A kind of polythiocarbamate and its preparation method and application

Abstract

The present invention discloses a polythiocarbamate, its preparation method, and application. The structural formula of the polythiocarbamate of the present invention is: wherein m is a natural number between 110 and 117, and n is a natural number between 6 and 17. The polythiocarbamate of the present invention has excellent biocompatibility and degradability. It can self-assemble in aqueous phase to form nanoparticles and be used as a transport vehicle for fluorescent probes and hydrophobic anticancer drugs. It can specifically amplify H2S signals at tumor sites and can be used for efficient and highly selective tumor imaging and treatment, possessing great potential for clinical application.

Description

Technical Field

[0001] The present invention relates to the technical field of polymer materials, and in particular to polythiocarbamate and a preparation method and application thereof. Background Art

[0002] Hydrogen sulfide (H2S), an endogenous cell signaling molecule, plays an important role in various physiological and pathological processes. Recent studies have shown that H2S can influence tumorigenesis by affecting tumor cell proliferation, energy metabolism, and drug resistance. Therefore, H2S has become a promising tumor imaging and signaling molecule and a potential multifunctional therapeutic agent.

[0003] Research has shown that the production of high-concentration H2S is often assisted by gaseous delivery of H2S donors. When exposed to stimuli such as reactive oxygen species, pH, external light, and highly active enzymes, various small molecule or polymeric H2S donors degrade and release H2S. However, H2S produced by exogenous donors may react with stimuli, reducing its levels and resulting in inefficient H2S delivery and failure to exert its intended biological function. Given the crucial role of H2S in regulating physiological and pathological processes, developing novel polymeric H2S donors that can specifically amplify H2S signals at lesions is of great significance, yet also presents significant challenges. Summary of the Invention

[0004] The purpose of the present invention is to provide a polythiocarbamate and a preparation method and application thereof.

[0005] The technical solution adopted by the present invention is:

[0006] A polythiocarbamate having the structural formula:

[0007] , where m is a natural number from 110 to 117, and n is a natural number from 6 to 17.

[0008] A method for preparing the polythiocarbamate as described above comprises the following steps:

[0009] 1) Nucleophilic substitution reaction of p-aminobenzyl alcohol and carbon disulfide to obtain , and then the nucleophilic aromatic substitution reaction of 4-hydroxybenzyl alcohol and 2,4-dinitrofluorobenzene was carried out to obtain ;

[0010] 2) Conduct The self-polymerization reaction Carry out polycondensation reaction to obtain ;

[0011] 3) Conduct The bonding reaction between the polyol and carboxyl-terminated polyethylene glycol monomethyl ether gives polythiocarbamate.

[0012] Preferably, in step 1), the molar ratio of p-aminobenzyl alcohol to carbon disulfide is 1:8-12.

[0013] Preferably, the nucleophilic substitution reaction in step 1) is carried out at room temperature (25° C. to 35° C.) and the reaction time is 1 h to 2 h.

[0014] Preferably, in step 1) The specific operation is: dispersing p-aminobenzyl alcohol, carbon disulfide and a basic catalyst in an organic solvent, then performing a nucleophilic substitution reaction, and then separating and purifying the product.

[0015] Preferably, the alkaline catalyst is at least one of sodium bicarbonate, 4-dimethylaminopyridine, di-tert-butyl dicarbonate, and triethylamine.

[0016] Preferably, the molar ratio of p-aminobenzyl alcohol to the alkaline catalyst is 1:0.8-2.2.

[0017] Preferably, the organic solvent is at least one of methanol, ethanol and tetrahydrofuran.

[0018] Preferably, the usage ratio of p-aminobenzyl alcohol and organic solvent is 1 g:5 mL to 10 mL.

[0019] Preferably, the separation and purification method is column chromatography.

[0020] Preferably, in step 1), the molar ratio of p-hydroxybenzyl alcohol to 2,4-dinitrofluorobenzene is 1:0.5-1.

[0021] Preferably, the nucleophilic aromatic substitution reaction in step 1) is carried out at a temperature of 50° C. to 70° C., and the reaction time is 12 h to 24 h.

[0022] Preferably, in step 1) The specific operation is: dispersing p-hydroxybenzyl alcohol, 2,4-dinitrofluorobenzene and a basic catalyst in an organic solvent, then performing a nucleophilic aromatic substitution reaction, and then separating and purifying the product.

[0023] Preferably, the molar ratio of p-hydroxybenzyl alcohol to the alkaline catalyst is 1:1-3.

[0024] Preferably, the alkaline catalyst is at least one of dimethylamine, triethylamine, aniline and pyridine.

[0025] Preferably, the organic solvent is at least one of N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran.

[0026] Preferably, the usage ratio of the p-hydroxybenzyl alcohol and the organic solvent is 1 g:5 mL to 15 mL.

[0027] Preferably, the separation and purification method is column chromatography.

[0028] Preferably, step 2) 、 The molar ratio is 1:0.5~2.

[0029] Preferably, the self-polymerization reaction in step 2) is carried out at a temperature of 50° C. to 85° C., and the reaction time is 4 h to 12 h.

[0030] Preferably, the polycondensation reaction in step 2) is carried out at a temperature of 50° C. to 85° C., and the reaction time is 12 h to 24 h.

[0031] Preferably, the specific operation of step 2) is: and catalyst are dispersed in an organic solvent for self-polymerization reaction, and then added Then a polycondensation reaction is carried out, and the product is separated and purified.

[0032] Preferably, the , the molar ratio of the catalyst is 1:0.01~0.07.

[0033] Preferably, the catalyst is at least one of an organic tin catalyst, dimethylcyclohexylamine, and an organic bismuth catalyst.

[0034] Preferably, the , the dosage ratio of organic solvent is 1g:1mL~3mL.

[0035] Preferably, the organic solvent is at least one of N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran.

[0036] Preferably, the specific operation of the separation and purification is: adding the product dropwise into icy ether for precipitation, and then performing centrifugal separation.

[0037] Preferably, step 3) , and the molar ratio of carboxyl-terminated polyethylene glycol monomethyl ether is 1:0.9-1.1.

[0038] Preferably, the bonding reaction in step 3) is carried out at room temperature (25° C. to 35° C.) for 24 to 36 hours.

[0039] Preferably, the specific operation of step 3) is: , carboxyl-terminated polyethylene glycol monomethyl ether and a catalyst are dispersed in an organic solvent, and then a bonding reaction is carried out, and then the product is separated and purified.

[0040] Preferably, the , the molar ratio of the catalyst is 1:2~4.5.

[0041] Preferably, the catalyst is at least one of sodium bicarbonate, 4-dimethylaminopyridine, triethylamine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0042] Preferably, the , the dosage ratio of organic solvent is 1g:10mL~15mL.

[0043] Preferably, the organic solvent is at least one of N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran.

[0044] Preferably, the separation and purification method is gel column separation and purification.

[0045] A drug carrier comprising the polythiocarbamate.

[0046] Preferably, the composition of the drug carrier further includes polyethylene glycol, and the polyethylene glycol is bonded to polythiocarbamate.

[0047] The beneficial effects of the present invention are as follows: the polythiocarbamate of the present invention has good biocompatibility and degradability, can self-assemble in an aqueous phase to form nanoparticles and be used as a transport carrier for fluorescent probes and hydrophobic anticancer drugs, can specifically amplify H2S signals at tumor sites, can be used for efficient and highly selective tumor imaging and treatment, and has great clinical application potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of compound 1 in Example 1.

[0049] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of compound 2 in Example 1.

[0050] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of polymer 1 in Example 1.

[0051] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the polythiocarbamate in Example 1.

[0052] Figure 5 These are GPC charts of polymers 1 to 3 in Examples 1 to 3.

[0053] Figure 6 This is a graph showing the changes in particle size of nanoparticles SNP under different conditions.

[0054] Figure 7 SNP p-Cy and inSNP p-Cy Confocal fluorescence images after incubation with CT26, Hepa 1-6, and L929 cells.

[0055] Figure 8 Tail vein injection of SNP p-Cy or inSNP p-Cy In vivo and ex vivo fluorescence images of orthotopic colorectal tumors.

[0056] Figure 9 MCF7, MCF7 / ADR and HUVEC cells and SNP p-DOX or inSNP p-DOX Cell viability test results after 24 hours of incubation.

[0057] Figure 10 Laser confocal images of P-gp distribution in MCF7 / ADR cells after treatment with different materials.

[0058] Figure 11 Drug-loaded nanoparticles SNP p-DOX Figure 2 shows the results of in vivo treatment trials.

[0059] Figure 12 This is the body weight change curve of mice in each experimental group in the in vivo treatment experiment. DETAILED DESCRIPTION

[0060] The present invention will be further explained and illustrated below with reference to specific embodiments.

[0061] Example 1:

[0062] A polythiocarbamate, the preparation method of which is as follows:

[0063] 1) Synthesis of Compound 1 and Compound 2:

[0064] 6.0 g (48 mmol) of p-aminobenzyl alcohol (ABA), 30 mL (510 mmol) of carbon disulfide (CS2) and 6.9 mL (51 mmol) of triethylamine (TEA) were dispersed in 50 mL of ethanol and stirred at room temperature for 1 h. The reaction solution was then placed in an ice bath and cooled to 0 ° C. After that, 9.6 g (45 mmol) of di-tert-butyl dicarbonate (Boc2O) and 0.12 g (0.96 mmol) of 4-dimethylaminopyridine (DMAP) were added. The reaction solution was removed from the ice bath, heated to room temperature, and continued to stir for 1 h. The mixture was extracted twice with dichloromethane (DCM), the organic layer was collected, and dried over anhydrous magnesium sulfate (MgSO4) to obtain a crude product. The crude product was purified by column chromatography using dichloromethane as an eluent and then dried in vacuo to obtain 4.8 g of (denoted as compound 1; white needle-shaped crystals, yield 60%);

[0065] 1.6 g (13 mmol) of p-hydroxybenzyl alcohol, 1.7 g (9.1 mmol) of 2,4-dinitrofluorobenzene and 1.7 mL (13 mmol) of triethylamine were dispersed in 15 mL of anhydrous N,N-dimethylformamide (DMF), and then placed under argon protection at 50 ° C in the dark for 16 hours, cooled to room temperature, and then extracted with ethyl acetate (50 mL of ethyl acetate was used for each extraction, and a total of 5 extractions were performed). The organic phase was collected and dried over anhydrous magnesium sulfate to obtain a crude product, and then the crude product was purified by column chromatography using a mixed solvent of n-hexane and ethyl acetate (the volume ratio of n-hexane to ethyl acetate was 8:1) as an eluent, and then vacuum dried to obtain 1.7 g of (denoted as compound 2; pale yellow solid, yield 64%);

[0066] 2) Synthesis of polymer 1:

[0067] 0.45 g (2.7 mmol) of compound 1 and 55 µL (0.09 mmol) of dibutyltin dilaurate (DBTDL) were dispersed in 1 mL of anhydrous N, N-dimethylformamide, and then stirred at 65 ° C for 7 h under argon protection. Then, a solution prepared by dispersing 0.52 g (1.8 mmol) of compound 2 in 0.1 mL of anhydrous N, N-dimethylformamide was added dropwise. After the addition, the mixture was stirred at 65 ° C for 16 h, cooled to room temperature, and then the reaction solution was added dropwise to excess icy ether for precipitation 3 times. Then, the mixture was centrifuged and the solid obtained by centrifugation was vacuum dried to obtain 0.25 g of (denoted as polymer 1, H2S-PTC, n=11; yellow solid, yield 45%);

[0068] 3) Synthesis of the final product:

[0069] 0.15 g (0.07 mmol) of polymer 1, 0.15 g (0.07 mmol) of carboxyl-terminated polyethylene glycol monomethyl ether (mPEG-COOH) with a number average molecular weight of 2000 g / mol, 28 mg (0.15 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and 18 mg (0.15 mmol) of 4-dimethylaminopyridine were dispersed in 1.5 mL of N,N-dimethylformamide. The mixture was stirred at room temperature under argon protection for 24 h. The solvent was then dried using a rotary evaporator and redissolved in 0.5 mL of N,N-dimethylformamide. The mixture was purified by gel column chromatography using N,N-dimethylformamide as the eluent and then dried in vacuum to obtain 0.18 g of polythiocarbamate (denoted as H2S-PTC-PEG; light yellow solid, yield 63%).

[0070] The synthetic reaction formula of polythiocarbamate is as follows:

[0071] .

[0072] Example 2:

[0073] A polythiocarbamate, the preparation method of which is as follows:

[0074] 1) Synthesis of polymer 2:

[0075] 0.45 g (2.7 mmol) of compound 1 (same as Example 1) and 110 μL (0.18 mmol) of dibutyltin dilaurate (DBTDL) were dispersed in 1 mL of anhydrous N, N-dimethylformamide, and then placed under argon protection at 85 ° C. and stirred for 12 h. Then, a solution prepared by dispersing 0.52 g (1.8 mmol) of compound 2 (same as Example 1) in 0.1 mL of anhydrous N, N-dimethylformamide was added dropwise. After the addition, the mixture was stirred at 85 ° C. and reacted for 24 h. After cooling to room temperature, the reaction solution was added dropwise to excess icy ether for precipitation three times, and then centrifuged. The solid obtained by centrifugation was vacuum dried to obtain 0.31 g of (denoted as polymer 2, H2S-PTC, n=17; yellow solid, yield 56%);

[0076] 2) Synthesis of the final product:

[0077] 0.15 g (0.07 mmol) of polymer 2, 0.15 g (0.07 mmol) of carboxyl-terminated polyethylene glycol monomethyl ether (mPEG-COOH) with a number average molecular weight of 2000 g / mol, 28 mg (0.15 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and 18 mg (0.15 mmol) of 4-dimethylaminopyridine were dispersed in 1.5 mL of N,N-dimethylformamide. The mixture was stirred at room temperature under argon protection for 24 h. The solvent was then dried using a rotary evaporator and redissolved in 0.5 mL of N,N-dimethylformamide. The mixture was purified by gel column chromatography using N,N-dimethylformamide as the eluent and then dried in vacuum to obtain 0.18 g of polythiocarbamate (denoted as H2S-PTC-PEG; light yellow solid, yield 71%).

[0078] Example 3:

[0079] A polythiocarbamate, the preparation method of which is as follows:

[0080] 1) Synthesis of polymer 3:

[0081] 0.45 g (2.7 mmol) of compound 1 (same as Example 1) and 55 μL (0.09 mmol) of dibutyltin dilaurate (DBTDL) were dispersed in 1 mL of anhydrous N, N-dimethylformamide, and then stirred at 50 ° C for 4 h under argon protection. Then, a solution prepared by dispersing 0.52 g (1.8 mmol) of compound 2 (same as Example 1) in 0.1 mL of anhydrous N, N-dimethylformamide was added dropwise. After the addition, the mixture was stirred at 50 ° C for 12 h, cooled to room temperature, and then the reaction solution was added dropwise to excess icy ether for precipitation 3 times. Then, the mixture was centrifuged and the solid obtained by centrifugation was vacuum dried to obtain 0.21 g of (denoted as polymer 3, H2S-PTC, n=6; yellow solid, yield 38%);

[0082] 2) Synthesis of the final product:

[0083] 0.15 g (0.07 mmol) of polymer 3, 0.15 g (0.07 mmol) of carboxyl-terminated polyethylene glycol monomethyl ether (mPEG-COOH) with a number average molecular weight of 2000 g / mol, 28 mg (0.15 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and 18 mg (0.15 mmol) of 4-dimethylaminopyridine were dispersed in 1.5 mL of N,N-dimethylformamide. The mixture was stirred at room temperature under argon protection for 24 h. The solvent was then dried using a rotary evaporator and redissolved in 0.5 mL of N,N-dimethylformamide. The mixture was purified by gel column chromatography using N,N-dimethylformamide as the eluent and then dried in vacuum to obtain 0.18 g of polythiocarbamate (denoted as H2S-PTC-PEG; light yellow solid, yield 55%).

[0084] Performance testing:

[0085] 1) Structural characterization:

[0086] a) The H NMR spectra of Compound 1, Compound 2, Polymer 1 and polythiocarbamate in Example 1 are as follows Figures 1 to 4 shown.

[0087] Depend on Figures 1 to 4 It can be seen that the average degree of polymerization (DP) of the polythiocarbamate in Example 1 is 11, that is, n=11, m=114.

[0088] b) Gel permeation chromatography (GPC) of polymers 1 to 3 in Examples 1 to 3 is shown in FIG. Figure 5 shown.

[0089] Depend on Figure 5 It can be seen that the molecular weights of polymers 1 to 3 with different polymerization degrees are uniform and stable.

[0090] 2) Preparation of nanoparticles:

[0091] a) Preparation of blank nanoparticles: 10 mg of the polythiocarbamate (H2S-PTC-PEG) prepared in Example 1 was dispersed in 1 mL of dimethyl sulfoxide (DMSO) and slowly added dropwise to 9 mL of ultrapure water. The mixture was stirred at room temperature for 3 h, then transferred to a dialysis bag (MWCO 3500) and dialyzed in ultrapure water for 24 h to remove DMSO, thereby obtaining H2S-responsive nanoparticles (denoted as SNPs).

[0092] b) Preparation of drug-loaded nanoparticles: 1 mg of H2S-responsive hemicyanine probe (p-Cy) or doxorubicin prodrug (p-DOX) was dispersed in 1 mL of dimethyl sulfoxide (DMSO), and 10 mg of the polythiocarbamate (H2S-PTC-PEG) described in Example 1 was added. After mixing, the mixture was slowly added dropwise to 9 mL of ultrapure water. The mixture was stirred at room temperature for 3 h, and then transferred to a dialysis bag (MWCO3500). The DMSO was removed by dialysis in ultrapure water for 24 h to obtain a nanoprobe (denoted as SNP) that specifically amplifies the H2S signal at the tumor site. p-Cy ) or nanoparticles (denoted as SNPs p-DOX The concentration of p-Cy or p-DOX was determined by detecting UV absorption at 590 nm and 480 nm using a multifunctional microwell assay plate analysis system.

[0093] 3) Responsiveness of nanoparticles:

[0094] Nanoparticle size changes: Nanoparticle SNP (0.02 mol / L) was incubated in PBS buffer or PBS buffer containing NaHS (sodium hydrosulfide, 2 mmol / L) for 24 h. The particle size changes of SNP under different conditions were tested. Figure 6 shown.

[0095] Depend on Figure 6 It can be seen that the nanoparticles SNP are uniform in size and well dispersed in PBS buffer, but after incubation with NaHS, the degradation of the polymer is triggered, resulting in the disaggregation of the nanoparticles SNP. The structure of the nanoparticles is completely destroyed and becomes irregular aggregates.

[0096] 4) Imaging effect experiment:

[0097] a) Nanoprobe SNP p-Cy Selectivity for different cells: SNPs observed by CLSM p-CyIntracellular fluorescence images after co-incubation with CT26 (H2S-rich tumor cells), Hepa 1-6 (H2S-deficient tumor cells), and L929 (fibroblasts). The test results are as follows: Figure 7 (Nanoprobe inSNP p-Cy As a control, inSNP p-Cy It refers to the nanoparticles formed by self-assembly of p-Cy encapsulated by non-responsive polythiocarbamate (Ctrl-PTC-PEG) prepared by replacing compound 2 with 4-methylbenzyl alcohol).

[0098] Depend on Figure 7 It can be seen that: p-Cy Co-incubated CT26 and Hepa 1-6 cells showed strong red fluorescence signals (CyOH), while the non-responsive control particles inSNP p-Cy In both CT26 and Hepa 1-6 cells, very weak fluorescence signals were observed, which were consistent with the SNP p-Cy The co-incubated normal cells L929 also showed weak fluorescence signals, indicating that SNP p-Cy It can specifically activate p-Cy in tumor cells.

[0099] b) Nanoprobe SNP p-Cy Distribution in the body and its NIR fluorescence imaging effect on tumors: Since colon cancer selectively upregulates the enzyme cystathionine-β-synthase (CBS), which produces H2S, the concentration of H2S is much higher than that in other tissues. Therefore, an in situ colon cancer model was constructed to investigate the SNP p-Cy The in vivo imaging capability of the mouse was investigated (SNP was injected into the tail vein of the mouse). p-Cy or inSNP p-Cy ), the test results are as follows Figure 8 shown.

[0100] Depend on Figure 8 It can be seen that: SNP p-Cy Colorectal tumors were clearly visualized, while fluorescence was barely detectable in other tissues; p-Cy Compared with mice treated with SNP p-Cy The fluorescence observed in very small colorectal tumors (about 2 mm) of mice with SNPs was stronger. p-Cy The fluorescence can be selectively restored at the tumor site, which has the potential to perform NIR fluorescence imaging of small tumors in mice.

[0101] 5) Treatment effect experiment:

[0102] a) Killing effect of nanoparticles on MCF-7 or MCF-7 / ADR cells: MCF7 cells, doxorubicin-resistant cells (MCF7 / ADR) or epithelial cells (HUVEC) were cultured with drug-loaded nanoparticles (SNPs) containing different DOX concentration gradients (0.025 μg / mL, 0.05 μg / mL, 0.1 μg / mL, 0.5 μg / mL, 1 μg / mL, 5 μg / mL, 10 μg / mL, 25 μg / mL, 50 μg / mL and 100 μg / mL). p-DOX or inSNP p-DOX ) were co-cultured for 24 h, and then the activity of tumor cells in each experimental group was detected by thiazole blue colorimetry (MTT method). The test results were as follows Figure 9 shown.

[0103] Depend on Figure 9 It can be seen that: SNP p-DOX It can effectively kill MCF7 and MCF7 / ADR cells, but shows low cytotoxicity in normal cells (HUVEC), indicating that SNP p-DOX Indeed, it is possible to selectively activate the prodrug in tumor cells and overcome MDR by upregulating H2S levels in tumor cells.

[0104] b) Mechanism of action of endogenous H2S elevation in MDR treatment: MCF-7 / ADR cells (1×10 5 cells / well) were seeded on a circular slide and p-DOX or inSNP p-DOX The cells were incubated with a medium containing 4 μg / mL DOX in the nanoparticles for 12 h, and the distribution of P-glycoprotein (P-gp) in MCF7 / ADR cells was observed by CLSM. The test results are shown in Figure 2. Figure 10 (Nanomedicine inSNP p-DOX As a control, inSNP p-DOX It refers to the nanoparticles self-assembled by p-DOX encapsulated by non-responsive polythiocarbamate (Ctrl-PTC-PEG) prepared by replacing compound 2 with 4-methylbenzyl alcohol).

[0105] Depend on Figure 10 It can be seen that: PBS group and inSNP p-DOX The P-gp of the group is mainly distributed on the cell membrane, while SNP p-DOX The P-gp of the group was mainly distributed in the cytoplasm, which may be due to the SNP p-DOX Amplifying H2S signals in MCF7 / ADR cells causes mitochondrial dysfunction, leading to insufficient ATP supply and interruption of P-gp transport to the cell membrane, indicating that SNP p-DOXThe induced H2S elevation can cause mitochondrial dysfunction and affect P-gp function.

[0106] c) In vivo anti-tumor therapy test: 15 NOD / SCID mice implanted with an orthotopic MCF-7 / ADR breast cancer model were selected. When the tumor volume reached 100 mm 3 Afterwards, the mice were randomly divided into 3 groups, with 5 mice in each group, and 100 μL of PBS, inSNP, and 100 μL of PBS were injected into the tail vein. p-DOX (5 mg / kg DOX, 100 µL) or SNP p-DOX The mice were treated with 5 mg / kg DOX (100 µL) every other day for a total of 5 times for a total of 22 days. During the entire treatment process, the tumor volume was measured with a vernier caliper every two days, and the weight changes of the mice in each experimental group were detected. The test results are shown in the figure below. Figure 11 and Figure 12 The formula for calculating tumor volume is as follows: Volume (mm 3 ) = 0.5 × length × width 2 .

[0107] Depend on Figure 11 It can be seen that: p-DOX Treated mice showed negligible tumor growth inhibition, likely due to the inSNP p-DOX The SNP group was unable to respond to H2S degradation and did not cause an increase in H2S levels, thus failing to overcome drug resistance and thus exhibiting a weaker inhibitory effect on tumor growth. p-DOX The tumor volume of mice in the treated group was significantly reduced.

[0108] Depend on Figure 12 It can be seen that: using SNP p-DOX The body weight of the treated mice was not significantly different from that of the other groups after treatment, which suggests that SNP p-DOX There is no obvious toxic side effect on mice, that is, polythiocarbamate has good biocompatibility.

[0109] In addition, the test found that the performance of the polythiocarbamates in Examples 2 and 3 was very close to that of the polythiocarbamate in Example 1.

[0110] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A polythiocarbamate, characterized in that The structural formula is: , where m is a natural number from 110 to 117, and n is a natural number from 6 to 17.

2. A method for preparing polythiocarbamate according to claim 1, characterized in that: The following steps are involved: 1) Nucleophilic substitution reaction of p-aminobenzyl alcohol and carbon disulfide to obtain , and then the nucleophilic aromatic substitution reaction of 4-hydroxybenzyl alcohol and 2,4-dinitrofluorobenzene was carried out to obtain ; 2) Conduct The self-polymerization reaction Carry out polycondensation reaction to obtain ; 3) Conduct The bonding reaction between the polyol and carboxyl-terminated polyethylene glycol monomethyl ether gives polythiocarbamate.

3. The preparation method according to claim 2, wherein: The molar ratio of p-aminobenzyl alcohol to carbon disulfide in step 1) is 1:8-12; the molar ratio of p-hydroxybenzyl alcohol to 2,4-dinitrofluorobenzene in step 1) is 1:0.5-1.

4. The preparation method according to claim 2 or 3, characterized in that: The nucleophilic substitution reaction in step 1) is carried out at room temperature for 1 to 2 hours; the nucleophilic aromatic substitution reaction in step 1) is carried out at a temperature of 50° C. to 70° C. for 12 to 24 hours.

5. The preparation method according to claim 2, wherein: The autopolymerization reaction in step 2) is carried out at a temperature of 50° C. to 85° C., and the reaction time is 4 h to 12 h. The polycondensation reaction in step 2) is carried out at a temperature of 50° C. to 85° C., and the reaction time is 12 h to 24 h.

6. The preparation method according to claim 2, wherein: Step 3) , and the molar ratio of carboxyl-terminated polyethylene glycol monomethyl ether is 1:0.9-1.

1.

7. The preparation method according to claim 2 or 6, characterized in that: Step 3) The bonding reaction is carried out at room temperature for 24 to 36 hours.

8. A drug carrier, characterized in that Contains the polythiocarbamate according to claim 1.

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