CN110787303A - Pt-SR adduct of Pt and mercapto compound, preparation and application - Google Patents
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Abstract
An adduct Pt-SR of Pt and mercapto compounds, preparation and application thereof, relating to the field of antitumor drugs. Mixing the Pt salt solution with a compound containing sulfydryl to form a mixed solution; under the conditions of certain temperature and pH, carrying out redox reaction on the mixed solution system to reduce high-valence Pt ions in the Pt salt into Pt atoms or Pt low-valence ions, wherein the Pt acts on sulfydryl of a sulfydryl compound to form the adduct Pt-SR; the sulfhydryl group is selected from water-soluble or fat-soluble proteins, peptides, polysaccharides, oligosaccharides, polymers and other sulfhydryl-containing molecules. The Pt-SR adduct disclosed by the invention has broad-spectrum anti-tumor activity, is easy to remove by the kidney, and has lower toxic and side effects compared with carboplatin; can be accumulated in tumor tissues at high concentration, greatly enhances the chemotherapeutic effect of the tumor, and the like. Can be used for treating various solid tumors such as breast cancer, ovarian cancer, non-small cell lung cancer, gastric cancer, etc.
Description
Technical Field
The invention relates to the field of antitumor drugs, in particular to a Pt-SR adduct for tumor treatment, a preparation method thereof and therapeutic application of the adduct in tumor growth inhibition.
Background
At present, the treatment means based on cancer in China mainly comprises radiotherapy, chemotherapy, surgical resection, traditional Chinese medicine therapy and immunotherapy. Chemotherapy is still the clinically most important treatment at present. Cisplatin, as a clinical chemotherapeutic agent, has broad-spectrum antitumor activity and is widely applied to the treatment of various tumors, such as prostate cancer, ovarian cancer, lung cancer, gastric cancer and other solid tumors. But it is accompanied by serious toxic and side effects such as nausea and vomiting, neurotoxicity, acute kidney injury, gastrointestinal reaction and the like, which severely limit the clinical application of the medicine. Carboplatin is the second generation of antitumor drug which is marketed after cisplatin in the middle of the 80 th century, and has equivalent antitumor activity to cisplatin, high solubility and relatively good biological safety. However, the traditional view points that the detoxification of the anti-cancer drug mediated by sulfydryl has one of the biggest problems in the Pt anti-tumor drug physical therapy, and further leads to the problem that the platinum anti-tumor drug is inactivated in vivo. When the platinum antineoplastic drugs enter into the body, various sulfhydryl-containing proteins, polypeptides and other substances in the body, such as glutathione GSH, can form GSH-Pt adducts with Pt, so that the platinum antineoplastic drugs lose the pharmaceutical activity. Based on this academic point, no study has been reported on the synthesis of thiol adducts of platinum and its tumor growth-inhibiting effect.
Disclosure of Invention
In order to explore the synthesis method of a sulfydryl adduct of platinum and the effect of the sulfydryl adduct on inhibiting tumor growth, the invention provides a novel platinum antitumor drug, namely an adduct Pt-SR formed by Pt and a sulfydryl compound (R-SH).
An adduct of Pt and a mercapto compound Pt-SR, wherein the molecular composition (Pt) of said adduct Pt-SRx(SR)yX is 1-30, y is 1-20, the SR is from a mercapto compound, and Pt acts on S in the mercapto compound; the sulfhydryl compound is selected from water-soluble or fat-soluble protein, peptide, polysaccharide, oligosaccharide, polymer and other sulfhydryl-containing molecules.
The hydrated particle size of the adduct Pt-SR is 1-5 nm.
The preparation method of the Pt-SH adduct of Pt and a mercapto compound is characterized by comprising the following steps: mixing a soluble Pt compound solution with a mercapto compound to form a mixed solution, and enabling the mixed solution system to perform redox reaction under certain temperature and pH conditions, wherein Pt atoms act on the mercapto group of the mercapto compound to form the adduct Pt-SR; wherein the sulfhydryl compound is selected from water-soluble or fat-soluble proteins, peptides, polysaccharides, oligosaccharides, polymers and other sulfhydryl-containing molecules, such as Glutathione (GSH), Serum Albumin (SA).
Wherein the reaction temperature is 1-100 ℃, the pH condition is acidic, neutral or alkaline, and the pH condition can be adjusted and selected according to needs. When the pH condition is acidic, an acidic Pt compound can be adopted; when the pH is basic, it is adjusted with a base which generates OH-ions, for example NaOH or KOH.
In the mixed solution, the concentration of the sulfhydryl compound is 1 mu M-10M, and the concentration of the Pt compound is 1 mu M-8M.
Wherein the Pt compound is a tetravalent or divalent inorganic compound of Pt, such as salts and the like.
Wherein the Pt ions in the tetravalent Pt compound are reduced to Pt atoms or monovalent and divalent Pt ions; the Pt ions in the divalent Pt compound are reduced to Pt atoms or monovalent Pt ions.
And carrying out redox reaction on the mixed solution, stirring the mixed solution for 5-10 h at 1-100 ℃ after the color of the solution is changed, and dialyzing and purifying the mixed solution for 6-12 h by using a dialysis bag to obtain the Pt-SR adduct.
The application of the Pt-sulfydryl compound adduct Pt-SR is used for preparing antitumor drugs. The tumor includes but is not limited to breast cancer, ovarian cancer, non-small cell lung cancer, gastric cancer and other solid tumors.
The application of the Pt-SR adduct of Pt and mercapto compounds is used for preparing the medicine for inhibiting the growth of cancer cells.
The cancer cells include, but are not limited to, breast cancer cells, ovarian cancer cells, non-small cell lung cancer cells, gastric cancer cells and other cancer cells.
The Pt-SR adduct provided by the invention has a plurality of advantages when being used for treating tumors: has broad-spectrum anti-tumor activity and higher anti-tumor activity compared with carboplatin; is easy to be cleared by the kidney and has lower toxic and side effects compared with carboplatin; can be accumulated in tumor tissues to greatly enhance the chemotherapeutic effect of tumors, and the like. The Pt-SR adduct of the novel platinum antitumor drug can be used for treating various solid tumors such as breast cancer, ovarian cancer, non-small cell lung cancer, gastric cancer and the like.
Drawings
FIG. 1a is a high resolution transmission electron micrograph of a Pt-SR adduct according to example 1 of the present invention;
FIG. 1b is a DLS particle size distribution plot of a Pt-SR adduct of example 1 of the present invention;
FIG. 1c is a graph of the UV absorption spectrum of a Pt-SR adduct of example 1 of the present invention;
FIG. 1d is a graph of the fluorescence spectrum of a Pt-SR adduct of example 1 of the present invention;
FIG. 1e is an electrospray (ESI-MS) mass spectrum of a Pt-SR adduct of example 1 of the present invention;
FIG. 2a is a graph of a statistical analysis of the effect of the Pt-SR adduct of example 2 of the invention on 4T1 (breast cancer cell) survival. Carboplatin injections were used as controls.
FIG. 2b is a graph of a statistical analysis of the effect of the Pt-SR adduct of example 2 of the invention on 16HBE (human bronchial epithelial cell) survival. Carboplatin injections were used as controls.
FIG. 3a is a graph of the statistical analysis of tumor volume after treatment of breast cancer model mice with the Pt-SR adduct of example 3 of the present invention. Saline and carboplatin injections were used as controls.
FIG. 3b is a graph of the statistical analysis of the change in body weight of mice after treatment of breast cancer model mice with the Pt-SR adduct of example 3 of the present invention. Saline and carboplatin injections were used as controls.
FIG. 3c is a graph of statistical analysis of survival of mice after treatment of breast cancer model mice with the Pt-SR adduct of example 3 of the present invention. Saline and carboplatin injections were used as controls.
FIG. 4a is a graph showing the comparison of Pt content in each organ of a breast cancer model mouse treated with the Pt-SR adduct of example 4 of the present invention. Carboplatin injections were used as controls.
FIG. 4b is a graph showing the Pt content in the blood of mice, which are breast cancer model mice, treated with the Pt-SR adduct of example 4 of the present invention, respectively. Saline and carboplatin injections were used as controls.
Detailed Description
Exemplary embodiments that embody features and advantages of the invention are described in detail below in the specification. It is to be understood that the invention is capable of other embodiments and that various changes in form and details may be made therein without departing from the scope of the invention and the description and drawings are to be regarded as illustrative in nature and not as restrictive.
The invention provides a preparation method of an adduct (Pt-SR) formed by a novel platinum antitumor drug Pt and a sulfhydryl compound (R-SH) and antitumor application thereof, which comprises the steps of providing a Pt salt solution, and mixing the Pt salt solution with the sulfhydryl compound to form a mixed solution; under certain temperature and pH conditions, carrying out oxidation-reduction reaction on the mixed solution system to reduce high-valence Pt ions in the Pt salt into Pt atoms or low-valence platinum ions, wherein the Pt atoms or the low-valence platinum ions act on sulfydryl of a sulfydryl compound to form the adduct (Pt-SR); wherein the thiol-containing molecule is selected from water-soluble or fat-soluble protein, peptide, polysaccharide, oligosaccharide, polymer or other thiol-containing molecule.
Preferably, the mixed liquor system is subjected to a redox reaction by adding a base to the mixed liquor, which base can provide OH "ions, such as NaOH or KOH.
The sulfhydryl-containing compound can be water-soluble or fat-soluble protein, peptide, polysaccharide, oligosaccharide, polymer or other sulfhydryl-containing molecules, preferably protein or peptide, and the protein can be natural SA (serum albumin) or artificially synthesized protein; the peptide may be GSH (glutathione) of natural origin or artificially synthesized polypeptide. Cysteine (Cys) may also be used.
The Pt salt solution selected for use in the present invention may be a tetravalent Pt salt solution, such as H2PtCl6. Or other divalent Pt salt solutions, e.g. K2PtCl4And (3) solution. In the preparation process, the tetravalent Pt ions are reduced into Pt atoms or monovalent and divalent Pt ions, and the divalent Pt ions are reduced into Pt atoms or monovalent Pt ions.
The preparation method of the novel platinum antitumor drug Pt-SR adduct comprises the following steps:
mixing a Pt salt solution with a compound containing sulfydryl, and stirring for 3-10 min to ensure that the Pt salt and the compound are fully contacted to form a mixed solution; and adding an alkali solution into the mixed solution to adjust the pH value of the mixed solution so as to enable the system to generate an oxidation-reduction reaction, and continuously stirring for 5-10 hours at 1-100 ℃ after the color of the solution is changed to finally obtain the Pt-SR adduct.
Further, the synthesized Pt-SR adduct can be dialyzed and purified for 6-12 h by using a dialysis bag to remove unreacted alkali and unreacted Pt salt, and finally freeze-dried and concentrated for later use.
Wherein, the molar ratio of the Pt salt to the mercapto compound can be (0.1-1.1): (1.1-1.3), preferably 1: 1. the alkali used for adjusting the pH value can be NaOH or KOH, and the concentration of the alkali can be 0.4-0.6M. The concentration of the Pt salt solution may be 1. mu.M to 0.8M, for example 50 mM; the concentration of the mercapto compound solution may be 1. mu.M to 1M, for example 0.15M.
The hydrated particle size of the Pt-SR adduct (Pt-SR) prepared by the preparation method of the adduct formed by Pt and a mercapto compound (R-SH) is 1-5 nm, and each Pt-SR adduct has an accurate molecular composition (Pt)x(SR)yX is 1-30, y is 1-20, and the fluorescent material has a photoluminescence characteristic.
The preparation method of the Pt-SR adduct synthesizes the Pt-SR adduct by using hydrosoluble or liposoluble protein, polypeptide and other compounds containing sulfydryl as ligands, the synthesis method of one reduction method is simple, and the obtained Pt-SR adduct has higher stability and is particularly suitable for in vivo antitumor treatment.
In the invention, sulfhydryl-containing protein, polypeptide and other substances are selected as ligands to be directly adducted with Pt salt to form a sulfhydryl-Pt adduct. In addition, the properties of biocompatibility, water solubility, chemical stability, size and surface properties of the Pt-SR adduct can be independently designed and modified to meet the requirements of a particular biomedical application.
The novel platinum antitumor drug Pt-SR adduct disclosed by the invention has the following advantages when used for treating tumors: (1) has broad-spectrum anti-tumor activity and higher anti-tumor activity compared with carboplatin; (2) is easy to be cleared by the kidney and has lower toxic and side effects compared with carboplatin; (3) can be accumulated in tumor tissues, and greatly enhances the chemotherapeutic effect of the tumor.
The Pt-SR adduct of the novel platinum antitumor drug can be used for treating various solid tumors such as breast cancer, ovarian cancer, non-small cell lung cancer, gastric cancer and the like, but not limited to.
The Pt-SR adduct of the invention, its preparation and use are further illustrated by the following examples. Wherein the Pt compound used in the examples is tetravalent H2PtCl6(ii) a The sulfhydryl compound is BSA or GSH. Determining the morphology and the particle size of the Pt-SR adduct by adopting a high-resolution transmission electron microscope (HRTEM) and a dynamic light scattering instrument (DLS); characterizing absorption and fluorescence spectrum characteristics of the synthesized Pt-SR adduct by adopting an ultraviolet and fluorescence spectrometer; the synthesized Pt-SR adduct is detected by ESI-MS.
Example 1 Pt-SR adduct Pt6(GS)4Preparation of (1 mL) and 15.4mg of GSH were dissolved at room temperature, and 1mL of 50mM H was added2PtCl6And stirring the solution for 2-3 min in the dark until the color of the solution is changed from yellow to light yellow, and continuously stirring the formed solution for 10h at 80 ℃. Synthesized Pt6(GS)4Free metal ions as well as unreacted GSH were removed with a 500 cut-off dialysis bag. Synthetic Pt6(GS)4The red brown fluorescent material shows red brown color under visible light and green fluorescent light under ultraviolet light.
HRTEM showed synthesized Pt as shown in FIGS. 1a and 1b6(GS)4Ultra-small particle size, fractionThe dispersibility is good, the grain diameter is about 2nm, and the hydrated grain diameter measured by DLS is about 2.3 nm. The UV absorption spectrum shown in FIG. 1c shows pure H2PtCl6Has a strong absorption peak at 260nm, GSH has no absorption peak at 260nm, Pt6(GS)4The absorption at 260nm is reduced, which indicates that a new substance is successfully synthesized. In addition, once Pt is formed6GS4Formed, it will exhibit fluorescent characteristics. FIG. 1d shows the fluorescence spectrum of Pt6(GS)4There is a fluorescence emission peak at 544 nm. The ESI-MS mass spectrum of FIG. 1e shows that the three main peaks have m/z of 405.6,485.5,605.25, which are assigned to [ Pt ]6(GS)4+3Na++3H+]6-,[Pt6(GS)4+Na++4H+]5-，[Pt6(GS)4+Na++3H+]4The composition of the GSH-Pt compound is Pt which can be obtained from an ESI-MS mass spectrum6(GS)4。
Example 2, Pt6(GS)4Cytotoxicity assays for 4T1 (breast cancer cells) and 16HBE (normal human bronchial epithelial cells)
5000 cells/well 4T1 and 16HBE cells were seeded onto 96-well plates and cultured overnight. Followed by a series of concentrations (Pt)6(GS)4The amount concentration of the substance of (1) is 0. mu.M, 2. mu.M, 4. mu.M, 8. mu.M, 16. mu.M and 32. mu.M), respectively, of Pt6GS4And carboplatin were injected into the wells, and incubated with cells for 48h in the dark after dosing, with 5 parallel samples per group. After 48h incubation, wash 3 times with PBS and incubate 2h with 10% (v/v) cck-8 solution at 37 ℃. Finally, the absorbance at 450nm of each well was read using a microplate reader, and the cell survival rate was calculated. The results are shown in FIG. 2a, Pt6(GS)4The carboplatin and the carboplatin have obvious inhibition effect on the proliferation of the breast cancer cell 4T1, and the pharmaceutical activity is equivalent, and the Pt has the advantages that6(GS)4IC of5015 μ M carboplatin IC50＝14μM。Pt6(GS)4It also has good selectivity for cancer cells, as shown in FIG. 2b, Pt6(GS)4Has no obvious cytotoxicity to human bronchial epithelial cells within 32 mu M.
Example 3: pt6(GS)4In vivo biological function test of
Drug treatment experiments were performed using a nude mouse subcutaneous xenograft tumor model. 4T1 cells were first inoculated into the right leg of five-week old female BALB/c mice (5 x 10 per mouse)5Cells), approximately one week later, when the tumor size reaches 50-100mm3Treatment is initiated. Mice with a subcutaneous breast tumor model were randomly divided into three groups, i.e., saline group, carboplatin group and Pt prepared in example 16(GS)4Groups of 6 model mice each. Each group was administered tail vein with normal saline, carboplatin (2mg Pt/kg) and Pt every 3 days6(GS)4(2mg Pt/kg). Tumor volume and body weight were monitored every 3 days. The treatment lasted 21 days. Tumor volume was calculated by the following formula: tumor volume is length × width/2.
FIG. 3a shows Pt6GS4The composition can well inhibit tumor growth, and the pharmaceutical activity is equivalent to the drug effect of clinical carboplatin. FIG. 3b shows Pt6(GS)4The weight of the nude mice in the group is not obviously reduced compared with the normal saline group, which indicates that the nude mice have relatively excellent biological safety. FIG. 3c shows Pt compared to carboplatin6(GS)4Can obviously prolong the survival time of the breast cancer model mouse. Taken together, the above results illustrate that we prepared Pt6GS4Has better anti-tumor activity compared with carboplatin, can effectively inhibit the proliferation of breast tumor, and has very low biological toxicity. (differential assay level set as P<0.05 (double-sided). times.P<0.01，***P<0.001，P<0.05 the difference was considered to be of particular statistical significance. )
Example 4: distribution of Pt content in each tissue and organ of nude mice.
At the end of treatment, major organs (including heart, liver, spleen, lung, kidney and tumor) were excised from the sacrificed mice. The tissue was dried using a lyophilizer. After weighing the mass of the freeze-dried tissue, 3mL nitric acid (67%) and 1mL hydrogen peroxide were added to each of these samples overnight. Thereafter, 1mL of nitric acid (67%) and 3mL of hydrochloric acid (37%) were added theretoOvernight, then digestion was performed again. Finally, it was diluted to final volume with mixed acid (2% HNO3 and 1% HCl). The saline group, carboplatin group, and Pt prepared in example 1 were then assayed by ICP-MS6(GS)4Pt content in the group samples.
FIG. 4a shows that Pt is distributed in various tissues and organs (including heart, liver, spleen, lung, kidney and tumor). By comparing carboplatin with Pt6(GS)4Accumulation ability in tumor was found in Pt6GS4The tumor uptake is obviously higher than that of carboplatin, and Pt is injected6(GS)4The uptake of murine tumors was almost 2.5 times that of carboplatin injected, probably due to Pt6(GS)4Has a greater tumor accumulation effect. In addition, Pt6(GS)4There is a high accumulation in the kidney, mainly due to the ultra-small Pt6(GS)4Clearance is via the kidneys. FIG. 4b shows that Pt6(GS)4The Pt content in the blood of the treated mice was lower than that of the carboplatin-treated mice, indicating that Pt is present6(GS)4Can be rapidly metabolized in the blood and transported to the tissue. The above description shows Pt6(GS)4The antitumor activity is obviously better than that of carboplatin, and the toxicity is low.
Example 5 preparation of Pt-SR adduct (BSA-Pt) 216mg BSA (bovine serum albumin) was dissolved in 5.8mL water at room temperature, stirred to dissolve completely and then added to 0.8mL 50mM H2PtCl6And stirring the solution for 2-3 min in the dark, then dropwise adding 0.4mL of 1M NaOH solution to adjust the pH value of the mixed solution to 12, and continuously stirring at room temperature for 2 h. The synthesized BSA-Pt was ultrafiltered with a cut-off of 3000 ultrafiltration tubes to remove free metal ions.
The characterization data and the application data of example 5 are similar to those of example 1, and the description thereof is omitted.
The preparation method of the Pt-SR adduct takes water-soluble or fat-soluble protein or peptide and other substances as templates to prepare the Pt-SR adduct with ultra-small particle size and good biocompatibility. The substances such as sulfhydryl protein or polypeptide and the like are directly added with Pt salt, and the obtained Pt-SR adduct avoids the problem that other platinum drugs are inactivated in vivo due to the detoxification effect of sulfhydryl-mediated anticancer drugs. And the Pt-SR adduct can be accumulated in a tumor site and then excreted through the kidney due to the ultra-small particle size, and has better antitumor activity and biological safety compared with carboplatin. The synthesized Pt-SR adduct can be used for treating various solid tumors such as breast cancer, ovarian cancer, non-small cell lung cancer, gastric cancer and the like.
Unless otherwise defined, all terms used herein have the meanings commonly understood by those skilled in the art.
The described embodiments of the present invention are for illustrative purposes only and are not intended to limit the scope of the present invention, and those skilled in the art may make various other substitutions, alterations, and modifications within the scope of the present invention, and thus, the present invention is not limited to the above-described embodiments but only by the claims.
Claims (10)
1. An adduct of Pt and a mercapto compound Pt-SR, wherein the molecular composition (Pt) of said adduct Pt-SRx(SR)yWherein x is 1 to 30 and y is 1 to 20, the SR is derived from a mercapto compound, and Pt acts on S in the mercapto compound.
2. Pt-SR adduct of Pt with a mercapto compound according to claim 1, characterized in that the mercapto compound is selected from water-or fat-soluble proteins, peptides, polysaccharides, oligosaccharides, polymers and other mercapto-containing molecules.
3. The Pt-SR adduct of Pt and a mercapto compound according to claim 1 or 2, wherein the hydrated particle size of the adduct Pt-SR is 1 to 5 nm.
4. A process for the preparation of the Pt-SR adduct of Pt with a mercapto compound according to any one of claims 1-3, comprising the steps of: and mixing a soluble Pt compound solution with a mercapto compound to form a mixed solution, and under the conditions of certain temperature and pH, enabling the mixed solution system to perform redox reaction, wherein the Pt atoms act on the mercapto group of the mercapto compound to form the adduct Pt-SR.
5. The method according to claim 4, characterized in that the sulfhydryl compound is selected from the group consisting of water-soluble or fat-soluble proteins, peptides, polysaccharides, oligosaccharides, polymers and other sulfhydryl-containing molecules, preferably Glutathione (GSH), Serum Albumin (SA), cysteine (Cys).
6. The method according to claim 4, wherein the reaction temperature is 1 to 100 ℃, and the pH condition is acidic, neutral or alkaline; when the pH condition is acidic, an acidic Pt compound can be adopted; when the pH is alkaline, the pH is adjusted by using a base which can generate OH-ions.
7. The method according to claim 4, wherein the mercapto compound is present at a concentration of 1 μ M to 10M and the Pt compound is present at a concentration of 1 μ M to 8M in the mixed solution.
8. The method according to claim 4, wherein the Pt compound is a tetravalent or divalent inorganic compound of Pt, such as a salt, etc.; wherein the Pt ions in the tetravalent compound are reduced to Pt atoms or monovalent and divalent Pt ions; the Pt ions in the divalent compound are reduced to Pt atoms or monovalent Pt ions.
9. The method according to claim 4, wherein the mixed solution undergoes redox reaction, after the color of the solution is changed, the solution is stirred for 5-10 h at 1-100 ℃, and dialyzed and purified for 6-12 h by a dialysis bag to obtain the Pt-SR adduct.
10. Use of the Pt-SR adduct of Pt with a mercapto compound as described in any one of claims 1-3 for the preparation of an anti-tumor drug, or for the preparation of a drug for inhibiting the growth of cancer cells; the tumors include but are not limited to breast cancer, ovarian cancer, non-small cell lung cancer, gastric cancer and other solid tumors; the cancer cells include, but are not limited to, breast cancer cells, ovarian cancer cells, non-small cell lung cancer cells, gastric cancer cells and other cancer cells.
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