CN114425092B - MRI/NIR II dual-mode imaging spray contrast agent and preparation method and application thereof - Google Patents
MRI/NIR II dual-mode imaging spray contrast agent and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a spraying contrast agent for MRI/NIR II dual-mode imaging, a preparation method and application thereof. The rare earth probe for MRI/NIR II dual-mode imaging comprises: lanthanide oxyfluoride nano material REOF: ln with near-infrared two-zone fluorescence imaging element and magnetic resonance imaging element, and dihydroartemisinin and carbamtinib loaded on the surface of the nano material REOF: ln, the general structural formula is as follows: and REOF is Ln-DHA-Cap, wherein RE and Ln are lanthanide elements, RE comprises a magnetic resonance imaging element, ln comprises a sensitizer element, an up-conversion luminescent element and a near-infrared two-region fluorescent element, DHA is dihydroartemisinin, and Cap is carbamatinib. The nano material REOF: ln in the rare earth probe for MRI/NIR II dual-mode imaging has better Magnetic Resonance Imaging (MRI) and near-infrared two-region fluorescence properties, the penetration depth is deep, the fluorescence intensity is strong, and the NIRII imaging effect of tongue cancer after spraying can be realized.
Description
Technical Field
The invention belongs to the technical field of biological materials, and particularly relates to a spraying contrast agent for MRI/NIR II dual-mode imaging, and a preparation method and application thereof.
Background
Currently, X-ray Computed Tomography (CT), magnetic Resonance Imaging (MRI), ultrasound imaging, photoacoustic imaging (PAI), positron emission computed tomography (PET), fluorescence in vivo imaging, and the like are clinically common tumor imaging modalities. Magnetic REsonance Imaging (MRI) has the advantages of being noninvasive, non-radiative, high-resolution and the like, but has the disadvantages of long examination time, high cost and the like. In the conventional visible light excitation probe for fluorescence imaging, due to the absorption of the tissue to visible light, the imaging effect of the visible light excitation probe cannot achieve a satisfactory effect.
In addition, the single imaging mode has certain limitation due to the complex diversity of the tumor, and in addition, the current common clinical contrast agents have no targeting property and low diagnosis specificity on diseases. How to realize accurate targeting and imaging of tumors is always a problem which needs to be solved in clinic.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a spraying contrast agent for MRI/NIR II dual-mode imaging, and a preparation method and application thereof. The technical problem to be solved by the invention is realized by the following technical scheme:
the invention provides a rare earth probe for MRI/NIR II dual-mode imaging, which comprises the following components in part by weight: the lanthanide oxyfluoride nano material REOF: ln with near-infrared two-zone fluorescence imaging elements and magnetic resonance imaging elements, and dihydroartemisinin and carbamatinib loaded on the surface of the nano material REOF: ln have the structural general formula: and REOF is Ln-DHA-Cap, wherein RE and Ln are lanthanide elements, RE comprises a magnetic resonance imaging element, ln comprises a sensitizer element, an up-conversion luminescent element and a near-infrared two-region fluorescent element, DHA is dihydroartemisinin, and Cap is carbamatinib.
In one embodiment of the invention, RE is one or more of La, gd, Y.
In one embodiment of the invention, ln is Yb, er, ce and Eu.
The invention provides a preparation method of a rare earth probe for MRI/NIR II dual-mode imaging, which comprises the following steps:
s1: preparing a precursor material REOHCO by adopting a coprecipitation method 3 F:Ln；
S2: subjecting the precursor material to REOHCO 3 Calcining the F: ln to generate a nano material REOF: ln;
s3: dissolving the nano material REOF: ln in ultra-clean water by ultrasonic dissolution, simultaneously adding EDC powder and NHS powder, stirring until the solution is uniform, then adding dihydroartemisinin solution, and stirring to obtain a REOF: ln-DHA solution;
s4: adding EDC powder and NHS powder into the REOF, ln-DHA solution, stirring until the solution is uniform, then adding carbamtinib under the condition of keeping out of the sun, and obtaining a rare earth probe REOF, ln-DHA-Cap of MRI/NIR II dual-mode imaging by centrifugation after stirring;
wherein, RE and Ln are lanthanide elements, RE comprises magnetic resonance imaging elements, and Ln comprises sensitizer elements, up-conversion luminescence elements and near-infrared two-zone fluorescence elements.
In one embodiment of the invention, RE is one or more of La, gd, Y, and Ln is Yb, er, ce and Eu.
In one embodiment of the present invention, the S1 includes:
s11: 1.5-3 g of urea is weighed and dissolved in 30-50 ml of deionized water, and RE (NO) is added simultaneously 3 ) 3 And Ln (NO) 3 ) 3 Then adding 0.08-0.12 g of KF and stirring until the solution is uniform;
s12: encapsulating the solution and placing the solution in a water bath at the temperature of 70-95 ℃ for coprecipitation reaction, wherein the reaction time is 2-4 h;
s13: centrifugally separating and drying the reaction product to obtain a precursor material REOHCO 3 F:Ln。
In an embodiment of the present invention, in S2, the calcination treatment process is: calcining for 3-5 h in air atmosphere at 400-600 ℃.
In an embodiment of the present invention, before preparing the nanomaterial REOF: ln, further comprising: optimizing the proportion of Yb, er, ce and Eu elements by using a genetic algorithm to obtain an optimal proportion, and preparing a nano material REOF: ln according to the optimal proportion; wherein, the matching optimization step comprises:
s01: n groups of Yb (NO) in different proportions 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 Preparing n groups of nano materials REOF, yb/Er/Ce/Eu, as raw materials;
s02: using the volume of each raw material of n groups of nano materials and the corresponding luminous intensity as primary luminous data;
s03: setting the eligibility probability r according to the primary luminescent powder data and the fitness of the genetic algorithm by taking the luminescent intensity, and calculating to obtain Yb (NO) by utilizing the genetic algorithm 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 The optimal proportion of the raw materials.
The invention provides a rare earth probe for MRI/NIR II dual-mode imaging, which is described in any one of the embodiments, application of the rare earth probe as a marker for spraying a contrast agent to mark and locate tumor tissues and cancer tissues, and application of a navigator for navigating and surgically removing the tumor tissues and the cancer tissues.
Compared with the prior art, the invention has the beneficial effects that:
1. ln has better Magnetic Resonance Imaging (MRI) and near-infrared two-region fluorescence properties, and has deep penetration depth and strong fluorescence intensity, thereby realizing the dual-mode imaging effect;
2. the MRI/NIR II dual-mode imaging rare earth probe is characterized in that the Caratinib is loaded on the surface of the nanomaterial REOF: ln, can be used for targeted marking and positioning of tumor tissues and cancer tissues and guiding surgical removal of the tumor tissues and the cancer tissues, and meanwhile, the dihydroartemisinin is loaded on the surface of the nanomaterial REOF: ln, so that the probe has a good photodynamic effect and can be used for photodynamic therapy of tumors;
3. the preparation method of the rare earth probe for MRI/NIR II dual-mode imaging adopts a coprecipitation method to prepare the nano material, the operation is simple and easy, the preparation process is green and environment-friendly, the dispersibility of the generated nano material is better, and the raw material ratio is optimized by combining a genetic algorithm in the preparation process to obtain the optimal ratio.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical means of the present invention more clearly understood, the present invention may be implemented in accordance with the content of the description, and in order to make the above and other objects, features, and advantages of the present invention more clearly understood, the following preferred embodiments are described in detail with reference to the accompanying drawings.
Drawings
FIG. 1 is an SEM image of a GdOF: yb/Er/Ce/Eu nano-material provided by an embodiment of the invention;
FIG. 2 is a near infrared two-region (NIR II) imaging diagram of a GdOF: yb/Er/Ce/Eu nano-material with an optimal ratio obtained through a genetic algorithm according to an embodiment of the invention;
FIG. 3 is a Magnetic Resonance Imaging (MRI) diagram of GdOF: yb/Er/Ce/Eu nano-material provided by the embodiment of the present invention under different Gd concentrations;
FIG. 4 is a graph of DPBF absorption at an excitation wavelength of 980nm for GdOF, yb/Er/Ce/Eu-DHA provided by an embodiment of the present invention;
FIG. 5 is an image of the NIR II region of mouse orthotopic tongue cancer targeted by the GdOF, yb/Er/Ce/Eu-DHA-Cap probe provided by the embodiment of the invention;
FIG. 6 is an image of NIR II of subcutaneous tumors targeted to mouse tongue carcinoma cell Cal27 using GdOF: yb/Er/Ce/Eu-DHA-Cap probe provided in the examples of the present invention.
Detailed Description
In order to further illustrate the technical means and effects of the present invention adopted to achieve the predetermined invention purpose, the following detailed description is provided for a spraying contrast agent for MRI/NIR II dual-mode imaging and the preparation method and application thereof according to the present invention with reference to the accompanying drawings and the detailed description.
The foregoing and other technical matters, features and effects of the present invention will be apparent from the following detailed description of the embodiments, which is to be read in connection with the accompanying drawings. The technical means and effects of the present invention adopted to achieve the predetermined purpose can be more deeply and specifically understood through the description of the specific embodiments, however, the attached drawings are provided for reference and description only and are not used for limiting the technical scheme of the present invention.
Example one
The embodiment provides a rare earth probe for MRI/NIR II dual-mode imaging, which comprises: the lanthanide oxyfluoride nano material REOF & ltLn & gt with near-infrared two-zone fluorescence imaging elements and magnetic resonance imaging elements, and dihydroartemisinin and carbamtinib loaded on the surface of the nano material REOF & ltLn & gt have the structural general formula: and REOF is Ln-DHA-Cap, wherein RE and Ln are lanthanide elements, RE comprises a magnetic resonance imaging element, ln comprises a sensitizer element, an up-conversion luminescent element and a near-infrared two-region fluorescent element, DHA is dihydroartemisinin, and Cap is carbamatinib.
In particular, the nanomaterial REOF: ln is formed from three parts, a host element, a sensitizer and an activator. RE is a matrix element, and can be one or more of La, gd and Y, wherein La 3+ The electron shell is in a full empty state at 4f, and no electrons exist; gd (Gd) 3+ The electron shells are in a half-filled state at 4 f; y is 3+ The electron shell is also fully controlled at 4f, with no electrons. The excitation level of the f-f transition is too high, and the ions do not emit light in a visible light region, so the ions are often used as matrix elements, and the matrix elements mainly influence the appearance of the rare earth probe and have small influence on the light emission of the rare earth probe. Gd element has a Magnetic Resonance (MRI) imaging effect.
Further, ln includes a sensitizer element and an activator element (including an up-conversion light emitting element and a near-infrared two-region fluorescent element). In this embodiment, ln is Yb, er, ce and Eu, where Yb is used as a sensitizer element, and when Yb is used as a sensitizer, yb 3+ -Er 3+ Codoped combination ofThe light emitting material is used for absorbing f-f narrow-band ions to realize 4f-4f transition, has a small absorption section and a linear spectrum, and is converted into short-wavelength visible light to emit light under long-wavelength excitation to be up-converted to emit light. Yb of 3+ -Eu 3+ -Ce 3+ The co-doping combination utilizes the absorption of f-d broadband ions, and converts the broadband ions into long-wavelength near-infrared two-region luminescence under the excitation of short wavelength to perform down-conversion luminescence. The down-conversion luminescence is applied to the penetration depth of living body imaging tissues, and has higher imaging resolution.
The nano material REOF: ln in the rare earth probe for MRI/NIR II dual-mode imaging of the embodiment has good Magnetic Resonance Imaging (MRI) and near infrared two-region (NIR II,1000-1700 nm) fluorescence properties, the penetration depth is deep, the fluorescence intensity is strong, and the dual-mode imaging effect can be realized.
Research shows that MET is overexpressed in various cancers such as oral cancer, breast cancer, thyroid cancer and the like, is also called Hepatocyte Growth Factor (HGF) receptor, belongs to a tyrosine protein kinase receptor family, is mainly positioned on the surface of a cell membrane, and can be divided into an extracellular region, a transmembrane region and an intracellular region. When HGF is specifically combined with MET, the molecular structure of MET is changed, and downstream protein signal transduction pathways are further activated by activating and promoting intracellular MET autophosphorylation, so that the proliferation, division, growth, invasion and transfer of cells are regulated. Thus, MET is an attractive target for tumor diagnosis and therapy. Caratinib is a small molecular substance which is approved by FDA and targets MET at present, is combined with the nano material REOF: ln and loaded on the surface of the nano material REOF: ln, can carry out targeted marking and positioning on tumor tissues and cancer tissues, and is used for guiding surgical resection of the tumor tissues and the cancer tissues.
Further, the principle of photodynamic therapy (PDT) is that photosensitizers are excited by excitation light to produce singlet oxygen or Reactive Oxygen Species (ROS) for therapeutic purposes. The artemisinin structure contains a peroxide bond, and free radicals can be generated in vivo in an antimalarial process to be combined with plasmodium proteins so as to change the cell membrane structure of plasmodium. The property of artemisinin for generating free radicals to influence surrounding cells is similar to the photodynamic action, and experimental research shows that dihydroartemisinin also has photodynamic action. However, artemisinin absorbs at visible wavelengths and does not penetrate sufficiently into tissues, and therefore upconverting nanoparticles with anti-stokes energy transfer (long wavelength excitation, short wavelength emission) can be used to enhance its penetration.
In this example, yb in the nanomaterial REOF: ln is used as a sensitizer 3+ -Er 3+ The co-doping combination realizes 4f-4f transition by utilizing f-f narrow-band ion absorption, has a small absorption cross section and is in a linear spectrum, is converted into short-wavelength visible light to emit light under the excitation of long wavelength, is up-conversion light to emit light (namely, anti-Stokes effect), and is coupled with Dihydroartemisinin (DHA) to form a compound, so that the treatment effect of PDT is enhanced.
The nano material REOF: ln in the rare earth probe for MRI/NIR II dual-mode imaging of the embodiment has rare earth doped nanoparticles with up-conversion and NIR II region luminescence, and has MRI imaging effect due to doping Gd element, so that dual-mode imaging effect of Magnetic Resonance Imaging (MRI) and near infrared two-region (NIR II) imaging can be realized. The nano material is coupled with Dihydroartemisinin (DHA) to form a compound, the treatment effect of PDT is enhanced, and meanwhile, the targeting small molecular substance carbaminib is loaded, so that the accurate targeting MRI/NIR II imaging and treatment effects on tumors can be realized.
Example two
This example provides a preparation method for preparing the rare earth probe for MRI/NIR II dual-mode imaging in example I.
The main synthesis methods of the nano material include a solid phase method and a liquid phase method, wherein the liquid phase method is widely used due to safe operation, simple equipment and uniform products. Liquid phase methods include coprecipitation, hydrothermal/solvothermal, sol-gel and high temperature pyrolysis. The product prepared by the coprecipitation method has the advantages of high crystallinity, narrow particle size distribution, good dispersibility, high yield and simple and feasible device. In this embodiment, the coprecipitation method of the rare earth oxide mainly comprises coprecipitating a rare earth trivalent nitrate and urea, and calcining at a high temperature to generate a uniform micro-nanocrystalline material.
Specifically, the preparation of the rare earth probe for MRI/NIR II dual-mode imaging is to use deionized water as a solvent and rare earth nitrate as a precursor, generate a monodisperse rare earth oxyfluoride precursor under the participation of urea and potassium fluoride, then generate a nano material through calcination, and further compound dihydroartemisinin and carbaminib to obtain the rare earth probe for MRI/NIR II dual-mode imaging. The method specifically comprises the following steps:
s1: preparing a precursor material REOHCO by adopting a coprecipitation method 3 F:Ln；
In this embodiment, RE is one or more of La, gd, and Y, and Ln is Yb, er, ce, and Eu.
Specifically, S1 includes:
s11: 1.5-3 g of urea is weighed and dissolved in 30-50 ml of deionized water, and RE (NO) is added at the same time 3 ) 3 And Ln (NO) 3 ) 3 Then adding 0.08-0.12 g of KF and stirring until the solution is uniform;
s12: encapsulating the solution and placing the solution in a water bath at the temperature of 70-95 ℃ for coprecipitation reaction, wherein the reaction time is 2-4 h;
s13: centrifugally separating and drying the reaction product to obtain a precursor material REOHCO 3 F:Ln。
S2: subjecting the precursor material REOHCO 3 Calcining the F: ln to generate a nano material REOF: ln;
wherein the calcining treatment process comprises the following steps: calcining for 3-5 h in air atmosphere at 400-600 ℃.
S3: dissolving a nano material REOF & ltLn & gt in ultra-clean water by ultrasonic dissolution, simultaneously adding EDC powder and NHS powder, stirring until the solution is uniform, then adding dihydroartemisinin solution into the solution, and stirring to obtain a REOF & ltLn & gt-DHA solution;
specifically, 50mg of nano material REOF: ln powder is weighed in a small beaker, 20mL of ultra-clean water is added for ultrasonic dissolution, and then 30mg of EDC powder and 90mg of NHS powder are added and stirred for half an hour; secondly, weighing 50mg of dihydroartemisinin DHA under the condition of keeping out of the sun, and adding 500 mu L of chloroform to obtain a dihydroartemisinin solution; finally, the dihydroartemisinin solution is added into a small beaker and stirred for 12 hours to obtain a REOF solution, namely Ln-DHA solution.
S4: adding EDC powder and NHS powder into a REOF (rare earth oxygen) Ln-DHA solution, stirring until the solution is uniform, then adding carbamtinib under the condition of keeping out of the sun, and obtaining a rare earth probe REOF (rare earth oxygen) Ln-DHA-Cap for MRI/NIR II dual-mode imaging by centrifugation after stirring.
Specifically, first, a small beaker containing a solution of REOF: ln-DHA is placed on a stirrer, and 30mg of EDC powder and 90mg of NHS powder are added and stirred for half an hour; secondly, adding 500 mu L of carbamatinib Capmatic under the condition of keeping out of the sun, and stirring for 12 hours on ice; and finally, obtaining a rare earth probe REOF (rare earth element) Ln-DHA-Cap for MRI/NIR II dual-mode imaging by centrifugation.
It should be noted that, in other embodiments, before the nano material REOF: ln is prepared, the concentrations of the sensitizer Yb and the activators Er, ce, and Eu may be guided by using a genetic algorithm, the mixture ratio of Yb, er, ce, and Eu elements is optimized, so as to find an optimal mixture ratio, and then the nano material REOF: ln is prepared according to the optimal mixture ratio, so as to improve the light emitting performance of the near-infrared region of the nano material REOF: ln.
Specifically, the proportioning optimization step comprises:
s01: n groups of Yb (NO) in different proportions 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 Preparing n groups of nano materials REOF, yb/Er/Ce/Eu, as raw materials;
s02: using the volume of each raw material of n groups of nano materials and the corresponding luminous intensity as primary luminous data;
s03: setting the eligibility probability r according to the primary generation luminescent powder data by taking the luminescent intensity as the fitness of the genetic algorithm, and calculating to obtain Yb (NO) by utilizing the genetic algorithm 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 The optimal proportion of the raw materials.
Specifically, the genetic algorithm comprises the steps of:
a: the volume of each raw material dosage of 20 groups of nano materials is used as male parent data, the imaging result of the nano materials in an NIR II area is measured, and the luminous intensity is used as the fitness of the algorithm.
It should be noted that, the selection of the data to be processed by the algorithm cannot cause the luminance overexposure, which may affect the real luminance acquisition and increase the error.
b: referring to the fitness, the higher the probability of selection, and in the elite process, the code with the highest male parent fitness is directly replaced into the code of the next generation.
c: and selecting two male parent codes to carry out single-point crossing to generate two new codes.
d: and carrying out single-point mutation operation on the newly generated codes.
e: and normalizing the generated new codes to obtain two filial generation codes.
f: looping steps a-e until 20 sub-generation codes are generated as the next generation of synthesized data,
until the luminous intensity is not increased any more by experiment, the theoretical optimal solution can be considered to be reached to obtain Yb (NO) 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 The optimal proportion of the raw materials.
The preparation method of the rare earth probe needle for MRI/NIR II dual-mode imaging adopts a coprecipitation method to prepare the nano material, the operation is simple and easy, the preparation process is green and environment-friendly, the dispersibility of the generated nano material is good, and the raw material ratio is optimized by combining a genetic algorithm in the preparation process to obtain the optimal ratio.
EXAMPLE III
In this example, the preparation of the nano material is illustrated by taking GdOF: yb/Er/Ce/Eu as an example, and the specific preparation steps are as follows:
step 1: 1.5g of urea was weighed out and dissolved in 30mL of deionized water while adding 1mmol of Gd (NO) 3 ) 3 And Yb (NO) 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 Wherein Yb (NO) 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 The total amount of (1) and (2) adding 0.1g of KF, and stirring until the solution is uniform;
step 2: packaging the solution and placing the solution in a water bath at 90 ℃ for coprecipitation reaction, wherein the reaction time is 3h;
and step 3: after the reaction is finished, centrifugally separating and drying the reaction product to obtain a precursor material GdOHCO 3 F:Yb/Er/Ce/Eu；
And 4, step 4: the precursor material GdOHCO is added 3 F, yb/Er/Ce/Eu is calcined in air at 500 ℃ for 3h to generate a nano material GdOF, yb/Er/Ce/Eu.
Referring to fig. 1, fig. 1 is an SEM (scanning electron microscope) image of the GdOF: yb/Er/Ce/Eu nanomaterial provided in the embodiment of the present invention, and it can be seen that the GdOF: yb/Er/Ce/Eu nanomaterial prepared by the co-precipitation method in the embodiment has better uniform dispersibility.
Referring to fig. 3, fig. 3 is a Magnetic Resonance Imaging (MRI) graph of GdOF: yb/Er/Ce/Eu nanomaterial provided by an embodiment of the present invention under different Gd concentrations, and it can be seen from the image that the larger the Gd concentration is, the greater the T1 signal is enhanced, some of the data are not linear enough, possibly because the larger the Gd concentration is, the precipitation is generated, so that the T1 signal is reduced.
Further, in this embodiment, the ratio of Yb, er, ce, and Eu elements is optimized by using a genetic algorithm to obtain an optimal ratio, and the nano material GdOF is prepared according to the optimal ratio. Referring to fig. 2, fig. 2 is a near infrared two-region (NIR II) imaging graph of the genetic algorithm-derived optimum ratio GdOF Yb/Er/Ce/Eu nanomaterial provided in the embodiment of the present invention, and it can be seen from the graph that the genetic algorithm-derived optimum ratio GdOF Yb/Er/Ce/Eu nanomaterial has strong near infrared two-region imaging at an excitation wavelength of 808 nm.
Example four
In this embodiment, the preparation method and the photodynamic therapy effect of GdOF, yb/Er/Ce/Eu-DHA are described as follows:
step 1: 1.5g of urea was weighed out and dissolved in 30mL of deionized water while adding 1mmol of Gd (NO) 3 ) 3 And Yb (NO) 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 In which Yb (NO) 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 The total amount of (1) and (2) adding 0.1g of KF, and stirring until the solution is uniform;
step 2: packaging the solution and placing the solution in a water bath at 90 ℃ for coprecipitation reaction, wherein the reaction time is 3h;
and step 3: after the reaction is finished, centrifugally separating and drying the reaction product to obtain a precursor material GdOHCO 3 F:Yb/Er/Ce/Eu；
And 4, step 4: the precursor material GdOHCO is added 3 F, calcining Yb/Er/Ce/Eu in air at 500 ℃ for 3h to generate a nano material GdOF, yb/Er/Ce/Eu;
and 5: weighing 50mg of nano material powder in a small beaker, adding 20mL of ultra-pure water for ultrasonic dissolution, adding 30mg of EDC powder and 90mg of NHS powder, and stirring for half an hour;
step 6: weighing 50mg of dihydroartemisinin DHA under the condition of keeping out of the sun, and adding 500 mu L of chloroform to obtain a dihydroartemisinin solution;
and 7: adding the dihydroartemisinin solution into a small beaker, stirring for 12h, and then centrifuging to obtain a GdOF: yb/Er/Ce/Eu-DHA sample.
Referring to FIG. 4, FIG. 4 is a diagram of the absorption of DPBF, which is used to detect the amount of ROS (reactive oxygen species) generated, of GdOF, yb/Er/Ce/Eu-DHA provided by an embodiment of the present invention, at an excitation wavelength of 980 nm. As can be seen from the figure, the absorption of GdOF, namely Yb/Er/Ce/Eu-DHA is reduced at 400nm under the irradiation of laser with the wavelength of 980nm, the existence of ROS when GdOF, namely Yb/Er/Ce/Eu-DHA is irradiated at 980nm exciting light is proved, and the GdOF, namely Yb/Er/Ce/Eu-DHA has certain photodynamic effect.
EXAMPLE five
In this embodiment, a GdOF/Er/Ce/Eu-DHA-Cap probe is taken as an example to explain the preparation method, imaging and targeting effects, and applications thereof, and the specific preparation steps are as follows:
step 1: 1.5g of urea was weighed out and dissolved in 30mL of deionized water while adding 1mmol of Gd (NO) 3 ) 3 And Yb (NO) 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 In which Yb (NO) 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 The total amount of (1) and (2) adding 0.1g of KF, and stirring until the solution is uniform;
step 2: packaging the solution and placing the solution in a water bath at 90 ℃ for coprecipitation reaction, wherein the reaction time is 3h;
and 3, step 3: after the reaction is finished, centrifugally separating and drying the reaction product to obtain a precursor material GdOHCO 3 F:Yb/Er/Ce/Eu；
And 4, step 4: the precursor material GdOHCO is added 3 F, calcining Yb/Er/Ce/Eu in air at 500 ℃ for 3h to generate a nano material GdOF, yb/Er/Ce/Eu;
and 5: weighing 50mg of GdOF;
step 6: weighing 50mg of dihydroartemisinin DHA under the condition of keeping out of the sun, and adding 500 mu L of chloroform to obtain a dihydroartemisinin solution;
and 7: adding the dihydroartemisinin solution into a small beaker, and stirring for 12 hours to obtain a GdOF (Yb/Er/Ce/Eu-DHA) solution;
and 8: placing a small beaker containing a GdOF Yb/Er/Ce/Eu-DHA solution on a stirrer, adding 30mg of EDC powder and 90mg of NHS powder, and stirring for half an hour;
and step 9: 500 μ L of carbamtinib (Capmatic) was added in the dark, stirred on ice for 12h, and then centrifuged to obtain a GdOF: yb/Er/Ce/Eu-DHA-Cap probe.
In the embodiment, a GdOF probe, namely Yb/Er/Ce/Eu-DHA-Cap, is adopted to mark the tongue carcinoma orthotopic tumor and subcutaneous tumor of the mouse and develop the tongue carcinoma orthotopic tumor and subcutaneous tumor. After an in-situ mouse is sacrificed, the tongue of the mouse is cut off, and NIR II imaging is performed after spraying and washing treatment is performed on the GdOF, namely Yb/Er/Ce/Eu-DHA-Cap, as shown in figure 5, the figure 5 is an imaging picture of the NIR II area of the mouse in-situ tongue cancer targeted by the GdOF, namely Yb/Er/Ce/Eu-DHA-Cap probe provided by the embodiment of the invention, and as can be seen from the figure, the probe is well gathered at a tumor part, and the targeting of the probe to a certain degree is verified. As shown in FIG. 6, FIG. 6 is an imaging diagram of NIR II of subcutaneous tumors targeted to Cal27 cells of mouse tongue cancer by using GdOF: yb/Er/Ce/Eu-DHA-Cap probe provided in the embodiments of the present invention. As can be seen from the figure, the brightness of the subcutaneous tumor part of the mouse is obviously gathered at 24h, and the GdOF, yb/Er/Ce/Eu-DHA-Cap probe has better targeting property.
It should be noted that, in this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that an article or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed. Without further limitation, an element defined by the phrases "comprising one of \8230;" does not exclude the presence of additional like elements in an article or device comprising the element.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (6)
1. A rare earth probe for MRI/NIR II dual-mode imaging, which is characterized by comprising: the lanthanide oxyfluoride nano material REOF: ln with near-infrared two-zone fluorescence imaging elements and magnetic resonance imaging elements, and dihydroartemisinin and carbamatinib loaded on the surface of the nano material REOF: ln have the structural general formula: REOF is Ln-DHA-Cap, wherein RE comprises magnetic resonance imaging elements, RE is Gd, ln comprises sensitizer elements, up-conversion luminescent elements and near-infrared second-zone fluorescent elements, ln is Yb, er, ce and Eu, DHA is dihydroartemisinin, cap is carbamatinib;
the rare earth probe for MRI/NIR II dual-mode imaging is used as a spraying contrast agent to realize the positioning effect of the probe.
2. A preparation method of a rare earth probe for MRI/NIR II dual-mode imaging is characterized by comprising the following steps:
s1: preparing a precursor material REOHCO by adopting a coprecipitation method 3 F:Ln；
S2: subjecting the precursor material to REOHCO 3 Calcining the F: ln to generate a nano material REOF: ln;
s3: dissolving the nano material REOF: ln in ultra-clean water by ultrasonic dissolution, simultaneously adding EDC powder and NHS powder, stirring until the solution is uniform, then adding dihydroartemisinin solution, and stirring to obtain a REOF: ln-DHA solution;
s4: adding EDC powder and NHS powder into the REOF, ln-DHA solution, stirring until the solution is uniform, then adding carbamtinib under the condition of keeping out of the sun, and obtaining a rare earth probe REOF, ln-DHA-Cap of MRI/NIR II dual-mode imaging by centrifugation after stirring;
wherein RE comprises a magnetic resonance imaging element, RE is Gd, ln comprises a sensitizer element, an up-conversion luminescent element and a near-infrared two-region fluorescent element, and Ln is Yb, er, ce and Eu;
the prepared MRI/NIR II dual-mode imaging rare earth probe is used as a spraying contrast agent to realize the positioning effect of the probe.
3. The method for preparing a rare earth probe for MRI/NIR II dual-mode imaging according to claim 2, wherein the S1 comprises:
s11: 1.5-3 g of urea is weighed and dissolved in 30-50 ml of deionized water, and RE (NO) is added at the same time 3 ) 3 And Ln (NO) 3 ) 3 Then adding 0.08-0.12 g of KF and stirring until the solution is uniform;
s12: encapsulating the solution and placing the solution in a water bath at the temperature of 70-95 ℃ for coprecipitation reaction, wherein the reaction time is 2-4 h;
s13: centrifugally separating and drying the reaction product to obtain a precursor material REOHCO 3 F:Ln。
4. The preparation method of the rare earth probe for MRI/NIR II dual-mode imaging according to claim 2, wherein in the S2, the calcination treatment process is: calcining for 3-5 h in air atmosphere at 400-600 ℃.
5. The method for preparing the rare earth probe for MRI/NIR II dual-mode imaging according to claim 2, wherein before preparing the nano material REOF: ln, the method further comprises: optimizing the proportion of Yb, er, ce and Eu elements by using a genetic algorithm to obtain an optimal proportion, and preparing nano materials REOF: ln according to the optimal proportion; wherein, the matching optimization step comprises:
s01: n groups of Yb (NO) in different proportions 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 Using the material as raw material to prepare n groups of nano materials REOF: yb/Er/Ce/Eu;
s02: using the volume of each raw material of n groups of nano materials and the corresponding luminous intensity as primary luminous data;
s03: setting the eligibility probability r according to the primary generation luminescence data and the fitness of the genetic algorithm by taking the luminescence intensity, and calculating to obtain Yb (NO) by utilizing the genetic algorithm 3 ) 3 、Er(NO 3 ) 3 、Ce(NO 3 ) 3 And Eu (NO) 3 ) 3 The optimal proportion of the raw materials.
6. The rare earth probe for MRI/NIR II dual mode imaging as claimed in claim 1, wherein the use as a marker for spray contrast agent marking and localization of tumor tissue and cancer tissue, the use of a navigator for navigated surgical resection of tumor tissue and cancer tissue.
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