CN115120719B - Self-assembled nano-sheet for synergistic treatment of colon cancer and preparation method thereof - Google Patents
Self-assembled nano-sheet for synergistic treatment of colon cancer and preparation method thereof Download PDFInfo
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Abstract
The invention provides a self-assembled nano-sheet for cooperatively treating colon cancer and a preparation method thereof, wherein the self-assembled nano-sheet relies on noncovalent interaction force to carry out Cu 2+ 、As 5+ Combined with AOAA to form H 2 S-responsive self-assembled nano-sheets can achieve the aim of treating colon cancer to the greatest extent by changing the microenvironment of the colon cancer and triggering cooperative therapy; solves the problem of high concentration H of colon cancer 2 S, the curative effect is limited due to the microenvironment; solves the problems of poor clinical effect, obvious toxic and side effects and the like of the monotherapy of colon cancer; solves the problem of toxic and side effects caused by high distribution of arsenic trioxide normal tissues as an effective component of arsenic trioxide。
Description
Technical Field
The invention belongs to the field of preparation of nano-sheets in the field of medicines, and particularly relates to a self-assembled nano-sheet capable of adjusting the concentration of hydrogen sulfide in a colon cancer microenvironment and triggering cooperative treatment and a preparation technology thereof.
Background
High concentration hydrogen sulfide (H) 2 S) is one of main characteristics of colon cancer microenvironment, is a unique pathological biological disorder for treating various diseases, and plays a vital role in promoting tumor proliferation, creating an immunosuppressive microenvironment, protecting tumor cells from oxidative damage and the like. Thus, modulation of colon cancer high concentrations of H 2 S microenvironment, breaking the protective barrier, can increase the sensitivity of the tumor to the drug.
Arsenic oxide (ATO) is the active ingredient of white arsenic, and injection is approved as a first-line Chemotherapy (CT) medicament for acute promyelocytic leukemia, and the anti-tumor mechanism mainly comprises the functions of inhibiting cell proliferation, inhibiting invasion and metastasis and promoting apoptosis. However, the nonspecific nature of ATO makes it easy to cause toxic and side effects on normal tissues, severely affecting patient quality of life. Furthermore, ATO is often limited by tumor resistance, resulting in poor therapeutic efficacy. Studies have shown that the toxicity and efficacy of ATO are mainly related to the valence state of the arsenic element contained in ATO, trivalent arsenic (As 3+ ) Has significantly higher toxicity and therapeutic effect than pentavalent arsenic (As 5+ ). The in-situ activation of the drug system can reduce the toxic and side effects caused by poor drug distribution specificity, H 2 S As a strongly reducing gas, as can be contained in 5+ Reduction to As 3+ Realizing colon cancer part As 5+ To As 3+ Thereby reducing the toxic and side effects of ATO on normal tissues; the reduction process is accompanied by H 2 S content is reduced, and H is contained in the product 2 S scavenging effect.
Copper ion (Cu) 2+ ) Has strong powerIs capable of combining with H 2 S reaction, consumption of H 2 S and simultaneously generating stable product copper sulfide. Copper sulfide is used as a photo-thermal material, so that the photo-thermal material has high photo-thermal conversion efficiency, and hydrogen peroxide (H) 2 O 2 ) Converts into highly oxidized hydroxyl radicals (OH), generates ROS to induce apoptosis, and plays a role in chemo-kinetic therapy (CDT).
Consumption H 2 S is one of strategies for regulating the microenvironment of colon cancer, and can only reduce H within a certain time 2 S concentration, the key to solving this problem is the generation of H 2 S source. Amino oxyacetic acid (AOAA) is a widely used H 2 S-production inhibitor capable of inhibiting H by inhibiting cystathionine-beta-synthase (CBS) activity 2 And S, generating. But the hydrophilic nature of AOAA makes it limited in efficacy; at present, methyl ester or ethyl ester and other groups are often modified to improve the physical and chemical properties of the medicament so that the medicament can be better absorbed by cells, but the method still has the problems of non-target site effect, toxic and side effects and the like, and needs to be solved.
Therefore, we propose a strategy for regulating the microenvironment of colon cancer by 'two-consumption one-inhibition', and Cu is utilized 2+ And As 5+ Double consumption H 2 S, AOAA inhibits H 2 S generation, reducing H in colon cancer microenvironment 2 S concentration increases the sensitivity of colon cancer to drugs. Subsequently, as 5+ Quilt H 2 S in situ reduction to As 3+ The toxic and side effects on normal tissues are reduced, but ATO alone has the problem of drug resistance, so that the treatment effect is poor. Cu (Cu) 2+ And H 2 The S reaction product, copper sulfide, is capable of producing ROS to induce apoptosis, however, this ability is limited by H in the tumor microenvironment 2 O 2 Limiting the content; the high-efficiency photo-thermal conversion capability of copper sulfide can kill tumors through high temperature without using ROS; the therapies of the three different action mechanisms cooperate with each other to ablate the tumor to the greatest extent. Studies have shown that copper sulfide has good catalysis of H 2 O 2 Ability to generate ROS to increase therapeutic effects to a greater extent, it is effective to find a combination of drugs that further enhances ROS-generating abilityThe way. As As 3+ Can exert Chemotherapy (CT) to promote tumor cell apoptosis by generating Reactive Oxygen Species (ROS), and the combination of the two therapies can further increase ROS generation and kill tumor better. Photothermal therapy (PTT) is a therapeutic method for killing cancer cells by converting light energy into heat energy under irradiation of an external light source after injecting a material having high photothermal conversion efficiency into the inside of a human body. PTT can achieve the purpose of killing tumors without the help of ROS, thus being capable of eliminating residual tumors with ROS resistance; in addition, the method has good biological safety due to the minimally invasive treatment mode. Copper sulfide is known to not only produce ROS to kill tumors, but also be a good photothermal conversion material, and can exert PTT effect under the irradiation of near infrared laser.
Self-assembly is the process of associating individual units of material into an ordered structure. It imparts unique properties to inorganic and organic structures through non-covalent interactions. At present, the self-assembled nano material is widely applied in the fields of nano technology, imaging technology, biological sensor, biomedical science and the like due to the characteristics of simplicity, spontaneity, expandability, multifunction, low cost and the like.
Disclosure of Invention
Aiming at the defects of the prior art, the patent provides a novel preparation technology of self-assembled nano-sheets for adjusting the concentration of hydrogen sulfide in the microenvironment of colon cancer and triggering cooperative treatment, and the self-assembled nano-sheets rely on noncovalent interaction force to carry out Cu 2+ 、As 5+ Combined with AOAA to form H 2 S-responsive self-assembled nano-sheets can achieve the aim of treating colon cancer to the greatest extent by changing the microenvironment of the colon cancer and triggering cooperative therapy.
This patent includes the following:
a self-assembled nano-sheet for the synergistic treatment of colon cancer is prepared from Cu by non-covalent interaction force 2+ 、As 5+ And the Cu-As-AOAA self-assembled nano-sheet with uniform particle size is prepared by combining with the amino oxyacetic acid AOAA by adopting a hydrothermal method.
Preferably, the preparation method of the self-assembled nano-sheet for treating colon cancer comprises the following steps:
(1) Copper chloride (CuCl) 2 ·2H 2 O), disodium arsenate (Na) 2 HAsO 4 ·7H 2 O) and amino-oxyacetic acid (AOAA) are respectively dissolved in ultrapure water to obtain three solutions;
(2) Sequentially adding CuCl under stirring of ice water bath 2 、Na 2 HAsO 4 And AOAA solution, and obtaining mixed solution after the reaction is finished;
(3) And (3) placing the mixed solution in a high-pressure hydrothermal kettle, and carrying out solid-liquid separation after reacting for a certain time to obtain the Cu-As-AOAA self-assembled nano-sheet.
Preferably, the CuCl in the preparation method of the self-assembled nano-sheet for treating colon cancer 2 ·2H 2 O、Na 2 HAsO 4 ·7H 2 The mass ratio of O to AOAA is 0-20: 10 to 30:1, preferably 0 to 0: 10-20:1.
Preferably, cuCl in the preparation method of the self-assembled nano-sheet for treating colon cancer 2 The mass fraction of the solution is 0.4 to 0.8 percent (preferably 0.5 to 0.7 percent), na 2 HAsO 4 The mass fraction of the solution is 0.8-2% (preferably 1-1.8%) and the mass fraction of the AOAA solution is 0.01-0.1% (preferably 0.03-0.08%).
Preferably, in the step (2) of the preparation method of the self-assembled nano-sheet for treating colon cancer, the ice water bath temperature is 0-8 ℃, preferably 2-6 ℃.
Preferably, in the step (2) of the preparation method of the self-assembled nano-sheet for treating colon cancer, the reaction time is 10 to 50min, preferably 20 to 40min.
Preferably, in the step (3) of the preparation method of the self-assembled nano-sheet for treating colon cancer, the reaction time is 15-45 min, preferably 25-35 min.
Preferably, in the step (3) of the preparation method of the self-assembled nano-sheet for treating colon cancer, the reaction temperature is 160-200 ℃, preferably 170-190 ℃.
Preferably, in step (3) of the preparation method of the self-assembled nano-sheet for treating colon cancer, the solid-liquid separation mode can adopt a centrifugal mode or a filtering mode.
Preferably, in the preparation method of the self-assembled nano-sheet for treating colon cancer, in the step (1), the CuCl 2 ·2H 2 O、Na 2 HAsO 4 ·7H 2 The mass ratio of O to AOAA is 0-10: 10-20:1; the CuCl 2 The mass fraction of the solution is 0.5 to 0.7 percent, na 2 HAsO 4 The mass fraction of the solution is 1 to 1.8 percent and the mass fraction of the AOAA solution is 0.03 to 0.08 percent;
in the step (2), the temperature of the ice water bath is 2-6 ℃; the reaction time is 20-40 min;
in the step (3), the reaction time is 25-35 min; the reaction temperature is 170-190 ℃.
The product prepared by the invention can be characterized by a Transmission Electron Microscope (TEM), an Atomic Force Microscope (AFM), an ultraviolet visible near infrared absorption spectrometer, a thermal imager and an inductively coupled plasma spectrometer.
The self-assembled nano-sheet provided by the invention can regulate the micro-environmental hydrogen sulfide concentration of colon cancer and trigger synergistic treatment, and is used for preparing antitumor drugs. Cu by non-covalent interaction force 2+ 、As 5+ Combining with AOAA, preparing Cu-As-AOAA self-assembled nano-sheets with uniform particle size by a hydrothermal method, performing intravenous injection, and then passively targeting to tumor tissues in H 2 Activating under the action of S to achieve the purposes of improving the microenvironment of colon cancer and cooperatively treating colon cancer. The Cu-As-AOAA self-assembled nano-sheet prepared by the invention has uniform shape; has good H in vitro 2 S response characteristic, the reaction product has photo-thermal conversion effect and OH generation capability. The Cu-As-AOAA self-assembled nano-sheet can reduce H in the microenvironment of colon cancer 2 S concentration, the Cu-As-AOAA self-assembled nano-sheet has the potential of improving the microenvironment of colon cancer; the combination treatment of the Cu-As-AOAA self-assembled nano-sheet solution with proper concentration and 1064nm laser irradiation can kill more than 90% of colon cancer tumor cells, which proves that the Cu-As-AOAA self-assembled nano-sheet has excellent in-vitro synergistic anti-tumor effect.
The technology of this patentThe effect is that high concentration H of colon cancer is solved 2 S, the curative effect is limited due to the microenvironment; solves the problems of poor clinical effect, obvious toxic and side effects and the like of the monotherapy of colon cancer; solves the problem of toxic and side effects caused by high distribution of arsenic trioxide as an active ingredient of arsenic trioxide in normal tissues.
The innovation point of this patent is:
1. aiming at the problem of limited curative effect caused by the high-concentration hydrogen sulfide microenvironment of colon cancer, the invention provides a two-consumption one-inhibition concept, namely double consumption is combined with specificity to inhibit hydrogen sulfide, thereby achieving the purpose of regulating the high-concentration hydrogen sulfide microenvironment of colon cancer and improving the treatment effect of colon cancer;
2. aiming at the problem of narrow arsenic trioxide treatment window, the invention utilizes the characteristics of different arsenic ion valence states and different toxicity to generate high-toxicity trivalent arsenic in situ by means of the strong reducibility of high-concentration hydrogen sulfide in colon cancer microenvironment, thereby solving the problem of narrow arsenic trioxide treatment window;
3. the invention provides a Cu-As-AOAA self-assembly nano-sheet preparation technology, which is used for responsively activating chemotherapy, photothermal therapy and chemical kinetics therapy under the action of high-concentration hydrogen sulfide, so As to solve the problems of poor treatment effect of colon cancer monotherapy and the like.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the invention, and that other drawings can be obtained according to these drawings without inventive faculty for a person skilled in the art.
FIG. 1 is a diagram of a transmission electron microscope (A) and an atomic force microscope (B) of a Cu-As-AOAA self-assembled nano-sheet prepared by the method of the patent.
FIG. 2 is a transmission electron microscope image of a Cu-As-AOAA self-assembled nanoplatelet prepared by the method of the patent after reacting with sodium hydrosulfide (NaHS) for a certain time.
FIG. 3 shows the absorption change between 800 nm and 1200nm after the Cu-As-AOAA self-assembled nano-sheet prepared by the method reacts with NaHS with different concentrations for a certain time.
FIG. 4 shows the temperature change (1064 nm, 1W/cm) of the Cu-As-AOAA self-assembled nanoplatelets prepared by the method of the present patent after reacting with NaHS of different concentrations for a certain period of time 2 )。
FIG. 5 is a thermal image (1064 nm, 1W/cm) of a Cu-As-AOAA self-assembled nanosheets prepared by the method of this patent reacted with NaHS of different concentrations for a certain period of time 2 )。
FIG. 6 shows the OH formation ability (1. Cu-As-AOAA+0mM H) of the Cu-As-AOAA self-assembled nanoplatelets prepared by the method of the present patent after a certain time of reaction with NaHS 2 O 2 ；2.0.5mM H 2 O 2 ；3.Cu-As-AOAA+0.05mM H 2 O 2 ；4.Cu-As-AOAA+0.1mM H 2 O 2 ；5.Cu-As-AOAA+0.2mM H 2 O 2 and 6.Cu-As-AOAA+0.5mM H 2 O 2 )。
FIG. 7 shows arsenic release curves of Cu-As-AOAA self-assembled nanoplatelets prepared by the method of the patent after reaction with NaHS of different concentrations.
FIG. 8 shows the intracellular H of colon cancer after different time of action of the Cu-As-AOAA self-assembled nano-sheet prepared by the method of the patent 2 Laser confocal plot of S concentration change.
FIG. 9 shows cell viability after co-culturing Cu-As-AOAA self-assembled nanoplatelets with colon cancer cells at different concentrations before and after light treatment.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are illustrative of the present invention and are not intended to limit the present invention thereto.
Examples
1. Material
Copper chloride dihydrate (CuCl) 2 ·2H 2 O) and disodium arsenate (Na) 2 HAsO 4 ·7H 2 O) (Sigma Aldrich company, usa); amino oxyacetic acid (AOAA, beijing qi pine biology company, china); sodium hydrosulfide (NaHS, 68-72%, beijing Walker Biotechnology Co., ltd., china).
2. Method of
1. Preparation
300mg of Na 2 HAsO 4 ·7H 2 O、170mg CuCl 2 ·2H 2 O and 18mg of AOAA were dissolved in 25mL of ultrapure water, respectively. The 3 solutions were placed in a round bottom flask with vigorous stirring in an ice-water bath for 30min, then the mixed solution was transferred to a autoclave and reacted at 180℃for 30min. And after the reaction is finished, centrifuging for 3 to 4 times, and adding pure water for dispersion to obtain the Cu-As-AOAA self-assembled nano-sheet.
2. Characterization of
2.1 morphology observations before and after reaction with NaHS
The 50. Mu.L of Cu-As-AOAA solution was measured by a pipette and dropped on a silicon wafer, and the wafer was naturally dried and observed for thickness by AFM. The 50. Mu.L of Cu-As-AOAA and the reacted solution were respectively measured by a pipette and dropped on a copper mesh, and the copper mesh was dried at room temperature and then loaded, and the morphology was observed by TEM, and the results are shown in FIGS. 1 and 2.
2.2 UV-visible near-infrared absorption Change detection
A certain amount of Cu-As-AOAA solution was reacted with NaHS (0, 0.5, 1, 2, 3 mM) solutions with different concentrations, and the change of absorption intensity in the wavelength range of 800-1200nm was measured by an ultraviolet-visible-near infrared spectrometer, and the result is shown in FIG. 3.
2.3 photo-thermal Effect experiment
A quantity of Cu-As-AOAA solution was reacted with different concentrations of NaHS (0, 0.5, 1, 2, 3 mM) solution at 1W/cm using a 1064nm laser 2 The solution was irradiated for 5min, and the temperature change of the reacted solution was recorded with a thermal imager every 30s, and the results are shown in fig. 4 and 5.
2.4 determination of hydroxyl radical production ability
The ability of the product to generate hydroxyl radicals after the reaction of Cu-As-AOAA and NaHS was examined by 3,3', 5' -tetramethylbenzidine chromogenic method. Combining the Cu-As-AOAA solution with H 2 O 2 After the solution reacts for a certain time, 3', 5' -tetramethyl benzidine solution is added, and the absorption change condition is detected by an enzyme-labeled instrument, and the result is shown in figure 6.
2.5 in vitro Release experiments
The Cu-As-AOAA solution is placed in a dialysis bag, the dialysis bag is immersed in PBS release medium of NaHS (0, 1, 2 and 3 mmol/L), liquid outside the dialysis bag is sucked at a specific time point, the release medium is supplemented, and the concentration of arsenic ions is detected by adopting an inductively coupled plasma spectrum, and the result is shown in figure 7.
3. In vitro cytological evaluation
3.1 intracellular H of colon cancer 2 S content variation
Labelling of intracellular H with 7-azido-4-methylcoumarin 2 S, observing fluorescence change by a laser confocal microscope (CLSM), and investigating Cu-As-AOAA self-assembled nano-sheet H 2 S consumption capacity, the result is shown in fig. 8.
3.2 cytotoxicity
The killing effect of Cu-As-AOAA self-assembled nano-sheets with different concentrations on colon cancer cells is examined by adopting a CCK-8 method, the biological safety and in-vitro anti-tumor effect of the nano-particles are examined, and the result is shown in figure 9.
The results show that: the prepared Cu-As-AOAA self-assembled nano-sheet has uniform shape; has good H in vitro 2 S response characteristic, the reaction product has photo-thermal conversion effect and OH generation capability. The Cu-As-AOAA self-assembled nano-sheet can reduce H in the microenvironment of colon cancer 2 S concentration, the Cu-As-AOAA self-assembled nano-sheet has the potential of improving the microenvironment of colon cancer; the combination treatment of the Cu-As-AOAA self-assembled nano-sheet solution with proper concentration and 1064nm laser irradiation energy can kill more than 90% of colon cancer tumor cells, which proves that the Cu-As-AOAA self-assembled nano-sheet has excellent in-vitro synergistic anti-tumor effect.
In addition, the specific examples described in the present specification may differ in terms of the respective raw materials, the names of the processes, and the like. All equivalent or simple changes according to the principles of this patent concept are included in the scope of this patent. Those skilled in the art may make various modifications or additions to the described embodiments or substitutions in a similar manner without departing from the scope of the invention as defined in the accompanying claims.
Claims (8)
1. Synergistic treatment of colonThe cancer self-assembled nano-sheet is characterized in that: the self-assembled nano-sheet for cooperatively treating colon cancer uses non-covalent interaction force to make Cu 2+ 、As 5+ And the Cu-As-AOAA self-assembled nano-sheet is prepared by combining with the amino oxyacetic acid AOAA.
2. The method for preparing self-assembled nanoplatelets for the synergistic treatment of colon cancer according to claim 1, characterized by comprising the following steps:
(1) Copper chloride CuCl 2 ·2H 2 O, arsine disodium Na 2 HAsO 4 ·7H 2 O and the amino oxyacetic acid AOAA are respectively dissolved in ultrapure water to obtain 3 parts of solution;
(2) Sequentially adding CuCl under stirring of ice water bath 2 、Na 2 HAsO 4 And AOAA solution, and obtaining mixed solution after the reaction is finished;
(3) And (3) placing the mixed solution in a high-pressure hydrothermal kettle, and carrying out solid-liquid separation after reacting for a certain time to obtain the Cu-As-AOAA nano-sheet.
3. The method for preparing the self-assembled nano-sheet for the synergistic treatment of colon cancer according to claim 2, which is characterized in that: the CuCl 2 The mass fraction of the solution is 0.4 to 0.8 percent, na 2 HAsO 4 The mass fraction of the solution is 0.8-2% and the mass fraction of the AOAA solution is 0.01-0.1%.
4. The method for preparing the self-assembled nano-sheet for the synergistic treatment of colon cancer according to claim 2, which is characterized in that: in the step (2), the temperature of the ice water bath is 0-8 ℃; the reaction time is 10-50 min.
5. The method for preparing the self-assembled nano-sheet for the synergistic treatment of colon cancer according to claim 2, which is characterized in that: in the step (3), the reaction time is 15-45 min.
6. The method for preparing the self-assembled nano-sheet for the synergistic treatment of colon cancer according to claim 2, which is characterized in that: in the step (3), the reaction temperature is 160-200 ℃.
7. The method for preparing the self-assembled nano-sheet for the synergistic treatment of colon cancer according to claim 2, which is characterized in that: in the step (3), the solid-liquid separation mode may be a centrifugal mode or a filtration mode.
8. The method for preparing the self-assembled nano-sheet for the synergistic treatment of colon cancer according to claim 2, which is characterized in that:
in step (1), the CuCl 2 The mass fraction of the solution is 0.5 to 0.7 percent, na 2 HAsO 4 The mass fraction of the solution is 1 to 1.8 percent and the mass fraction of the AOAA solution is 0.03 to 0.08 percent;
in the step (2), the temperature of the ice water bath is 2-6 ℃; the reaction time is 20-40 min;
in the step (3), the reaction time is 25-35 min; the reaction temperature is 170-190 ℃.
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