Preparation and application of nano-catalyst for interfering colorectal cancer formic acid metabolism
By preparing AuPd@GO@PVP nanocatalysts, using its ability to catalyze formic acid degradation, the problems of formic acid metabolism driven invasion and metastasis in colorectal cancer are solved, and efficient treatment of colorectal cancer is achieved.
Patent Information
- Application Number
- CN202411923796.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-25
- Publication Date
- 2025-05-13
AI Technical Summary
In colorectal cancer, Floranula acts on invasion and metastasis of cancer cells by secreting formic acid. The prior art is difficult to effectively inhibit formic acid metabolism, making it difficult for cancer to control.
By synthesizing gold-palladium alloy nanoparticles and loading them on a graphene oxide support, the biocompatible material PVP is modified, and AuPd@GO@PVP nanocatalyst can be prepared, which can efficiently catalyze formic acid degradation at room temperature and pressure, generate hydrogen, and inhibit the invasion and metastasis of cancer cells.
This nanocatalyst can effectively inhibit the invasion and metastasis of colorectal cancer induced by formic acid. At the same time, the hydrogen produced has a reductive killing effect on cancer cells, achieving efficient treatment of colorectal cancer.
Smart Images
Figure CN119972062A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of biomedicine technology and relates to drugs for treating colorectal cancer, and in particular to a nanocatalyst for treating colorectal cancer and a preparation method thereof. Background Art
[0002] Colorectal cancer (CRC) is a type of cancer with high morbidity and mortality, which seriously threatens human life and health. One of the main causes of death from CRC is its easy invasion and metastasis. Studies have shown that the intestinal microbiome is closely related to the occurrence, development, invasion and metastasis of CRC. Isolated intestinal microorganisms have been shown to induce changes in CRC genetic genes and microenvironment, leading to rapid proliferation and metastasis of cancer cells. It is worth noting that Fusobacterium nucleatum in colorectal cancer can trigger AhR signaling by secreting the metabolite formic acid, further driving CRC tumor invasion and increasing cancer stemness. Therefore, consuming and degrading formic acid in colorectal cancer has important research significance for inhibiting the development and invasion of colorectal cancer and achieving efficient treatment of colorectal cancer.
[0003] Formic acid dehydrogenation is a common technology used in industry to produce hydrogen. Usually, formic acid (HCOOH) is degraded into hydrogen (H2) and carbon dioxide (CO2) under specific conditions. With the help of specific catalysts, formic acid is efficiently catalytically decomposed at room temperature and pressure. Recently, Jiang Qing et al. constructed a series of solid-phase catalysts for heterogeneous catalytic formic acid dehydrogenation by loading single / bimetallic nanoparticles on amino-modified graphene oxide substrates. By regulating the element ratio between bimetallic nanoparticles and the structure-activity relationship between bimetallic and graphene oxide, a formic acid hydrogen production catalyst with excellent performance can be obtained. Therefore, if the industrial formic acid dehydrogenation technology can be used for the catalytic degradation of formic acid in colorectal cancer, it is expected to effectively inhibit the utilization of formic acid, a metabolite of Fusobacterium nucleatum, by colorectal cancer cells, thereby inhibiting the invasion and metastasis of colorectal cancer. At the same time, the hydrogen produced by the catalytic degradation of formic acid is also expected to break the redox homeostasis of colorectal cancer cells, produce a reductive therapeutic killing property on colorectal cancer cells, and further inhibit their occurrence and development. Summary of the invention
[0004] Based on an innovative strategy of interfering with the formic acid metabolism of colorectal cancer, the present invention constructs a nanocatalyst that interferes with the formic acid metabolism of colorectal cancer, which is used to catalyze the degradation of formic acid in the colorectal rectum, inhibit the invasion and metastasis of colorectal cancer, and simultaneously achieve efficient reductive hydrogen therapy for colorectal cancer cells.
[0005] The technical idea of the present invention is as follows: a novel AuPd@GO@PVP nanocatalyst is prepared by synthesizing a certain ratio of gold-palladium alloy and loading it on a graphene oxide carrier, and modifying PVP with good biocompatibility. The nanocatalyst can efficiently catalyze the degradation of formic acid at room temperature and pressure to generate carbon dioxide and hydrogen. At the cellular level, the nanocatalyst AuPd@GO@PVP can efficiently inhibit the invasion and metastasis of colorectal cancer induced by formic acid, and the hydrogen generated can achieve efficient reductive killing of colorectal cancer cells, ultimately achieving efficient treatment of colorectal cancer.
[0006] Based on the above research, the technical solution to be protected by the present invention is as follows:
[0007] In a first aspect, the present invention provides a method for preparing a nanocatalyst for interfering with formic acid metabolism in colorectal cancer, comprising the following steps:
[0008] A. Preparation of AuPd@GO Nanocatalyst
[0009] The dispersant was added to a 1-2 mg / mL graphene oxide aqueous solution, and the graphene was completely dispersed by ultrasound at room temperature. The same concentrations of tetrachloroauric acid trihydrate (HAuCl4·3H2O) and sodium chloropalladate (Na2PdCl4) were added to the mixture, and after stirring, a freshly prepared sodium borohydride (NaBH4) aqueous solution was added dropwise to the mixed solution. After stirring for a certain period of time, the product was centrifuged and washed with pure water several times to obtain a black solid named AuPd@GO.
[0010] Preferably, the dispersant is selected from 3-aminopropyltriethoxysilane APTS, and the volume ratio of APTS to graphene oxide is 2-5:200-400;
[0011] The initial concentrations of tetrachloroauric acid trihydrate and sodium chloropalladate were both 0.02 M, the volume ratio to the graphene solution was 1:12, and the stirring time after addition was 2 min; the initial concentration of sodium borohydride was 100 mM, the volume ratio to the graphene solution was 1:10-40, and the stirring time after addition was 30 min.
[0012] B. Biocompatibility modification
[0013] Five times the mass of biocompatible material (polyvinyl pyrrolidone PVP) was added to a 0.1 g / mL AuPd@GO aqueous solution and stirred for reaction for 24 h. Finally, it was centrifuged and washed to obtain a PVP-modified catalyst named AuPd@GO@PVP.
[0014] In a second aspect, the present invention provides a nanocatalyst for interfering with formic acid metabolism in colorectal cancer, which is prepared by the method described above.
[0015] The new nanocatalytic drug was characterized by TEM and SEM, and the hydrated particle size of the catalyst AuPd@GO@PVP before and after catalyzing formic acid was detected using a nanoparticle Zeta potential instrument. The results showed that the graphene surface was a metal nanoparticle with a particle size of 2.3nm, indicating that the AuPd alloy was successfully loaded; the hydrated particle size of AuPd@GO@PVP was smaller than that of AuPd@GO, indicating that the dispersion of AuPd@GO@PVP in water was better than that of AuPd@GO.
[0016] The third aspect of the present invention provides the use of the nanocatalyst that interferes with formic acid metabolism in colorectal cancer in the preparation of drugs for treating colorectal cancer.
[0017] In a specific embodiment of the present invention, nanocatalysts with different concentration gradients (0.05, 0.1, 0.2 mg / mL) were used to catalyze formic acid (5mM, 10mM, 20mM), and the results showed that the ultraviolet absorption peak of formic acid gradually decreased with the catalysis time, indicating that AuPd@GO@PVP had a catalytic effect on formic acid; the results at the cellular level showed that the nanocatalytic drug AuPd@GO@PVP had a certain inhibitory effect on the invasion and metastasis of colorectal cancer induced by formic acid.
[0018] In a fourth aspect, the present invention provides a drug for treating colorectal cancer, comprising an active component and a pharmaceutically or immunologically acceptable excipient, wherein the active component is the above-mentioned nanocatalyst that interferes with formic acid metabolism in colorectal cancer.
[0019] The pharmaceutically acceptable excipients described in the present invention refer to additives commonly used in the pharmaceutical field other than active ingredients, such as diluents (starch, sugar, cellulose and inorganic salts), excipients, etc., fillers such as starch sucrose, binders such as water, ethanol, cellulose derivatives, gelatin and polyvinyl pyrrolidone, disintegrants such as dry starch, sodium carboxymethyl starch, solubilizers such as polysorbates and polyoxyethylene fatty acid esters, etc., absorption promoters, surfactants such as Tween and Span, adsorption carriers, lubricants such as magnesium stearate, micro-powder silica gel, etc. In addition, other excipients such as flavoring agents, sweeteners, etc. can also be added to the composition.
[0020] In terms of administration, the drug can be administered to patients who need such treatment in the form of a pharmaceutical composition by oral administration, nasal inhalation, rectal administration, parenteral administration or transdermal administration. When used for oral administration, it can be made into conventional solid preparations such as tablets, powders, granules, capsules, pills, sustained-release pellets, solid dispersions, inclusion compounds, etc., and liquid preparations such as suspensions, emulsions, melts, syrups, mixtures, solutions, etc. When used for parenteral administration, it can be made into solutions for injection, water or oily suspensions, emulsions, liposomes, microcapsules, microspheres, nanoparticles, etc., and can also be made into various sustained-release and controlled-release preparations. The preferred form is injection, and injections with targeted release at specific sites are particularly preferred.
[0021] Preferably, the drug combination can also be used in combination with other drugs for treating colorectal cancer.
[0022] When the drug of the present invention is administered to animals including humans, the dosage varies depending on the patient's age and weight, disease characteristics and severity, and route of administration. The results of animal experiments and various circumstances can be referred to, and the total dosage cannot exceed a certain range.
[0023] Functions and Effects of the Invention
[0024] The present invention successfully prepares a preparation method of a new type of nanocatalytic drug for efficiently treating colorectal cancer that can interfere with formic acid metabolism and a formic acid catalysis process, which has the following advantages and characteristics: 1. The raw materials are cheap and easily available, the reaction conditions are mild, the synthesis steps are few, the synthesis time is short, and the product treatment is simple; 2. The catalytic conditions for catalyzing formic acid by the new type of nanocatalytic drug are mild, the catalytic efficiency is high, and the stability is good; 3. The AuPd@GO@PVP nanocatalyst with a concentration of 0.2 mg / mL can completely catalyze formic acid with a concentration of 20 mM within 90 minutes; the nanocatalyst can interfere with the metabolism of formic acid in colorectal cancer, realize the rapid degradation of formic acid in colorectal cancer tumors, and produce reducing hydrogen; the purpose of inhibiting the invasion and metastasis of colorectal cancer and efficiently killing colorectal cancer cells is achieved, and it has the advantages of high catalytic efficiency, strong catalytic stability and high killing efficiency. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) images of the nanocatalyst in Example 1 are shown.
[0026] Figure 2 A diagram showing the hydrated particle size of the novel nanocatalytic drug in Example 1 is shown.
[0027] Figure 3The ability of AuPd@GO@PVP nanocatalyst to catalyze the release of hydrogen from different contents of formic acid (5mM, 10mM, 20mM) at different concentrations (0.05mg / mL, 0.1mg / mL and 0.2mg / mL) analyzed by gas chromatography in Example 2 is shown.
[0028] Figure 4 The inhibitory effect of nanocatalytic drug AuPd@GO@PVP on formic acid-induced colorectal cancer invasion and metastasis was shown by cellular level study. DETAILED DESCRIPTION
[0029] The present invention is described in detail below in conjunction with the embodiments and the accompanying drawings. However, the following embodiments should not be considered as limiting the scope of the present invention.
[0030] Example 1: Preparation and characterization of novel nanocatalytic drug AuPd@GO@PVP
[0031] (1) Preparation of AuPd@GO nanoparticles: First, 3-aminopropyltriethoxysilane APTS (0.4 mL) was added to an aqueous solution of graphene oxide GO (1.43 mg / mL, 30 mL) and ultrasonicated at room temperature 25 °C until the graphene was completely dispersed. Then, tetrachloroauric acid trihydrate (HAuCl4·3H2O) (0.02 M, 2.5 mL) aqueous solution and sodium chloropalladate (Na2PdCl4) (0.02 M, 2.5 mL) aqueous solution were added to the above mixture and magnetically stirred. Freshly prepared NaBH4 (100 mM, 1 mL) was added to the above mixed solution and magnetically stirred. The black AuPd@rGO product was obtained by washing with water several times.
[0032] (2) Preparation of AuPd@GO@PVP: Add 5 times the mass of polyvinyl pyrrolidone (PVP) to the AuPd@GO aqueous solution (0.1 g / ml), stir, and react for 24 h. Then, centrifuge and wash to obtain the PVP-modified catalyst AuPd@GO@PVP.
[0033] (3) The novel nanocatalytic drug obtained in the above steps was subjected to TEM and SEM characterization tests; similarly, the hydration particle size of the catalyst AuPd@GO@PVP before and after catalyzing formic acid was detected using a nanoparticle size Zeta potential instrument.
[0034] Electron microscopy results can be found in Figure 1 : A is the TEM of graphene oxide loaded with metal nanoparticles; B is the SEM of graphene oxide loaded with metal nanoparticles, showing that the graphene surface is metal nanoparticles with a particle size of 2.3 nm, indicating that the AuPd alloy is successfully loaded.
[0035] Figure 2The hydrated particle size diagram of the novel nanomedical catalytic drug AuPd@GO@PVP in Example 1 is shown. The results show that the hydrated particle size of AuPd@GO@PVP is smaller than that of AuPd@GO, indicating that the dispersibility of AuPd@GO@PVP in water is better than that of AuPd@GO.
[0036] Example 2 AuPd@GO@PVP has excellent formic acid degradation ability
[0037] The prepared AuPd@GO@PVP catalyst (0.1-0.2 mg / mL) was added into a flask with formic acid (FA) and sodium formate solution (10 mM, 100-200 μL) respectively at a temperature of 25-40 °C, and the hydrogen (H2) produced by the reaction was monitored by gas chromatograph.
[0038] Using UV-visible spectrophotometer, the changes in the UV absorption of AuPd@GO@PVP nanocatalytic drugs with different concentrations (0.05 mg / mL, 0.1 mg / mL and 0.2 mg / mL) to different contents of formic acid (FA) (5 mM, 10 mM, 20 mM) at different time points were analyzed, and the reaction kinetics were statistically analyzed. The final results are shown in the attached figure. Figure 3 As shown: (AC) The UV absorption of formic acid (5mM, 10mM, 20mM) catalyzed by AuPd@GO@PVP with a concentration of 0.05mg / mL at different time points; (DF) The UV absorption of formic acid (5mM, 10mM, 20mM) catalyzed by AuPd@GO@PVP with a concentration of 0.1mg / mL at different time points; (GI) The UV absorption of formic acid (5mM, 10mM, 20mM) catalyzed by AuPd@GO@PVP with a concentration of 0.2mg / mL at different time points. It shows that the UV absorption peak of formic acid gradually decreases with the catalytic time, indicating that AuPd@GO@PVP has a catalytic effect on formic acid.
[0039] Example 3 AuPd@GO@PVP has an inhibitory effect on the growth of colorectal cancer cells induced by formic acid
[0040] Different concentrations of AuPd@GO@PVP (0.2 mg / mL, 0.1 mg / mL, 0.05 mg / mL, 0.025 mg / mL, 0.0125 mg / mL, 0.00625 mg / mL, 0.003125 mg / mL and 0.0015625 mg / mL) were added to HT29 colorectal cancer cells, and the inhibitory effect on the growth of HT29 cells was studied.
[0041] The results are as follows Figure 4As shown, after adding AuPd@GO@PVP material to HT29 colorectal cancer cells, the proliferation of HT29 cells was inhibited, with a certain concentration dependence. This shows that the nanocatalytic drug AuPd@GO@PVP has an inhibitory effect on the growth of colorectal cancer cells induced by formic acid.
[0042] The basic principles, main features and significant advantages of the present invention have been described in detail above. The purpose of the description in the embodiments and the specification is only to further explain the operating principle of the present invention. Without violating the core idea of the present invention and the statutory protection scope, the present invention allows and covers all kinds of reasonable changes and improvements. These changes and improvements will be deemed to be within the scope of protection requested by the present invention. Specifically, the scope of protection of the present invention will be clearly and strictly defined by the attached claims and their equivalents with equal legal effect.
Claims
1. A method for preparing a nanocatalyst for interfering with formic acid metabolism in colorectal cancer, characterized in that: The steps include: A. Preparation of AuPd@GO Nanocatalyst The dispersant was added to the graphene oxide aqueous solution, and the graphene was completely dispersed by ultrasound. The same concentrations of tetrachloroauric acid trihydrate (HAuCl4·3H2O) and sodium chloropalladate (Na2PdCl4) were added to the above mixture, and after stirring, the freshly prepared sodium borohydride (NaBH4) aqueous solution was added dropwise to the above mixed solution. After stirring for a certain period of time, the product was centrifuged and washed with pure water for several times to obtain a black solid, named AuPd@GO. B. Biocompatibility modification An excess amount of biocompatible material was added to the AuPd@GO aqueous solution, and the reaction was stirred for 24 h. Finally, the solution was centrifuged and washed to obtain a biocompatible modified nanocatalyst.
2. The method for preparing the nanocatalyst for interfering with formic acid metabolism in colorectal cancer according to claim 1, characterized in that: in, In step A, the concentration of graphene oxide is 1-2 mg / mL; The dispersant is selected from 3-aminopropyltriethoxysilane APTS, and the volume ratio of APTS to graphene oxide is 2-5:200-400; The graphene oxide dispersion is carried out at room temperature.
3. The method for preparing the nanocatalyst for interfering with formic acid metabolism in colorectal cancer according to claim 1, characterized in that: in, In step A, the initial concentrations of tetrachloroauric acid trihydrate and sodium chloropalladate were both 0.02 M, the volume ratio to the graphene solution was 1:12, and the stirring time after addition was 2 min; The initial concentration of sodium borohydride is 100 mM, the volume ratio of sodium borohydride to the graphene solution is 1:10-40, and the stirring time after addition is 30 min.
4. The method for preparing the nanocatalyst for interfering with formic acid metabolism in colorectal cancer according to claim 1, characterized in that: in, In step B, the biocompatible material is selected from polyvinylpyrrolidone (PVP); During the modification, 5 times the mass of PVP was added to the AuPd@GO aqueous solution and stirred for reaction for 24 hours; finally, centrifuged and washed to obtain a PVP-modified catalyst, named AuPd@GO@PVP.
5. The method for preparing the nanocatalyst for interfering with formic acid metabolism in colorectal cancer according to claim 4, characterized in that: in, The concentration of AuPd@GO aqueous solution was 0.1 g / mL.
6. A nanocatalyst for interfering with formic acid metabolism in colorectal cancer, characterized in that: The method is prepared by any one of claims 1 to 5.
7. Use of the nanocatalyst for interfering with formic acid metabolism in colorectal cancer as claimed in claim 6 in the preparation of drugs for treating colorectal cancer.
8. A drug for treating colorectal cancer, characterized in that: The invention comprises an active component and pharmaceutically or immunologically acceptable auxiliary materials, wherein the active component is the nanocatalyst for interfering with formic acid metabolism of colorectal cancer as claimed in claim 6.
9. The drug for treating colorectal cancer according to claim 8, characterized in that: This treatment is used in combination with other colorectal cancer treatments.