CN114246946B - Nanometer contrast agent for diagnosis and treatment integration and preparation method thereof - Google Patents
Nanometer contrast agent for diagnosis and treatment integration and preparation method thereof Download PDFInfo
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- CN114246946B CN114246946B CN202111615038.6A CN202111615038A CN114246946B CN 114246946 B CN114246946 B CN 114246946B CN 202111615038 A CN202111615038 A CN 202111615038A CN 114246946 B CN114246946 B CN 114246946B
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- iron
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Classifications
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
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- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
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- Physics & Mathematics (AREA)
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- Inorganic Chemistry (AREA)
- General Physics & Mathematics (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention relates to the technical field of nano-drug presentation systems and contrast agents, in particular to a nano-contrast agent for diagnosis and treatment integration and a preparation method thereof. A nano-contrast agent for diagnosis and treatment integration comprises an iron-tungsten oxide nano-sheet, wherein the mass ratio of iron element to tungsten element is 1:1.13. According to the technical scheme, under the conditions that dibenzyl ether is used as a solvent, 1, 2-dodecanediol is used as a reducing agent, and oleic acid oleylamine is used as a surfactant, a high-temperature reaction is carried out to obtain iron-tungsten oxide nanosheets FWO NSs, and further PEG modification is carried out on the surfaces to obtain the FWO-PEG NSs with good water solubility. The nano-sheet can realize photothermal, photodynamic and chemodynamic treatment and simultaneously can realize monitoring of MRI/CT/PA triple imaging, is a nano-drug presentation system and contrast agent with medical imaging means for real-time monitoring and regulation, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of nano-drug presentation systems and contrast agents, in particular to a nano-contrast agent for diagnosis and treatment integration and a preparation method thereof.
Background
Phototherapy (PDT and PTT) is mediated by photosensitizer, and under the action of external laser, the tumor cells are effectively killed by the photothermal effect of heating and the photodynamic effect generated by toxic active oxygen, and the advantages of being minimally invasive and non-invasiveThe traditional Chinese medicine composition is successfully applied to clinic, however, the photothermal treatment leads to tumor resistance, the photodynamic treatment is influenced by the intratumoral hypoxia environment, and the antitumor effect is not ideal in a single treatment mode. In addition, chemotherapy (CDT) uses certain substances for low pH and rich H 2 O 2 Tumor treatment is performed by the effect of simultaneous response of tumor microenvironments at the level. Wherein the metal (common Fe, cu, mn, etc.) can be H in tumor 2 O 2 The occurrence of an in situ chemical Fenton/Fenton-like reaction, with the resulting free toxic hydroxyl groups, is a potential tumor treatment strategy, however, single CDT treatment is often less than ideal due to its slower response rate. Therefore, how to effectively combine the strategies of photo-thermal, photodynamic and chemodynamic treatment and further develop a nano-drug presentation system integrating the treatment modes into a whole becomes a hot spot of current research.
In addition, CT imaging tends to clearly show soft tissue structures and organs with small density differences due to high density resolution and non-overlapping tissue structure images, but cannot be used repeatedly in large amounts due to its radioactivity. MRI imaging plays an important role in assessing efficacy and guiding follow-up planning due to its lack of radio toxicity and good soft tissue contrast. Photoacoustic imaging (PA) can obtain tissue images with high resolution and high contrast due to the combination of the advantages of high selectivity in pure optical tissue imaging and deep penetration in pure ultrasound tissue imaging. How to concentrate the advantages of the imaging mode on a nano system, correspondingly combine the information in different mode images to obtain more comprehensive and visual information, and has profound significance for medical detection. Also, if multiple therapeutic strategies and multiple diagnostic modalities could be integrated into the same nano-drug presentation system, this would greatly advance the development of tumor diagnosis and treatment technology. In the tumor treatment mediated by the nano contrast agent, the quantity, distribution, metabolism and the like of nano particles reaching the inside of the tumor are very important to the treatment result, so that the development of a diagnosis and treatment integrated nano drug presentation system with the medical imaging means and the real-time monitoring and control is very necessary.
Disclosure of Invention
The invention aims to provide a diagnosis and treatment integrated nano-contrast agent, which aims to solve the technical problems of the prior art that a nano-drug presentation system or a contrast agent with photothermal, photodynamic and chemodynamic treatment functions and multiple diagnosis modes are integrated.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the nanometer contrast agent for diagnosis and treatment integration comprises an iron-tungsten oxide nanometer sheet, wherein the mass ratio of iron element to tungsten element in the iron-tungsten oxide nanometer sheet is 1:1.13.
The principle adopting the technical scheme has the beneficial effects that: the material adopted in the scheme is FeWO 4 The iron-tungsten oxide nano-sheet is used as the raw material of the nano-contrast agent, and simultaneously realizes the purposes of diagnosis and treatment. The iron and tungsten elements have the effect of photo-thermal conversion, and can realize photo-thermal treatment and photo-acoustic imaging. The iron oxide material has nuclear magnetic resonance imaging characteristics, and the tungsten oxide material can be subjected to CT imaging. Iron ions can be co-located with intratumoral H 2 O 2 In-situ chemical reaction occurs to generate toxic hydroxyl radical to kill tumor cells and realize the effect of chemical dynamic treatment. The nano contrast agent is in a sheet structure, the sheet structure nano material is a granular nano particle, the surface area of the nano particle exposed in tumor cells is larger, and the nano particle is exposed in the tumor environment 2 O 2 More Fe atoms, and greater reaction efficiency in the chemo-kinetic treatment.
In addition, the iron-tungsten oxide nano-sheet can also generate active oxygen under the action of laser, so that tumor cells are effectively killed, and the photodynamic treatment effect is realized. The nano contrast agent for diagnosis and treatment integration can realize the monitoring of MRI/CT/PA triple imaging while realizing photothermal, photodynamic and chemodynamic treatment.
The nano contrast agent of the scheme also has high absorption coefficient in a near infrared two-region (1000-1700 nm), the penetrating capacity of a light source of the two-region is stronger (3-5 cm), and the nano contrast agent can effectively irradiate internal tissues of tumors and improve the tumor treatment effect. Most of the existing materials (nano particles) only have infrared absorption in a near infrared first region (700-1000 nm), and the penetration capability of laser in the near infrared first region is limited, so that the internal tissues of the tumor cannot be effectively irradiated, and the tumor treatment effect is limited.
The nano contrast agent also has the advantages of small size, fast liver and kidney metabolism, low toxicity, good biological safety and the like, has good application prospect, and solves the technical problem that the prior art lacks of a nano drug presentation system or contrast agent integrated in various diagnostic modes and has the functions of photo-thermal, photodynamic and chemodynamic treatment.
Further, the iron-tungsten oxide nano-sheet is externally wrapped with DSPE-PEG 2000 to form FWO-PEG NSs. In order to ensure that the iron-tungsten oxide nano-sheet has better water solubility and biocompatibility, DSPE-PEG 2000 is modified on the surface of FWO NSs, and the final product FWO-PEG NSs with good water solubility is generated.
Further, the average hydrated particle size of FWO-PEG NSs was 102.6nm.
After DSPE-PEG 2000 is modified, the particle size of the nano contrast agent is slightly increased, but the nano contrast agent is also suitable for being presented to a tumor part as a nano drug, and enters tumor tissues through the high permeability and retention effect of solid tumors, so that the purposes of treating and diagnosing tumors are realized.
Further, the absorption peak of the absorption spectrum of FWO-PEG NSs is located at 1000-1700 nm.
The nano contrast agent has higher absorption in a near infrared two-region (1000-1700 nm), can be used as a photo-thermal therapeutic agent in the two-region, has ideal penetrating effect (3-5 cm) in a light source in the two-region, can effectively irradiate internal tissues of tumor, and improves the tumor treatment effect.
The scheme also provides a preparation method of the nanometer contrast agent for diagnosis and treatment integration, which comprises the following steps in sequence:
s1: synthesizing an iron-tungsten oxide nano-sheet;
s2: respectively dissolving iron-tungsten oxide nano-sheets and DSPE-PEG 2000 in chloroform to respectively obtain nano-sheet dispersion liquid and PEG dispersion liquid;
s3: adding PEG dispersion liquid into the nano-sheet dispersion liquid, and simultaneously carrying out ultrasonic treatment on the nano-sheet dispersion liquid to obtain an ultrasonic dispersion mixed liquid;
s4: stirring and drying the ultrasonic dispersion mixed solution to obtain FWO-PEG NSs.
By adopting the technical scheme, in order to ensure that the iron-tungsten oxide nano-sheet has better water solubility and biocompatibility, DSPE-PEG 2000 is modified on the surface of FWO NSs, so that the final product FWO-PEG NSs with good water solubility is generated. The method can realize stable surface modification of FWO NSs by DSPE-PEG 2000.
Further, the iron-tungsten oxide nanosheets are prepared by the following method: preparing a mixed solution I containing dibenzyl ether, 1, 2-dodecanediol and six-carbon tungsten; heating the mixed solution I, and then adding oleic acid and oleylamine to obtain a mixed solution II; and heating the mixed solution II, adding ferrous acetylacetonate, and reacting to obtain a mixed solution III, wherein the mixed solution III contains the iron-tungsten oxide nano-sheets.
The iron-tungsten oxide nano-sheet is synthesized by a high-temperature decomposition method, tungsten hexacarbonyl for providing a tungsten source and ferrous acetylacetonate for providing an iron source are used as precursors, dibenzyl ether is used as a high-temperature organic solvent, 1, 2-dodecanediol is used as a reducing agent, and oleylamine oleate is used as a surfactant. The two precursors are first fully decomposed in an organic phase, and then react at high temperature to generate flaky iron-tungsten oxide nano-sheets (FWO NSs).
Further, in the mixed solution I, the ratio of dibenzyl ether, 1, 2-dodecanediol and tungsten hexacarbonate was 20ml:1.5g:1mmol. The volume of dibenzyl ether is very important for the formation of the morphology of the nanomaterial, and when the volume reduction reaction system is reduced, more reactants can participate in the growth stage of the nanomaterial, the size of the generated nanoparticles can be increased, and the requirements of a nano drug presentation system are not met. In addition, the use of 1, 2-dodecanediol is very important for obtaining the flaky nano material, and the shorter carbon chain of the 1, 2-dodecanediol plays a main role in anisotropic growth of nano particles, so that reaction products can be aggregated and grown in different modes, and the nano flaky structure is formed. In the prior art, when synthesizing single iron nanoparticles, 1, 2-hexadecane diol is used as a reducing agent, but the 1, 2-dodecanediol in the technical scheme is not used, and the obtained nanoparticles are granular, rather than the flaky structure in the scheme.
Further, heating the mixed solution I to 120 ℃ in a nitrogen environment, and then adding oleic acid and oleylamine to obtain a mixed solution II; heating the mixed solution II to 260 ℃ in a nitrogen environment, adding ferrous acetylacetonate, and reacting for 30 minutes to obtain a mixed solution III; the molar ratio of tungsten hexacarbonyl to ferrous acetylacetonate is 1:1.
the reaction temperature and time have obvious influence on the shape of the nano material, and the shape change of the nano material can influence the performances of the nano material such as catalytic activity, photo-thermal conversion activity and the like. By adopting the reaction temperature and time of the scheme, the flaky iron-tungsten oxide nano material can be successfully synthesized. In example 1, the inventors tried to shorten the reaction time at 260 ℃ and also tried to slightly raise the reaction temperature, but the results showed that a sheet-like nanomaterial could not be synthesized. It can be seen that the synthesis reaction conditions of 260 ℃ for 30 minutes are necessary to obtain the iron-tungsten oxide nano-sheet according to the technical scheme. In the technical scheme, the molar ratio of the hexacarbon-based tungsten to the ferrous acetylacetonate precursor is 1:1, and when the ratio is too high or too low, the obtained nanomaterial cannot show a relatively uniform nanosheet morphology.
The scheme also provides application of the diagnosis and treatment integrated nano-contrast agent in preparing tumor treatment medicines and application of the diagnosis and treatment integrated nano-contrast agent in preparing CT contrast agents, MRI contrast agents or photoacoustic imaging contrast agents.
The monitoring of MRI/CT/PA triple imaging can be realized while the photothermal, photodynamic and chemodynamic treatment is realized. Examples 2-4 of the present application demonstrate the photothermal, photodynamic and chemodynamic therapeutic properties of the nanocomposite (nanocontrast agent), respectively; examples 5-7 demonstrate the performance of Magnetic Resonance Imaging (MRI), photoacoustic imaging (PA) and CT imaging, respectively, of the nanocomposite. Moreover, the inventor applies the nanocomposite prepared by the scheme to in-vitro treatment of breast cancer cells, and the nano contrast agent shows ideal treatment effect.
Drawings
FIG. 1 is a graph showing XPS survey spectra of FWO NSs of example 1 of the present invention.
Fig. 2 is an XRD pattern of FWO NSs of example 1 of the present invention.
Fig. 3 is an EDS line scan of FWO NSs of example 1 of the present invention.
FIG. 4 is a mapping graph of FWO NSs of example 1 of the present invention.
Fig. 5 is a TEM image of FWO NSs of example 1 of the present invention.
FIG. 6 is a TEM image of FWO-PEG NSs of example 1 of the present invention.
FIG. 7 is a particle size distribution diagram of FWO-PEG NSs of example 1 of the present invention.
FIG. 8 is a potential diagram of FWO NSs and FWO-PEG NSs of example 1 of the present invention.
FIG. 9 is an absorption spectrum of FWO-PEG NSs of example 1 of the present invention.
FIG. 10 is a TEM image of comparative nanomaterial I of example 1 of the present invention.
FIG. 11 is a TEM image of comparative nanomaterial II of example 1 of the present invention.
FIG. 12 is a photo-thermal temperature profile of FWO-PEG NSs of example 2 of the present invention at various concentrations.
FIG. 13 is an ultraviolet plot of DPBF in a system of example 3 of the present invention with different laser irradiation times.
FIG. 14 is a UV curve of TMB after incubation of the system of example 4 of the present invention for various periods of time.
FIG. 15 is an in vitro MRI imaging and standard curve of FWO-PEG NSs at various concentrations in example 5 of the present invention.
FIG. 16 is an in vitro PA imaging and standard curve for FWO-PEG NSs at various concentrations in accordance with example 6 of the present invention.
FIG. 17 is an in vitro CT imaging and standard curve of FWO-PEG NSs at various concentrations in example 7 of the present invention.
FIG. 18 shows the results of in vitro apoptosis evaluation experiments for FWO-PEG NSs of example 8 of the present invention.
FIG. 19 shows the biosafety evaluation result of FWO-PEG NSs of example 9 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. Unless otherwise indicated, the technical means used in the following examples and experimental examples are conventional means well known to those skilled in the art, and the materials, reagents and the like used are all commercially available.
Example 1: preparation of nano contrast agent
1. And (3) placing the mixed solution I consisting of dibenzyl ether, 1, 2-dodecanediol and six-carbon tungsten into a three-neck flask with intense magnetic stirring, and heating under the protection of nitrogen. The dosage ratio of the dibenzyl ether, the 1, 2-dodecanediol and the six-carbon tungsten is 20ml:1.5g:1mmol.
2. When the system temperature is heated to 120 ℃, oleic acid and oleylamine (the volume ratio of oleic acid to oleylamine to dibenzyl ether is 1:1:20) are added into the mixed solution I to obtain a mixed solution II, and then the mixed solution II is continuously heated to raise the temperature.
3. When the temperature of the mixed solution II is raised to 260 ℃, ferrous acetylacetonate is added into the mixed solution II, and the reaction is continued for 30 minutes, so as to obtain a mixed solution III. Wherein, the mol ratio of tungsten hexacarbonyl to ferrous acetylacetonate is 1:1.
the whole process of the steps 1-3 needs to be isolated from air and is carried out under the protection of nitrogen.
4. After the reaction is completed, the mixed solution III is cooled to room temperature, excessive absolute ethyl alcohol (the volume of the absolute ethyl alcohol relative to the mixed solution III is ensured to be excessive) is added, nano sheet-shaped substances in the mixed solution III are separated out, and the solid phase is obtained by centrifugation. Then cyclohexane is used for resuspending the solid phase, so as to wash out excessive oleic acid and oleylamine on the surface of the nano lamellar substance, and facilitate the subsequent modification of PEG. Then adding excessive absolute ethyl alcohol (the volume ratio is kept at 1:1-1:2) into cyclohexane, separating out nano sheet-shaped substances, and centrifuging to obtain a solid phase. The above process of absolute ethanol precipitation and cyclohexane resuspension is repeated once more to obtain unmodified nano contrast agent iron-tungsten oxide nano-sheet (FeWO 4 nanosheets, abbreviated FWO NSs).
5. The oleophilic phase FWO NSs is then further modified to transfer to the aqueous phase. Unmodified FWO NSs and amphiphilic DSPE-PEG 2000 are respectively dissolved in chloroform to respectively obtain a nano-sheet dispersion liquid and a PEG dispersion liquid, the nano-sheet dispersion liquid is placed in an ultrasonic cleaner, the PEG dispersion liquid is dripped into the nano-sheet dispersion liquid while ultrasonic processing is carried out, and ultrasonic processing is continued for 30 minutes after the dripping is completed. The dosage ratio of FWO NSs to chloroform was 10mg:2mL, DSPE-PEG 2000 and chloroform in an amount ratio of 40mg:2mL.
6. The mixture was then stirred at room temperature (25.+ -. 2 ℃) for 2 hours and dried with nitrogen to obtain the modified nanocontrast agent, FWO-PEG NSs.
7. The obtained FWO-PEG NSs were dissolved in deionized water and filtered using a microporous syringe filter having a pore size of 0.22. Mu.m.
The nanometer contrast agent is synthesized by a high-temperature decomposition method, tungsten hexacarbonyl providing a tungsten source and ferrous acetylacetonate providing an iron source are used as precursors, dibenzyl ether is used as a high-temperature organic solvent, 1, 2-dodecanediol is used as a reducing agent, and oleic acid and oleylamine are used as surfactants. The two precursors are first fully decomposed in an organic phase, and then react at high temperature to generate flaky iron-tungsten oxide nano-sheets (FWO NSs). In order to ensure that the material has better water solubility and biocompatibility, DSPE-PEG 2000 is modified on the surface of FWO NSs, and the final product FWO-PEG NSs with good water solubility is generated.
The synthesized FWO NSs are prepared into powder samples after freeze drying, the powder is subjected to element analysis by X-ray photoelectron spectroscopy (XPS), the experimental result is shown in figure 1, and the element analysis shows that three elements of Fe, W and O in the material exist effectively. XRD patterns of FWO NSs are shown in FIG. 2, and it can be seen that the chemical formula of the iron-tungsten oxide in FWO NSs is FeWO 4 . EDS line scan of FWO NSs referring to FIG. 3, mapping of three elements referring to FIG. 4, it is also demonstrated that the three elements Fe, W, O are effectively present in the material. Fe as measured by ICP-OES: the ratio of W mass is 1:1.13.
FWO NSs electron microscopy image referring to FIG. 5, it can be seen that under transmission electron microscopy, the iron-tungsten double oxide is seen as a platelet-like structure. Referring to FIG. 6, the FWO-PEG NSs electron microscope image shows that under the transmission electron microscope, the iron-tungsten double oxide modified by PEG is round-like, and the dispersibility is good. The FWO NSs has an average particle size of about 40 nm; the particle size distribution of FWO-PEG NSs is shown in FIG. 7, with a particle size of 102.6nm. The potential diagrams of FWO NSs and FWO-PEG NSs are shown in FIG. 8. FIG. 9 is an ultraviolet absorption spectrum of FWO-PEG NSs, which shows that the nano-contrast agent has an absorption peak at 1060nm, and the nano-contrast agent in the scheme has a high absorption coefficient in a near infrared two region (1000-1700 nm), has stronger penetrating power (3-5 cm) of a light source in the two regions, can effectively irradiate internal tissues of tumors, and improves the tumor treatment effect. Most of the existing materials (nano particles) only have infrared absorption in a near infrared first region (700-1000 nm), and the penetration capability of laser in the near infrared first region is limited, so that the internal tissues of the tumor cannot be effectively irradiated, and the tumor treatment effect is limited.
The inventors have tried various technical parameters when studying the synthesis method of the present nano-contrast agent, wherein in step "3", the following technical scheme is adopted: the temperature of the mixed solution II was raised to 260℃and then ferrous acetylacetonate was added to the mixed solution II, and the reaction was continued for 20 minutes. The rest of the synthesis process is consistent with the optimal conditions described above. The transmission electron microscope of the nanomaterial (comparative nanomaterial i) obtained by this scheme is shown in fig. 10, and it can be seen that a part of the rod-shaped decomposed precursor does not synthesize the morphology of the nanoplatelets due to insufficient time. In addition, in step "3", the inventors also adopted the following technical scheme: the temperature of the mixed solution II was raised to 260℃and then ferrous acetylacetonate was added to the mixed solution II, and the reaction was continued for 30 minutes. The remaining synthesis process is consistent with the optimal conditions set forth above. The transmission electron microscope image of the nanomaterial (comparative nanomaterial ii) obtained by this scheme is shown in fig. 11, and it can be seen that the synthesized nanoparticles are spherical and no longer in a lamellar structure, and the nanoparticle particle size is about 8.69nm as measured by Nano measure particle size software. Therefore, the reaction temperature and time of the step '3' have a significant influence on the shape of the nano material, and the shape change of the nano material can influence the performances of the nano material, such as catalytic activity, photo-thermal conversion activity and the like.
In addition, in the prior art, 1, 2-hexadecane diol is used as a reducing agent when synthesizing individual iron nanoparticles, but 1, 2-dodecanediol of the present technical scheme is not used, and the obtained nanoparticles are in a granular form, rather than in a sheet-like structure of the present scheme. The inventors analyzed the reason for: the 1, 2-dodecanediol with a shorter carbon chain plays a main role in anisotropic growth of nano particles, so that reaction products aggregate and grow in different modes, and the nano lamellar structure is formed. In addition, in the technical scheme, when the mol ratio of the hexacarbon-based tungsten to the ferrous acetylacetonate precursor is 1:1 and the ratio is too high or too low, the obtained nanomaterial cannot show a relatively uniform nanosheet morphology. The volume of dibenzyl ether is very important for the formation of the morphology of the nanomaterial, and when the volume reduction reaction system is reduced, more reactants can participate in the growth stage of the nanomaterial, the size of the generated nanoparticles can be increased, and the requirements of a nano drug presentation system are not met.
Example 2: photothermal properties of nano-contrast agents
The photothermal properties of the nano-contrast agents were evaluated by laser irradiation of various concentrations of FWO-PEG NSs in water (0, 50, 100, 200, 400. Mu.g/mL), and the temperature in the liquid was monitored and recorded strictly with an IVIS spectral imaging system. Experimental results referring to FIG. 12, FWO-PEG NSs at various concentrations were placed in 96-well plates at 1060nm (1.0W/cm 2 ) The temperature of the solution at different time points is recorded, the temperature of the solution gradually rises along with the increase of irradiation time, and the higher the concentration is, the faster the temperature rising rate is, thus indicating the excellent photo-thermal conversion performance of FWO-PEG NSs.
Example 3: photodynamic properties of nano-contrast agents
The photodynamic property of the nano contrast agent is detected by adopting a DPBF (diphenyl isobenzofuran) method. FWO-PEG NSs were mixed with DPBF and added to PBS buffer (pH 6.0) (500. Mu.g/mL FWO-PEG NSs and 15. Mu.L of 1mg/mL DPBF were mixed and added to 1mL PBS system), followed by laser irradiation for various times (0, 5, 10, 15, 20, 25 and 30 min). And observing the absorbance change at 418nm by using an ultraviolet spectrophotometer observation system. The experimental results are shown in FIG. 13 (the curves in the figure represent the test results with irradiation times of 0, 5, 10, 15, 20, 25 and 30min in order from top to bottom), 1 O 2 can react with the reagent DPBF specifically, so that the characteristic peak of the reagent DPBF is reduced. The system was found to be at 1060nm (0.5W/cm 2 ) The characteristic peak of DPBF at 418nm gradually decreases under different laser irradiation time, which proves that the irradiation time is prolonged, and the DPBF is in the system 1 O 2 The yield is increased, the irradiation time is positively correlated, and the photodynamic performance of the nano contrast agent is excellent.
Example 4: chemical dynamic therapeutic properties of nano-contrast agents
TMB (tetramethylbenzidine) is used as an indicator to detect the chemodynamic therapeutic properties of the nano-contrast agent. TMB and FWO-PEG NSs and H 2 O 2 Added to PBS buffer (pH 6.0) (4. Mu.L TMB (80 mM) in 1mL PBS containing 500. Mu.g/mL FWO-PEG NSs and 10mM H) 2 O 2 ). After different reaction times (0, 0.5, 1,2, 4 and 6 h), the peak change of TMB at 652nm was observed using an ultraviolet spectrophotometer. The results of the experiment are shown in FIG. 14 (the curves in the figure represent the test results with reaction times of 0, 0.5, 1,2, 4 and 6 hours in order from bottom to top), and the OH can specifically react with the reagent TMB to increase the absorbance at 652 nm. Under the condition that the systems are incubated together for different time, the characteristic peak value of TMB at 652nm rises, the fact that the irradiation time is prolonged, the OH yield in the systems rises, the positive correlation with the incubation time is achieved, and the effective chemical power treatment performance of the nano contrast agent is proved.
Example 5: MRI imaging of nano-contrast agents
FWO-PEG NSs with different concentrations are prepared and dispersed in physiological saline, and MRI signals are measured under a magnetic resonance imager to obtain a standard curve of concentration and signal value. The experimental results are shown in fig. 15, after the FWO-PEG NSs with different concentrations are scanned by an MRI imager, the signal value of the FWO-PEG NSs is increased along with the increase of the concentration, the linear correlation is good, and the nano contrast agent has excellent MRI imaging performance.
Example 6: photoacoustic PA imaging of nano-contrast agents
Preparing FWO-PEG NSs water solutions with different concentrations, detecting in-vitro photoacoustic signals of the nano contrast agent under a photoacoustic imager, and obtaining a standard curve of the concentration and the signal value. The experimental results are shown in fig. 16, after the FWO-PEG NSs with different concentrations are scanned by a photoacoustic imager, the signal value of the FWO-PEG NSs is increased along with the increase of the concentration, the linear correlation is good, and the nano contrast agent has excellent PA imaging performance.
Example 7: CT imaging of nano-contrast agents
FWO-PEG NSs with different concentrations are prepared and dispersed in physiological saline, and CT signals are measured under a spiral CT imager, so that a standard curve of the concentration of the nano contrast agent and the signal value is obtained. The experimental results are shown in fig. 17, after the FWO-PEG NSs with different concentrations are scanned by a spiral CT imaging instrument, the CT signal value of the FWO-PEG NSs is increased along with the increase of the concentration, the linear correlation is good, and the nano contrast agent has CT imaging performance.
Example 8: apoptosis evaluation of nano contrast agent for treating breast cancer cells
Murine breast cancer 4T1 cells were cultured in six well plates for 24 hours, each treatment group was supplemented with formulated nano contrast agent FWO-PEG NSs (400 μg mL) -1 ) And incubated for 4 hours, followed by the addition of H to CDT group 2 O 2 (100. Mu.M), PDT receive power density of 0.5W/cm 2 (1060 nm) laser irradiation for 10min as PDT conditions, PTT group received 1.0W/cm 2 (1060 nm) laser irradiation for 5min was used as PTT condition, and the CPP group, i.e. three therapeutic synergistic groups, was first treated with nano-contrast agent and H 2 O 2 Incubating together, then receiving two kinds of laser irradiation, after the end of the laser irradiation, incubating for 30min, then collecting the treated cells, re-suspending in 200 mu L PBS, quantitatively detecting by flow cytometry, and evaluating the apoptosis condition. The flow cytometry detection results are shown in FIG. 18, and the in vitro anti-breast cancer apoptosis of the nano-contrast agent is visible, and the control group, laser, H 2 O 2 The three groups of cells have no obvious apoptosis, and the safety is proved, wherein the single sphere FWO-PEG NSs group has tiny apoptosis due to the addition of the nano contrast agent, but the survival cells are still more than 80 percent, and the safety of the nano contrast agent is proved. The apoptosis number of the CDT group is 17.75%, the apoptosis number of the PDT group is increased to 25.04% due to the cooperative apoptosis cells of the photodynamic therapy, the apoptosis number of the PTT group is effectively increased to 27.67% due to the cooperative apoptosis cells of the photothermal therapy, and finally the apoptosis number of the CPP group is highest and reaches 59.26% due to the cooperation of the CDTT/PDT/PTT, which proves the excellent treatment effect of the nanometer contrast agent。
Example 9: biosafety test
Female Kunming mice were taken for 30 animals, 5 animals each, 200. Mu.L FWO-PEG NSs (4 mg/mL) were administered to the tail vein, 200. Mu.L physiological saline was administered to the control group, mice were sacrificed on 1/3/5/7/14 days of administration, and heart, liver, spleen, lung and kidney were taken for HE observation. After the nano contrast agent is given, the viscera of each group of mice are not abnormal in cell structure morphology and tissue, so that the nano contrast agent is proved to have good in vivo safety, and can be further applied to in vivo treatment, and the experimental result is shown in fig. 19, and the scale is 50 μm.
The foregoing is merely exemplary of the present invention, and specific technical solutions and/or features that are well known in the art have not been described in detail herein. It should be noted that, for those skilled in the art, several variations and modifications can be made without departing from the technical solution of the present invention, and these should also be regarded as the protection scope of the present invention, which does not affect the effect of the implementation of the present invention and the practical applicability of the patent. The protection scope of the present application shall be subject to the content of the claims, and the description of the specific embodiments and the like in the specification can be used for explaining the content of the claims.
Claims (9)
1. The utility model provides a be used for diagnosing nanometer contrast agent of integration which characterized in that: the nano-sized iron-tungsten oxide composite material comprises an iron-tungsten oxide nano-sheet, wherein the mass ratio of iron element to tungsten element in the iron-tungsten oxide nano-sheet is 1:1.13; the iron-tungsten oxide nano-sheet is wrapped with DSPE-PEG 2000 to form FWO-PEG NSs; the nano contrast agent is used for preparing a photothermal therapeutic agent, a photodynamic therapeutic agent and a chemodynamic therapeutic agent;
the preparation method comprises the following steps:
s1: synthesizing an iron-tungsten oxide nano-sheet;
s2: respectively dissolving iron-tungsten oxide nano-sheets and DSPE-PEG 2000 in chloroform to respectively obtain nano-sheet dispersion liquid and PEG dispersion liquid;
s3: adding PEG dispersion liquid into the nano-sheet dispersion liquid, and simultaneously carrying out ultrasonic treatment on the nano-sheet dispersion liquid to obtain an ultrasonic dispersion mixed liquid;
s4: stirring and drying the ultrasonic dispersion mixed solution to obtain FWO-PEG NSs.
2. A nano-contrast agent for medical integration according to claim 1, wherein: the average hydrated particle size of FWO-PEG NSs was 102.6nm.
3. A nano-contrast agent for medical integration according to claim 2, wherein: the absorption peak of the absorption spectrum of FWO-PEG NSs is located at 1000-1700 nm.
4. A method for preparing a diagnostic integrated nano-contrast agent according to claim 3, wherein: the method comprises the following steps of:
s1: synthesizing an iron-tungsten oxide nano-sheet;
s2: respectively dissolving iron-tungsten oxide nano-sheets and DSPE-PEG 2000 in chloroform to respectively obtain nano-sheet dispersion liquid and PEG dispersion liquid;
s3: adding PEG dispersion liquid into the nano-sheet dispersion liquid, and simultaneously carrying out ultrasonic treatment on the nano-sheet dispersion liquid to obtain an ultrasonic dispersion mixed liquid;
s4: stirring and drying the ultrasonic dispersion mixed solution to obtain FWO-PEG NSs.
5. The method for preparing the diagnosis and treatment integrated nano-contrast agent according to claim 4, wherein the iron-tungsten oxide nano-sheet is prepared by the following method: preparing a mixed solution I containing dibenzyl ether, 1, 2-dodecanediol and six-carbon tungsten; heating the mixed solution I, and then adding oleic acid and oleylamine to obtain a mixed solution II; and heating the mixed solution II, adding ferrous acetylacetonate, and reacting to obtain a mixed solution III, wherein the mixed solution III contains the iron-tungsten oxide nano-sheets.
6. The method for preparing the diagnosis and treatment integrated nano-contrast agent according to claim 5, wherein the ratio of dibenzyl ether, 1, 2-dodecanediol and hexacarbon-based tungsten in the mixed solution I is 20ml:1.5g:1mmol.
7. The method for preparing the diagnosis and treatment integrated nano contrast agent according to claim 6, wherein the mixed solution I is heated to 120 ℃ in a nitrogen environment, and oleic acid and oleylamine are added to obtain a mixed solution II; heating the mixed solution II to 260 ℃ in a nitrogen environment, adding ferrous acetylacetonate, and reacting for 30 minutes to obtain a mixed solution III; the molar ratio of tungsten hexacarbonyl to ferrous acetylacetonate is 1:1.
8. use of a nano-contrast agent for diagnosis and treatment integration according to any one of claims 1-3 for the preparation of a medicament for tumor treatment.
9. Use of a nano-contrast agent for medical integration according to any of claims 1-3 for the preparation of CT contrast agents, MRI contrast agents or photoacoustic imaging contrast agents.
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