CN114272388A - Composite material based on two-dimensional nano carbon sheet and preparation and application thereof - Google Patents
Composite material based on two-dimensional nano carbon sheet and preparation and application thereof Download PDFInfo
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Abstract
The invention relates to a composite material based on a two-dimensional carbon nano-sheet, and preparation and application thereof, and belongs to the technical field of nano-materials. Calcining the eutectic polymer in a vacuum environment to deiodinate and carbonize the eutectic polymer to obtain a layered carbide, crushing the layered carbide, adding the crushed layered carbide into an aqueous solution of an amphiphilic polymer, and performing ultrasonic treatment to obtain the two-dimensional nano carbon sheet. Adding the two-dimensional carbon nano-sheets and montmorillonite into a phosphate buffer solution, and carrying out ultrasonic treatment to enable the two-dimensional carbon nano-sheets and montmorillonite to form a composite material through pi-pi stacking. The nano composite material can perform chemical kinetic treatment by converting high-level expressed hydrogen peroxide into high-activity hydroxyl radicals in a weak acid tumor microenvironment, and combines photo-thermal treatment generated by the nano composite material under the illumination of a near-infrared region II. In addition, the nanocomposite material shows magnetic resonance imaging and photoacoustic imaging capabilities for guiding tumor therapy. The imaging and the treatment capability are combined, and an integrated treatment and diagnosis platform is established for precise medicine.
Description
Technical Field
The invention belongs to the technical field of nano materials, and particularly relates to a composite material based on a two-dimensional nano carbon sheet, and preparation and application thereof.
Background
Photothermal therapy is a new treatment mode, and due to the advantages of no wound, negligible drug resistance, low systemic toxicity and the like, the research on tumor diseases is becoming a focus, and most of the reported photothermal therapy preparations at present, including gold nano-materials, metal sulfide oxide materials, carbon nano-materials, organic dyes and the like, mainly carry out photothermal therapy in the near-infrared I region (700-. However, for deep solid tumor tissues, the penetration depth of light in the near infrared i region is still insufficient due to severe light attenuation caused by absorption and scattering of light by blood and other biological components. Therefore, photothermal therapeutic formulations with longer wavelengths in the near infrared region II (1000-1700 nm) are of more interest, with deeper tissue penetration, less energy loss, and less tissue damage. Photothermal therapy agents, on the other hand, generally have good photoacoustic imaging capabilities. Compared with the near infrared I region, the near infrared II region photothermal therapeutic preparation can greatly improve the signal to noise ratio and provide higher resolution morphological information, so that the near infrared II region photothermal therapeutic preparation is more beneficial to cancer diagnosis and treatment.
In recent years, carbon nanomaterials (e.g., graphene, carbon dots, carbon nanotubes) have attracted much attention in biomedical applications due to their advantages, such as photostability, biocompatibility, and low toxicity. Among them, two-dimensional carbon nanomaterials are considered as promising photothermal agents due to their excellent plasma characteristics in the near infrared region. The unique quantum confinement around the conduction and valence band edges promotes a high density of energy generation, so that free electron-hole pairs are more easily excited by energy close to the band gap, resulting in a two-dimensional nanomaterial exhibiting high light absorption efficiency. In addition, the two-dimensional carbon nano-material can adjust the optical performance by changing the number of layers or doping other heteroatoms. The large surface area and planar structure of two-dimensional carbon nanomaterials makes it possible to load other drugs or form heterostructures by stacking with other two-dimensional materials, which offers great potential for synergistic therapies based on photothermal therapy. However, current two-dimensional material synthesis methods focus primarily on top-down and bottom-up methods, which suffer from low yields and complex procedures, respectively. Simple and reliable preparation of two-dimensional nanocarbon materials with controllable size, shape and purity remains challenging. In addition, most of the carbon nanomaterials reported so far support near-infrared region i photothermal therapy, and the development of carbon-based photothermal therapeutic agents having good performance in the near-infrared region ii window is urgent for further tissue treatment.
Disclosure of Invention
The invention solves the technical problems that in the prior art, the photothermal treatment effect of a near-infrared region I is poor, the preparation of a two-dimensional carbon material is difficult, the imaging effect cannot effectively guide treatment, and the biocompatibility is poor. The novel two-dimensional carbon nano-sheet is obtained by vacuum calcination of the conjugated carbon-iodine polymer, shows strong absorption and remarkable photothermal conversion efficiency in a near-infrared II-region biological window, and can be used for deep tissue treatment.
According to a first aspect of the present invention, there is provided a method for preparing a two-dimensional nanocarbon sheet, comprising the steps of:
(1) calcining the eutectic polymer in a vacuum environment, wherein the calcining is carried out for 6-24 h at the temperature of 300-1000 ℃ so as to deiodinate and carbonize the eutectic polymer and obtain layered carbide; the structural formula of the eutectic polymer is as follows:
(2) and (2) crushing the layered carbide obtained in the step (1), adding the crushed layered carbide into an aqueous solution of an amphiphilic polymer, and performing ultrasonic treatment to obtain the two-dimensional carbon nano-sheet.
Preferably, the heating rate of the calcination is 5 ℃ min-1-15℃min-1。
Preferably, the hydrophobic end of the amphiphilic polymer is an alkyl chain with 10 or more carbon atoms, and the hydrophilic end is polyethylene glycol.
According to another aspect of the invention, the two-dimensional carbon nano-sheet prepared by any one of the methods is provided.
According to another aspect of the invention, there is provided the use of the two-dimensional nanocarbon sheets, in particular for the preparation of photothermal therapeutic agents and/or photoacoustic imaging agents.
According to another aspect of the invention, a preparation method of a composite material of two-dimensional nanocarbon sheets is provided, wherein the two-dimensional nanocarbon sheets and montmorillonite are added into phosphate buffer solution and subjected to ultrasonic treatment, and the two-dimensional nanocarbon sheets and montmorillonite form the composite material through pi-pi stacking.
Preferably, the mass ratio of the two-dimensional nanocarbon chips to the montmorillonite is 1 (0.5-2).
According to another aspect of the invention, the two-dimensional nano carbon sheet composite material prepared by the method is provided.
According to another aspect of the invention, the application of the composite material of the two-dimensional nano carbon sheet in preparing a photoacoustic imaging agent and/or a magnetic resonance imaging agent is provided.
According to another aspect of the invention, the application of the composite material of the two-dimensional nano carbon sheet is provided, in particular the application of the composite material for preparing a photothermal treatment agent and/or a chemical dynamic treatment agent.
Generally, compared with the prior art, the above technical solution conceived by the present invention mainly has the following technical advantages:
(1) the invention synthesizes a novel two-dimensional carbon nano sheet with strong absorptivity and 34.6 percent high photothermal conversion efficiency in a near-infrared II-region biological window, and is beneficial to deep tissue photothermal therapy. In order to improve the dispersibility and biocompatibility of the two-dimensional carbon nano-flake, the layered nano-clay montmorillonite and the amphiphilic polymer are utilized to derive the stable nano-composite aqueous solution. Montmorillonite can be used for chemodynamic treatment by releasing iron under tumor acidic microenvironment to catalyze highly expressed hydrogen peroxide to generate highly active hydroxyl radicals. To upregulate the hydrogen peroxide levels, glucose oxidase was introduced into the system to further facilitate the chemo-kinetic treatment process. In addition, the nano composite material shows good photoacoustic imaging and magnetic resonance imaging capabilities, and can help determine the accurate time point with the highest drug accumulation for efficient laser treatment with low side effect. The efficient near-infrared II-region light-activated photothermal therapy and continuous long-acting chemical dynamic therapy combined treatment based on the nano composite material can effectively inhibit tumor growth under the guidance of magnetic resonance imaging and photoacoustic imaging. Therefore, the design strategy of the nano composite material provides a new idea for establishing an integrated diagnosis and treatment platform for multi-mode diagnosis and treatment of tumors.
(2) The photothermal effect of the existing organic material is mainly reflected in a near-infrared region I, and the photothermal conversion efficiency is relatively low, so that the actual photothermal effect of the organic material on deep tumors in a living body is severely limited. The novel nano carbon sheet synthesized by the method can be used for photo-thermal treatment through 34.6% of high photo-thermal conversion efficiency under the light irradiation of a near-infrared II region 1060nm, and the application range of the organic nano material in the field of photo-thermal treatment is greatly expanded.
(3) Photothermal therapy, as a single therapeutic means, still has disadvantages in some aspects, such as limited killing ability against internal and deep tumors under effective power, and the light dependence makes it impossible to continuously inhibit tumor growth. The invention combines the two-dimensional carbon sheet with the two-dimensional layered montmorillonite to obtain the nano composite material, can realize the synergistic treatment of photothermal treatment and chemical power treatment, combines the high-efficiency short-term tumor killing of the photothermal treatment with the long-acting tumor inhibition of the chemical power treatment, simultaneously can improve the corresponding chemical power treatment effect by the photothermal treatment of local photothermal, can solve the problem of deep residual tumor of the photothermal treatment and can more effectively inhibit the tumor growth by the chemical power treatment.
(4) The photoacoustic imaging and magnetic resonance imaging are combined, so that repeated injection of various contrast agents can be avoided, accurate positioning of tumors before treatment can be realized, drug distribution is tracked in the treatment process, the curative effect is determined after treatment, and accurate dual treatment under the guidance of accurate dual imaging can be realized.
(5) Montmorillonite is an FDA approved biological material and is widely applied to the field of pharmacy. The toxicity of montmorillonite is often due to its surface negative charge which limits its further use in vivo. The nano carbon sheet serving as a pure carbon material has good biocompatibility, and simultaneously shields strong negative charges of montmorillonite in the composite material, so that the defect that the montmorillonite easily causes hemolysis is overcome, and a foundation is provided for the safety of subsequent biological application.
Drawings
FIG. 1 is a diagram of nanocomposite preparation and performance characterization.
Fig. 2 is a graph for verifying the photothermal conversion efficiency and the hydroxyl radical generating ability of the nanocomposite.
FIG. 3 is a chart of in vitro combination anti-cancer effect verification of photothermal therapy and chemokinetic therapy.
Fig. 4 is a graph showing the effect of in vivo drug tracking by magnetic resonance imaging and photoacoustic imaging techniques.
FIG. 5 is a graph demonstrating the combined in vivo anticancer effects of photothermal therapy and chemokinetic therapy.
Fig. 6 is a graph of in vivo bio-safety verification of nanocomposites.
Figure 7 is the preparation of the nanocomposite and its application in photoacoustic/magnetic resonance bimodal imaging to guide photothermal/chemokinetic synergistic cancer treatment.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The invention relates to the first successful preparation of non-additional doped two-dimensional carbon materials with absorption in the near infrared II region. In order to improve the dispersibility and biocompatibility of the two-dimensional nano carbon sheet, the stable nano composite material is obtained by utilizing the montmorillonite which is widely used at present as a drug carrier and the amphiphilic polymer C18-PMH-PEG. Montmorillonite is an FDA approved biological material and is widely applied to the field of pharmacy. It is a two-dimensional layered aluminosilicate mineral, and various cations such as iron, manganese and the like are filled in interlayer space of montmorillonite. Therefore, the montmorillonite can convert hydrogen peroxide highly expressed in a tumor part into high-activity hydroxyl radicals in a weak-acid tumor microenvironment through Fenton reaction. To facilitate the chemokinetic therapeutic process, glucose oxidase was introduced to further up-regulate the hydrogen peroxide levels. Therefore, the nano composite material can not only carry out high-efficiency photothermal treatment under 1060nm light irradiation by high photothermal conversion efficiency of 34.6%, but also release iron from montmorillonite, and generate high-activity hydroxyl radicals through Fenton reaction to continue the treatment. This combination of efficient tumor ablation with near-infrared zone ii activated photothermal therapy and sustained inhibition of chemokinetic therapy provides a promising strategy for more effective cancer treatment. In addition, the nano composite material shows magnetic resonance imaging and photoacoustic imaging capabilities in tumor diagnosis, and an integrated therapeutic diagnosis platform is established for precise medicine.
Preparation of a PIDA eutectic and C18-PMH-PEG: the PIDA eutectic is synthesized from 1, 4-bis (trimethylsilyl) -1, 3-diacetylene, and the C18-PMH-PEG is synthesized from poly (maleic anhydride)-alt-1-octadecene) with mNH2PEG synthesis.
The PIDA co-crystal and its synthesis method are described in patent application No. 202111441503.9.
The reaction formula for the PIDA eutectic synthesis is as follows:
the synthesis method comprises the following steps:
a. adding iodine-substituted ethylene diyne shown in a formula 1 and a ligand shown in a formula 2 into methanol, ethanol or isopropanol, wherein the ligand and the iodine-substituted ethylene diyne are regularly arranged to form an intermediate shown in a formula 3;
b. in the formula 3, iodine atoms on iodine substituted ethylene diyne and pyridine group nitrogen atoms at the tail end of a ligand in the formula 2 are topologically polymerized through halogen bonds to obtain a conjugated carbon iodine polymer with a structure shown in a formula I;
preferably, in the step a, the iodine-substituted ethylene diyne shown in the formula 1 and the ligand shown in the formula 2 are added into methanol, ethanol or isopropanol, and then are placed at the temperature of-30 to-10 ℃ for 5 to 10 days, and then are placed at the temperature of 10 to 30 ℃ for 5 to 12 hours.
In some embodiments, the carbonized derivative is prepared from a PIDA eutectic: 200 mg of the PIDA eutectic were placed in a tube furnace. Heating from room temperature to 600 deg.C in vacuum (heating rate: 10 deg.C for min)-1). The temperature was maintained at 600 ℃ for 12 hours and allowed to cool to room temperature. Gray black layered carbide is obtained.
Preparing carbon nano sheets: 20 mg of the carbonized derivative was pulverized into powder in a mortar. The product was added to 10mL of deionized water containing 20 mg of C18-PMH-PEG. The mixture was sonicated in an ice bath for 4 hours with a sonicator (650W, 60%). The black suspension was lyophilized and resuspended to the corresponding concentration before each use.
Preparing a nano composite material: 20 mg of carbon nanosheets and 10 mg of montmorillonite were added to 10ml of phosphate buffer. After the sample was sonicated in an ice bath for 4h, 10mL of nanocomposite was obtained.
The application of the two-dimensional carbon nanocrystallines is based on that the two-dimensional carbon nanocrystallines can generate a photothermal effect under the illumination of a near-infrared region II, and is particularly used for preparing a photothermal treatment reagent and/or a photoacoustic imaging reagent.
The composite material of the two-dimensional nano carbon sheet is applied to preparation of photoacoustic imaging reagents and/or magnetic resonance imaging reagents.
The application of the composite material of the two-dimensional carbon nanochannel is that the composite material based on the two-dimensional carbon nanochannel can generate a photothermal effect under the illumination of a near-infrared region II, and the composite material of the two-dimensional carbon nanochannel can convert hydrogen peroxide into hydroxyl radicals through Fenton reaction, and is particularly the application for preparing a photothermal treatment reagent and/or a chemical kinetic treatment reagent.
Example 1: nanocomposite preparation and Performance characterization
The invention uses N1，N2The (E) -bis (2- (pyridine-3-yl) ethyl) oxamide is used as a main body, the diiodo diacetylene monomer is used as an object, and the PIDA eutectic is obtained through topochemical polymerization. The formed eutectic appears metallic, is well aligned and highly polymerized. Iodine atoms directly attached to a conjugated carbon skeleton are prone to shedding under various stimuli (lewis base, temperature). Studies have shown that the loss of the iodine substituent begins at 120 ℃ and that evaporation of the bulk occurs in the temperature range of 150 ℃ to 170 ℃. The present invention therefore attempts to remove the bulk and iodine atoms by heating the eutectic to different temperatures. The carbonization process of the PIDA eutectic was monitored by energy dispersive spectroscopy and raman spectroscopy. The chemical formula of the PIDA eutectic is (C)4I2·C16H18N4O2) n is the same as the formula (I). Elemental analysis of the PIDA eutectic by energy dispersive spectroscopy indicated the presence of carbon (42.9 wt%), nitrogen (10.3 wt%), oxygen (6.0 wt%) and iodine (40.8 wt%), consistent with the PIDA eutectic theory (40.0% carbon, 9.3% nitrogen, 5.3% oxygen, and 42.3% iodine) (a in fig. 1). After 12 hours of heat treatment in a vacuum environment, the carbon content of the PIDA eutectic gradually increased while the iodine content decreased with increasing temperature (a in fig. 1). When the temperature reached 600 ℃, negligible iodine was detectedAnd element, which reflects the complete deiodination and carbonization process of the PIDA at the temperature.
Raman spectra of the PIDA eutectic show three main bands: are respectively 960cm-1(C-C)、1394cm-1(C ═ C) and 2053cm-1(C ≡ C) (B in FIG. 1). When the temperature of the PIDA eutectic crystal is higher than 300 ℃, the temperature is 1340cm-1(disordered sp)2D band of hybridized carbon) and 1600cm-1Two broad peaks (of the G band of graphitic carbon) appear due to the sp of carbon2Hybridization is carried out. As the heating temperature increased, the ratio of the D band and the G band increased, indicating a disordered rise in the carbonized product. In addition, the X-ray diffraction results also reflect the decrease in the crystal characteristics of the PIDA eutectic during carbonization (C in fig. 1). Fourier transform infrared spectroscopy of the PIDA eutectic and the carbonized derivative also confirmed that the PIDA eutectic was fully carbonized at 600 ℃.
According to Scanning Electron Microscope (SEM) images, the carbonized derivatives exhibited a multilayer layered structure. Next, the layered carbonized derivative was pulverized into two-dimensional nanocarbon sheets by treatment with strong ultrasonic waves in an ethanol solution. The obtained carbon nanoflakes showed a circular structure with a diameter of about 40 nm (D in fig. 1) and an average height of about 4nm (E, F in fig. 1), showing a unique and uniform wafer morphology. Carbon nanoflakes disperse well in ethanol solutions, but tend to aggregate in aqueous solutions. Thus, polyethylene glycol grafted poly (maleic anhydride-alt-1-octadecene) (C18-PMH-PEG), an amphiphilic surfactant, was introduced to stabilize the carbon nanoplatelets in water and obtain a relatively stable aqueous nanocomposite solution. Transmission electron microscopy images of the carbon platelets showed that the diameter of the carbon nanoflakes encapsulated in C18-PMH-PEG micelles was about 200nm (G in FIG. 1). In order to further improve the biological application of the compound in vivo, the popular drug carrier montmorillonite is used for improving the dispersibility and biocompatibility of the two-dimensional carbon nanosheet. Montmorillonite is a highly dispersible two-dimensional layered aluminosilicate with various cations, such as iron (3.31%), filled in the interlayer spaces of montmorillonite. The layered montmorillonite has large specific surface area and can be used for loading two-dimensional carbon nano-flakes to form a two-dimensional-two-dimensional composite. The nanocomposite loaded with carbon nanoflakes and modified with C18-PMH-PEG had larger diameters of about 300 nanometers (H and I in fig. 1). The two-dimensional carbon nanosheets adsorb to the surface of the two-dimensional montmorillonite sheet and form nanoclusters (H in fig. 2). Furthermore, the toxicity of montmorillonite is often due to its negative surface charge which limits its use in vivo. The zeta potential result shows that the carbon sheet shields the strong negative charge of the montmorillonite and provides a foundation for the safety of subsequent biological application. Notably, the nanocomposites exhibited the best dispersion and stability in various solutions compared to water, phosphate buffered saline, 0.9% NaCl solution, 1640 medium, and fetal bovine serum.
Example 2: photothermal conversion efficiency and hydroxyl radical generating ability of nanocomposite
The two-dimensional carbon nanoflakes carbonized by PIDA showed stronger absorption in the near-infrared i region and near-infrared ii region (a in fig. 2) compared to common carbon nanomaterials such as graphene oxide. B and C in FIG. 2 study of carbon sheets and nanocomposites at 1064nm laser irradiation (1.5W cm)-2) The photothermal heating curves of the following different concentrations. Both carbon sheets and nanocomposites exhibit significant concentration-dependent photothermal effects, where temperature changes are directly proportional to sample concentration. The photothermal performance of the nano composite material is consistent with that of the carbon sheet, and the photothermal performance of the carbon nano sheet is not influenced by the introduction of the montmorillonite. In contrast, the conventional graphene oxide shows no photothermal effect under the same 1064nm laser irradiation condition. Furthermore, the photothermal properties of the carbon nanoflakes are also determined by the laser power. The photothermal conversion efficiency of the carbon sheet calculated by the heating-cooling process of the carbon sheet under 1064nm laser irradiation is 34.6%, which shows that the carbon sheet has excellent photothermal performance under near-infrared II region irradiation. The stronger the laser power, the greater the temperature change. In addition, the nanocomposites showed good photothermal stability in the heating-cooling cycling test (D in fig. 2), indicating that carbon nanoflakes have good prospects for photothermal therapy. The invention compares the photo-thermal conversion capability of the nano composite material in biological tissues under 808nm (near infrared I region) and 1064nm laser (near infrared II region) respectively. Bacon was used to evaluate the relative attenuation ratio of 1064nm laser and 808nm laser, and was modeled as having no attenuationThe tumor tissue of the same layer (each layer having a thickness of 3 mm) is shown as E in fig. 3. For bacon penetrating the same thickness, the 808nm laser showed a more pronounced photothermal effect attenuation (E in fig. 2) than the 1064nm laser, indicating that the nanocomposite was more effective in photothermal treatment under 1064nm (near infrared region II) excitation than under 808nm (near infrared region I) excitation.
Because iron ions exist in interlayer space of montmorillonite, under a slightly acidic tumor microenvironment, the nanocomposite generates high-activity hydroxyl radicals through Fenton reaction. Here, 3,3',5,5' -tetramethyl-benzidine (TMB) was used to evaluate the generation of hydroxyl radicals, since colorless TMB can be oxidized to blue oxide (oxTMB), with a corresponding increase in absorbance at 650 nm. The present invention evaluates the peroxidase catalytic performance of nanocomposites by the classical TMB-hydroperoxide two substrate method (F in figure 2). As the concentration of the nanocomposite increases, the peroxidase activity of the nanocomposite also increases. It should be noted that in a weakly acidic environment (pH 6.5), the nanocomposite can generate more hydroxyl radicals than in a neutral solution, making it more selective for tumor cells in a weakly acidic tumor microenvironment. The above results indicate that the nanocomposite has great potential in chemokinetic therapy.
Due to the good photothermal conversion capability and the presence of iron ions of the nanocomposite, photoacoustic signals and magnetic resonance responses were detected. Both montmorillonite and nanocomposite showed concentration dependent magnetic resonance response (G in fig. 2). However, no magnetic response signal was detected in the carbon flake solution, confirming that the magnetic signal was from montmorillonite. In addition to the magnetic resonance imaging effect provided by montmorillonite, the carbon nanosheets in the nanocomposite material also provide excellent photoacoustic imaging effect in the near infrared ii region (H in fig. 2). The combination of photoacoustic imaging and magnetic resonance imaging capabilities allows for tracking of drug locations and guiding therapy with imaging, ultimately achieving a desired "integrated" therapeutic diagnostic platform.
Example 3: combined in vitro anticancer effect of photothermal therapy and chemokinetic therapy
Considering the good properties of the nanocompositeThe efficiency of photothermal conversion and the ability of generating hydroxyl radicals, and the chemodynamic/photothermal treatment effect of the cells are further evaluated by in vitro mouse prostate cancer cells (RM-1) and Human Umbilical Vein Endothelial Cells (HUVEC). As shown in A in FIG. 3, montmorillonite-PEG reached even 200. mu.g mL-1Is not toxic to normal tissue cells, whereas with increasing montmorillonite-PEG concentration, significant toxicity to cancer cells is observed. The selective killing ability of montmorillonite on cancer cells is due to highly expressed hydrogen peroxide levels in tumor cells, which promotes the fenton reaction, thereby generating more hydroxyl radicals. As expected, the chemo-kinetic therapeutic effect of montmorillonite-PEG on RM-1 cells was significantly enhanced as the hydrogen peroxide concentration was increased. Glucose oxidase (GOx) can catalyze glucose into gluconic acid and simultaneously generate hydrogen peroxide, so that the content of the hydrogen peroxide can be effectively improved by introducing the glucose oxidase. The experimental results show that the chemodynamic therapeutic effect of montmorillonite-PEG is obviously enhanced after the glucose oxidase is added (B in figure 3).
For photothermal therapy, carbon sheets induced RM-1 cell death in a dose-dependent and laser power-dependent manner under 1064nm laser irradiation (C in fig. 3). The photo-induced cytotoxicity of the nanocomposite material on RM-1 cells was significantly enhanced over the carbon sheet, reflecting the highly synergistic effect of the combination of photothermal and chemokinetic treatments on killing cancer cells (D in fig. 3). The cell viability of the nanocomposite-treated RM-1 cells was further reduced by about 20% (E in fig. 3) by adding glucose oxidase again, showing a more potent anti-tumor capacity. The hemolysis experiment proves that the montmorillonite can cause obvious hemolysis effect due to strong negative charges on the surface, and the two-dimensional nano carbon sheet can not cause hemolysis. The nanocomposite material combining both also did not cause hemolysis, showing good biosafety (F in fig. 3). In order to reveal the mechanism of action of the chemokinetic treatment in the nanocomposite material in vitro, the intracellular reactive oxygen species level was detected using a typical reactive oxygen species detection fluorescent probe, 2',7' -dichlorodihydrofluorescein diacetate (DCFH-DA). The PBS, PBS + Light, and carbon plate groups showed no fluorescence in RM-1 cells, indicating no reactive oxygen species generated by Light or carbon. While the smectite-containing groups such as smectite-PEG, smectite-PEG + GOx and nanocomposite + GOx showed a clear green fluorescence in RM-1 cells, reflecting the active oxygen produced by the smectite through the Fenton reaction (G in FIG. 3). Therefore, the nano composite material can realize the dual functions of photo-thermal treatment/chemical dynamic treatment in cells, and is expected to be used for treating tumors in vivo.
Example 4: in vivo drug tracking by magnetic resonance imaging and photoacoustic imaging techniques
To examine whether the nanocomposite could be used to identify tumor sites in living mice, the nanocomposite (100. mu.L, 2mg mL) was injected intravenously-1) Different periods (pre-injection, 0.5h, 2h, 6h, 12h and 24h post-injection) (a in fig. 4). The magnetic resonance signal of the nanocomposite at the tumor site can reflect the accumulation of the nanocomposite at different times by tail vein injection. An increase in magnetic resonance signal was observed 0.5h after injection, which can be attributed to the blood perfusion effect. The magnetic resonance signal reached a maximum 12 hours after injection, indicating that the accumulation of nanocomposite material in the tumor was the highest at this time. Since magnetic resonance can only give a macroscopic outline of the drug location in the mouse, detailed distribution of the drug within the tumor can be detected by photoacoustic imaging measurements. Acquisition of an Ultrasound (US) image and a Photoacoustic (PA) image are shown as B and C in fig. 4. Under the guidance of the ultrasound image, the photoacoustic imaging signal clearly shows the detailed enrichment process of the nanocomposite material in the tumor. Consistent with the magnetic resonance imaging results, the photoacoustic imaging signal began to decrease after 24 hours, indicating the metabolic process of the nanocomposite material in vivo. To further confirm the distribution of the nanocomposites in mice, the commonly used fluorescent marker 1, 1-diazadecyl-3, 3,3, 3-tetramethylthiotricarbocyaine (DIR) was introduced into the nanocomposite nanoclusters. The fluorescence imaging result is completely consistent with magnetic resonance imaging and photoacoustic imaging, and reflects the Enhanced Permeation and Retention (EPR) process of the nano-composite material nano-cluster to cancerous tumors. Under the guidance of magnetic resonance imaging and photoacoustic imaging technologies, the accurate time point with the highest drug accumulation amount can be determined, so that high-efficiency low-side-effect laser therapy is performedAnd (4) treating.
Example 5: combined in vivo anticancer effects of photothermal therapy and chemokinetic therapy
The excellent chemokinetic and photothermal therapeutic effects of the nanocomposite material in vitro motivate us to further verify the anticancer efficacy thereof in vivo. RM-1 cells were injected into the right forelimb axilla of male C57/BL6(18-20g) mice to construct prostate cancer models. When the tumor size reaches about 100mm3At the time, mice were randomly divided into six groups: (a) PBS; (b) PBS + light; (c) montmorillonite + GOx; (d) carbon sheet + light; (e) nanocomposite + GOx; (f) nanocomposite + GOx + light. According to the above photoacoustic imaging, magnetic resonance imaging results, light irradiation was performed 12 hours after intravenous injection. Tumor size and body weight of mice were recorded every two days (a and E in fig. 5). As shown in A in FIG. 5, there was little difference between the "PBS" and "PBS + light" groups, indicating a 1064nm laser (1.5W cm)-210 minutes) had negligible effect on tumor tissue. Notably, the tumor volumes were significantly suppressed for the "montmorillonite + GOx", "carbon sheet + light", "nanocomposite + GOx", and "nanocomposite + GOx + light" groups compared to the control group (E in fig. 5). Accordingly, the survival of these four groups was also significantly prolonged (B in fig. 5). Among them, the "nanocomposite + GOx + light" group showed better effects in inhibiting tumor growth and prolonging survival time of mice, which should be attributed to the synergistic antitumor effects of photothermal therapy and chemokinetic therapy. The weight and size of the dissected tumor also showed similar results (C and D in fig. 5). To further confirm the efficacy, tumor tissues collected on day 10 were subjected to hematoxylin eosin (H)&E) Staining and TdT-mediated dUTP nick end labeling (TUNEL) staining assay. Tumors dissected from the "nanocomposite + GOx + light" group were observed to exhibit the most severe local necrosis and the highest level of apoptosis (F in fig. 5). Therefore, when the nano composite material is used for treating RM-1 tumor in vivo, the cancer cell proliferation can be successfully inhibited through the dual treatment effects of chemodynamic treatment and photothermal treatment, and the nano composite material is expected to become a promising prostate cancer treatment strategy.
Example 6: biological safety of nanocomposites in vivo
The biological safety of the nanocomposite is the first prerequisite for biomedical applications, so we have fully evaluated the in vivo biological safety. After various treatments, the blood biochemical examination of each group of mice has no significant difference compared with the PBS group, which shows that the nano composite material and the laser treatment have no influence on the physiological state of the mice (A, B, C and D in figure 6). Furthermore, H & E staining of major organ tissues on day 10 also confirmed that none of the above treatments caused significant toxicity in all groups during treatment (E in fig. 6). Therefore, the good biological safety and biocompatibility of the nanocomposite material provide excellent guarantee for the dual-mode imaging guided photothermal therapy/chemokinetic therapy in cooperation with cancer therapy and diagnosis (fig. 7).
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A preparation method of a two-dimensional nano carbon sheet is characterized by comprising the following steps:
(1) calcining the eutectic polymer in a vacuum environment, wherein the calcining is carried out for 6-24 h at the temperature of 300-1000 ℃ so as to deiodinate and carbonize the eutectic polymer and obtain layered carbide; the structural formula of the eutectic polymer is as follows:
(2) and (2) crushing the layered carbide obtained in the step (1), adding the crushed layered carbide into an aqueous solution of an amphiphilic polymer, and performing ultrasonic treatment to obtain the two-dimensional carbon nano-sheet.
2. The method of claim 1, wherein the calcining is performed at a temperature increase rate of 5 ℃ for min-1-15℃min-1。
3. The method for preparing a two-dimensional nanocarbon sheet according to claim 1 or 2, wherein the hydrophobic end of the amphiphilic polymer is an alkyl chain having 10 or more carbon atoms, and the hydrophilic end is polyethylene glycol.
4. A two-dimensional nanocarbon sheet produced by the method according to any one of claims 1 to 3.
5. Use of a two-dimensional nanocarbon sheet according to claim 4, in particular for the preparation of photothermal therapeutic agents and/or photoacoustic imaging agents.
6. A method for preparing a two-dimensional nanocarbon sheet composite, characterized in that the two-dimensional nanocarbon sheet according to claim 4 and montmorillonite are added into a phosphate buffer solution and subjected to ultrasound, so that the two-dimensional nanocarbon sheet and montmorillonite form a composite through pi-pi stacking.
7. The method for preparing a two-dimensional nanocarbon sheet composite material according to claim 6, wherein the mass ratio of the two-dimensional nanocarbon sheet to the montmorillonite is 1 (0.5-2).
8. A composite material of two-dimensional nanocarbon flakes prepared by the method of claim 6 or 7.
9. Use of a composite material of two-dimensional nanocarbon platelets according to claim 8 for the preparation of a photoacoustic imaging agent and/or a magnetic resonance imaging agent.
10. Use of a composite of two-dimensional nanocarbon sheets according to claim 8, in particular for the preparation of photothermal and/or chemokinetic therapeutic agents.
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| US20180126368A1 (en) * | 2016-11-07 | 2018-05-10 | Council Of Scientific & Industrial Research | Process for the production of graphene sheets with tunable functionalities from seaweed promoted by deep eutectic solvents |
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| US20180126368A1 (en) * | 2016-11-07 | 2018-05-10 | Council Of Scientific & Industrial Research | Process for the production of graphene sheets with tunable functionalities from seaweed promoted by deep eutectic solvents |
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