifugation at 10000rpm for 10min, the contents of MTX and SAS in the plasma were quantitatively determined by fluorescence spectrophotometry and High Performance Liquid Chromatography (HPLC), respectively. The results are shown in FIG. 18 and FIG. 19, wherein FIG. 18 shows the variation of MTX concentration in plasma of rats in different administration groups with time, FIG. 19 shows the variation of SAS concentration in plasma of rats in different administration groups with time, and it can be seen from FIG. 18 and FIG. 19 that both PD @ MS and PAD @ MS are effective in increasing the effective drug concentration in blood compared with the free drugs MTX and SAS, wherein the MTX concentration and SAS concentration in plasma of rats in PD @ MS and PAD @ MS are respectively 4.54 times and 6.42 times of that in the free drug group; on the other hand, PD @ MS and PAD @ MS can prolong the circulation time of the drug in vivo, and can delay this process compared to the free drug group being cleared rapidly.
Further comparing PAD @ MS and PD @ MS effects on mouse colorectal cancer cell MC38 under normoxic and hypoxic conditions, mouse colorectal cancer cell MC38 was seeded in 96-well plates at a density of 2 × 10 3 Adding 200 mu L of DMEM medium into each cell/well, dividing the cells into an experimental group and a blank control group, adding 200 mu L of the DMEM medium containing different amounts of PD @ MS and PAD @ MS into corresponding wells in the experimental group to treat MC38 cells, adding 200 mu L of DMEM medium into the blank control group, and respectively placing the cells in the experimental group and the blank control group in normal oxygen (5% CO) 2 And 95% air) and hypoxic (1% O) 2 ，5％CO 2 And balance N 2 ) Adhesion was performed for 24h under the conditions. The cells in the experimental and control groups were then incubated in normoxia (5% CO) 2 And 95% air) and hypoxic (1% O) 2 ，5％CO 2 And balance N 2 ) And (5) incubating for 48h under the condition. Detection of mouse colorectal cancer according to the instructions of the cell counting kit-8 (CCK-8)The results of the activity of the cancer MC38 cells are shown in FIG. 20 and FIG. 21, and it can be seen from FIG. 20 and FIG. 21 that the inhibition effect of PAD @ MS and PD @ MS on mouse colorectal cancer MC38 cells under normoxic conditions is not very different, but the survival rate of the mouse colorectal cancer MC38 cells after PAD @ MS treatment is remarkably reduced when the concentration of MTX is 0-0.5 mug/mL (the concentration of SAS is 0-3 mug/mL) under hypoxic conditions, which indicates that PAD @ MS in the embodiment of the invention has a more remarkable inhibition effect on mouse colorectal cancer MC38 cells under hypoxic conditions.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (10)

1. The preparation method of the nano material is characterized in that the nano material is obtained by reacting a raw material containing azophenyl, a soluble skeleton polymer and a polyphenol compound in a solvent;
wherein the raw material containing the azophenyl group comprises any one of 4,4 '-dicarboxylic acid azobenzene, 4-carboxyl-4' -amino azobenzene and 3,3 ', 5, 5' -tetracarboxylic acid azobenzene; the soluble skeleton polymer comprises mPEG-NH 2 Any one of mPEG-COOH; the polyphenol compound comprises any one of dopamine and 6-hydroxy dopamine; the solvent comprises any one of pyridine, chloroform and dimethyl sulfoxide.
2. The nanomaterial prepared by the method of claim 1, wherein the particle size of the nanomaterial is 120-140 nm.
3. Nanomaterial according to claim 2, characterized in that the potential of the nanomaterial is between-14 and-16 mV.
4. Use of a nanomaterial according to any of claims 2 to 3 in a drug delivery vehicle.
5. A pharmaceutical composition, which comprises the nanomaterial of any one of claims 2 to 3, a drug containing a phenolic hydroxyl group or a carboxyl group, and a metal ion having a coordinating ability.
6. The pharmaceutical composition of claim 5, wherein the drug containing a phenolic hydroxyl group or a carboxyl group is an antitumor drug.
7. The pharmaceutical composition of claim 6, wherein the anti-tumor drug comprises one or a combination of mitoxantrone, sulfasalazine, brequinar, catechin, epicatechin, gallocatechin, pemetrexed, indomethacin, doxorubicin, paclitaxel, docetaxel.
8. The pharmaceutical composition of claim 5, wherein the drug is attached to the nanomaterial of any one of claims 2 to 3 via a coordination bond.
9. A process for the preparation of a pharmaceutical composition according to any one of claims 5 to 8, characterized in that it comprises the following steps: mixing the nanomaterial of any one of claims 2-3, a drug containing phenolic hydroxyl or carboxyl, and a metal ion with coordination ability, wherein the drug is preferably an antitumor drug.
10. Use of the pharmaceutical composition of any one of claims 5-8 in the preparation of an anti-tumor medicament.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
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CN108641096A (en) * 2018-04-27 2018-10-12 同济大学 With weary oxygen, pH dual responsiveness mixed micelles and preparation method thereof
CN108938594A (en) * 2018-07-18 2018-12-07 单玲玲 A kind of medicinal composition and the preparation method and application thereof

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