Preparation method and application of a magnetic resonance imaging nano probe capable of penetrating pancreatic cancer tumor interstitium

Abstract

The application discloses a preparation method and application of a magnetic resonance imaging nano probe capable of penetrating pancreatic cancer tumor interstitium and belongs to the technical field of self-driven magnetic resonance imaging nano probes. The magnetic resonance imaging nano probe Ag / Ag2S-GP capable of penetrating pancreatic cancer tumor interstitium can have an oxidation-reduction reaction with H2O2 in a tumor microenvironment, continuously generate oxygen gas flow, and the back thrust of the gas flow can autonomously drive the probe to move to the deep part of the tumor interstitium. The Plectin-1 targeting peptide on the surface of the Ag / Ag2S-GP can also specifically combine with the Plectin-1 protein highly expressed by pancreatic cancer cells, and realize precise spatial positioning and monitoring of the pancreatic cancer under the guidance of MRI. Meanwhile, the Ag / Ag2S-GP can reduce a Schottky barrier under the piezoelectric catalysis of ultrasonic excitation, generate hydroxyl radicals, induce tumor cell apoptosis, and thus enhance the diagnosis and treatment effect of the pancreatic cancer.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of self-driven magnetic resonance imaging nanoprobes, in particular to a preparation method and application of a magnetic resonance imaging nanoprobe capable of penetrating pancreatic cancer tumor interstitium. BACKGROUND

[0002] Pancreatic cancer is a digestive system malignant tumor with extremely poor prognosis, and the 5-year survival rate is only 13%. It is the third leading cause of cancer-related deaths worldwide. Due to its insidious onset and no obvious early symptoms, about 80% of patients are in the advanced stage when diagnosed, losing the opportunity for surgery. At present, chemotherapy is still the main treatment. Although new anti-tumor drugs are emerging, the prognosis of pancreatic cancer patients has not improved significantly, which is mainly due to the drug delivery obstacle caused by dense tumor interstitium.

[0003] During the evolution of pancreatic cancer, tumor-associated fibroblasts and pancreatic stellate cells secrete a large amount of extracellular matrix components such as collagen, fibronectin and hyaluronic acid through complex interactions, forming a highly dense fibrous connective tissue microenvironment. This unique structure not only increases the interstitial pressure of the tumor, but also hinders the effective penetration and distribution of drugs to the tumor parenchyma through the physical barrier effect, reducing the therapeutic effect. Therefore, developing a new drug delivery system that can overcome the physical barrier and enhance drug penetration has become a key research direction to improve the treatment effect and prognosis of pancreatic cancer.

[0004] The "self-propelled" technology represented by nanomotor can convert external environmental energy into its own mechanical kinetic energy, which is expected to penetrate the dense interstitial barrier of the tumor and realize more efficient drug delivery and imaging diagnosis functions. The Ag / Ag2S Schottky junction is an asymmetric heterostructure formed by the interface contact of metal Ag and semiconductor Ag2S. Its unique interface electron characteristics and energy band structure can catalyze the redox reaction of H2O2 to continuously generate oxygen (O2). With the reaction, O2 molecules gradually accumulate on the surface of Ag / Ag2S and form microbubbles. The periodic formation, growth and detachment of microbubbles produce micro-scale thrust, driving the directional movement of Ag / Ag2S. This characteristic of Ag / Ag2S provides a new exploration direction for breaking through the interstitial barrier of the tumor, and is expected to improve the treatment effect of the tumor by promoting the directional transmission of drugs.

[0005] In addition, Ag / Ag2S has important application value in the field of piezocatalysis. Ag2S is a sulfide semiconductor, and its unique crystal structure can change the relative position between atoms under the action of ultrasonic vibration, causing crystal deformation. Based on the piezoelectric effect, this crystal deformation can generate a piezoelectric potential, driving the directional migration of electrons within the material and forming a local electric field. The metal Ag, with its excellent electrical conductivity, can serve as an efficient electron transport channel, accelerating the migration of electrons in the piezocatalytic process and enabling them to participate more efficiently in subsequent chemical reactions. The Schottky barrier can precisely control the direction of electron transfer, further enhancing the efficiency of piezocatalysis. As mentioned above, the Ag / Ag2S Schottky junction, under the action of ultrasonic-induced piezocatalysis, can efficiently generate hydroxyl radicals with cytotoxicity, providing a new strategy for the precise treatment of pancreatic cancer. SUMMARY

[0006] The purpose of the present application is to provide a preparation method and application of a magnetic resonance imaging nanoprobes that can penetrate the interstitial matrix of pancreatic cancer tumor, in order to solve the problem of drug delivery for pancreatic cancer.

[0007] To achieve the above-mentioned purpose, the present application provides a preparation method of a magnetic resonance imaging nanoprobes that can penetrate the interstitial matrix of pancreatic cancer tumor, comprising the following steps:

[0008] S1, preparing Ag / Ag2S solution with acetylacetone silver and thioacetamide as raw materials;

[0009] S2, dissolving SH-PEG-NHS and Gd-DOTA in deionized water, stirring for 6 hours under ice bath to obtain Gd-DOTA-PEG-SH solution;

[0010] S3, mixing pancreatic cancer targeting peptide KTLLPTP and SH-PEG-NHS, stirring for 6 hours under ice bath to obtain PTP-(CO-NH)-PEG-SH solution;

[0011] S4, mixing Ag / Ag2S solution, Gd-DOTA-PEG-SH solution and PTP-(CO-NH)-PEG-SH solution, stirring under ice bath, washing with pure water to obtain the final product, magnetic resonance imaging nanoprobes Ag / Ag2S-Gd-PTP. g2 S solution, Gd-DOTA-PEG-SH solution and PTP-(CO-NH)-PEG-SH solution, stirring under ice bath, washing with pure water to obtain the final product, magnetic resonance imaging nanoprobes Ag / Ag2S-Gd-PTP.

[0012] Preferably, in S1, the preparation of Ag / Ag2S solution comprises:

[0013] S11, dissolving acetylacetone silver and trisodium citrate in ethylene glycol, adding polyethyleneimine, stirring for 2 hours to obtain solution A;

[0014] S12, 0.05M thioacetamide and 0.5mL triethanolamine were added into solution A under stirring to obtain a mixture; the mixture was reacted by solvothermal method at 200℃ for 1h to obtain Ag / Ag2S solution.

[0015] Preferably, in S11, the volume mass ratio of silver acetylacetonate: trisodium citrate: ethylene glycol: polyethyleneimine is 0.186mg: 0.882mg: 15mL: 150mg.

[0016] Preferably, in S12, the volume ratio of thioacetamide: triethanolamine: solution A is 1.5mL: 0.5mL: 15mL.

[0017] Preferably, in S2, the mass volume ratio of SH-PEG-NHS: Gd-DOTA: deionized water is 3mg: 0.5mg: 4mL.

[0018] Preferably, in S3, the mass ratio of KTLLPTP: SH-PEG-NHS is 20μg: 1mg.

[0019] Preferably, in S4, the volume ratio of Ag / Ag2S solution: Gd-DOTA-PEG-SH solution: PTP-(CO-NH)-PEG-SH solution is 17mL: 4mL: 4mL.

[0020] In another aspect, the application provides a pancreatic cancer tumor interstitium-penetrating magnetic resonance imaging nano probe Ag / Ag2S-Gd-PTP prepared by the above preparation method.

[0021] In another aspect, the application provides a use of the above nano probe Ag / Ag2S-Gd-PTP in the preparation of a pancreatic cancer active targeting, interstitium-penetrating, piezoelectric catalysis and magnetic resonance imaging drug.

[0022] Therefore, the application has the following beneficial effects:

[0023] (1) Ag / Ag2S-GP and high concentration of H2O2 in tumor microenvironment undergoes redox reaction to continuously generate O2, and the back thrust of gas flow is used to drive the penetration of tumor interstitium;

[0024] (2) Ag / Ag2S-GP is specifically combined with Plectin-1 protein highly expressed in pancreatic cancer cells through surface modified Plectin-1 targeting peptide, so that the targeting of the diagnosis and treatment probe is improved;

[0025] (3) Based on the T1 weighted relaxation performance of Gd-DOTA, the distribution and running track of Ag / Ag2S-GP in vivo can be visualized in real time under the guidance of MRI, so as to provide spatial positioning for subsequent ultrasound-induced piezoelectric catalysis;

[0026] (4) Under the piezoelectric catalysis of Ag / Ag2S-GP under ultrasound excitation, water is oxidized into hydroxyl radicals, and these strong oxidizing free radicals are used to induce tumor cell apoptosis;

[0027] (5) The synthesis method of the magnetic resonance imaging nano probe capable of penetrating the interstitial matrix of pancreatic cancer tumors is simple and easy to operate, and the synthesized product is stable and has repeatability;

[0028] (6) The magnetic resonance imaging nano probe capable of penetrating the interstitial matrix of pancreatic cancer tumors synthesized by the application has good biocompatibility;

[0029] (7) The magnetic resonance imaging nano probe capable of penetrating the interstitial matrix of pancreatic cancer tumors synthesized by the application is beneficial to clinical disease diagnosis and treatment.

[0030] The technical solutions of the application will be further described in detail below with the help of the accompanying drawings and examples. DETAILED DESCRIPTION

[0031] In order to more clearly illustrate the technical solutions of the embodiments of the application, the drawings needed to be used in the description of the embodiments of the application will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the application, and other drawings can be obtained by those skilled in the art without creative labor.

[0032] Figure 1 It is a transmission electron microscope image of Ag / Ag2S-GP;

[0033] Figure 2 It is a high-resolution transmission electron microscope lattice analysis image of Ag / Ag2S-GP;

[0034] Figure 3 It is an X-ray diffraction image of Ag / Ag2S-GP;

[0035] Figure 4 It is a mapping atlas of Ag / Ag2S-GP;

[0036] Figure 5 It is a hydrated particle size image of Ag / Ag2S-GP;

[0037] Figure 6 It is a Zeta potential image of Ag / Ag2S, Ag / Ag2S-G, Ag / Ag2S-GP;

[0038] Figure 7 The statistical diagram of the hydrated particle size of Ag / Ag2S-GP within 5 days;

[0039] Figure 8 Binding energy analysis of Ag / Ag2S, where A is the XPS spectrum of Ag 3d signals of Ag and Ag / Ag2S, and B is the XPS spectrum of S 2p signals of Ag2S and Ag / Ag2S;

[0040] Figure 9 Nyquist plots of Ag, Ag / Ag2S and Ag2S;

[0041] Figure 10 Analysis of the oxygen production capacity of Ag / Ag2S-GP, where A is the dissolved oxygen content curve of Ag / Ag2S-GP treated with H2O2 for different time periods, and B is a picture of the dissolved oxygen generation process;

[0042] Figure 11 Analysis of the "self-propelled" penetration ability of Ag / Ag2S-GP, where part A is a Z-stack tomographic fluorescence image of Ag / Ag2S-GP with or without H2O2 after co-incubation with micro-tumor spheres for 6 hours; part B is the distribution of Ag / Ag2S-GP along the white dotted line at 150 μm;

[0043] Figure 12 Figure 3 shows the generation of hydroxyl radicals by Ag / Ag2S-GP under ultrasound stimulation, where A is the fluorescence image of PANC-1 cells stained with DCFH-DA after different treatments, and B is the quantification of the fluorescence image in A.

[0044] Figure 13 The contrast-enhanced magnetic resonance imaging performance analysis of Ag / Ag2S-GP is shown in Figure 1, where A is the MRI image of Ag / Ag2S-GP and B is the T1WI relaxation rate.

[0045] Figure 14 These are H&E-stained images of tissue sections of important organs (heart, liver, spleen, lung, and kidney) of healthy mice 7 days after tail vein injection of Ag / Ag2S-GP. DETAILED DESCRIPTION

[0046] The technical solution of the present invention is further described below with reference to the accompanying drawings and embodiments.

[0047] In order to make the purpose, technical solutions and advantages of the present application clearer, more thorough and more complete, the technical solutions of the present invention are clearly and completely described below through the accompanying drawings and Examples. The following detailed description is an explanation of the embodiments and is intended to provide further details of the present invention. Unless otherwise specified, all technical terms used in the present invention have the same meaning as those generally understood by those skilled in the art to which the application belongs.

[0048] The instrument equipment and reagent materials used in the examples are obtained through commercial channels.

[0049] Example 1

[0050] A preparation method of a magnetic resonance imaging nanoprobe capable of penetrating the interstitial space of a pancreatic cancer tumor, comprising the following steps:

[0051] S1, Preparation of Ag / Ag2S nanoprobe.

[0052] Dissolve 0.186 mg silver acetylacetone and 0.882 mg trisodium citrate in 15 mL ethylene glycol, then add 150 mg polyethyleneimine and stir thoroughly for 2 hours. Under stirring, add 1.5 mL 0.05M thioacetamide and 0.5 mL triethanolamine in sequence, transfer the resulting mixture to a microwave synthesis instrument, and react at 200°C for 1 hour to obtain an Ag / Ag2S solution. The product is dispersed in water and stored at 4°C for use.

[0053] S2, Preparation of Gd-DOTA-PEG-SH solution.

[0054] Dissolve 3 mg SH-PEG-NHS (mercapto polyethylene glycol active ester) and 0.5 mg magnetic resonance contrast agent Gd-DOTA (Gd III-1, 4, 7-tris (tert-butoxycarbonylmethyl) -10- (acetic acid) -1, 4, 7, 10-tetraazacyclododecane) in 4 mL deionized water, and stir thoroughly at 4°C for 6 hours to obtain a Gd-DOTA-PEG-SH solution.

[0055] S3, Preparation of PTP-(CO-NH)-PEG-SH solution.

[0056] Mix 20 μg of target peptide PTP (KTLLPTP) and 1 mg of SH-PEG-NHS, and stir thoroughly at 4°C for 6 hours to obtain a PTP-(CO-NH)-PEG-SH solution.

[0057] S4, Preparation of Ag / Ag2S-GP.

[0058] Mix 17 mL of Ag / Ag2S, 4 mL of Gd-DOTA-PEG-SH, and 4 mL of PTP-(CO-NH)-PEG-SH solution, stir in an ice bath, and wash with pure water to obtain the final product, magnetic resonance imaging nanoprobe Ag / Ag2S-Gd-PTP (abbreviated as Ag / Ag2S-GP).

[0059] Test Example 1

[0060] (1) After diluting the Ag / Ag2S-GP solution, take 10 μL and drop it onto a 200-mesh copper grid covered with a carbon film and let it air dry. Subsequently, the morphology of the Ag / Ag2S-GP was observed and imaged. The transmission electron microscope image of the Ag / Ag2S-GP is shown in Figure 2. Figure 1 The lattice composition of Ag / Ag2S-GP was analyzed using high-resolution transmission electron microscopy. Figure 2 shown.

[0061] The transmission electron microscopy (TEM) images of Ag / Ag2S-GP show a uniform heterojunction morphology with good dispersion and an average particle size of approximately 8 nm. High-resolution TEM images clearly show the independent lattice fringes of the two components, where the lattice spacing of 0.24 nm corresponds to the (111) crystal plane of the cubic phase Ag, while the lattice spacing of 0.31 nm corresponds to the (111) crystal plane of the monoclinic phase Ag2S. It is worth noting that the high-resolution TEM images show the presence of an atomically smooth interface and a continuous lattice between Ag2S and Ag, confirming the formation of a Schottky junction rather than a simple physical mixing.

[0062] Test Example 2

[0063] Ag / Ag2S-GP was dried and ground into powder. The XRD instrument was calibrated with standard samples to ensure accurate angles and intensities. The instrument was started and the sample was scanned according to the set parameters to record the diffraction data. The data was processed using software to identify the diffraction peaks. The phase was determined by comparing with the standard database. Figure 3 As shown in Figure 3, the X-ray diffraction pattern further verified the successful synthesis of Ag / Ag2S-GP, and the positions and relative intensities of all diffraction peaks were completely consistent with the standard cards of cubic phase Ag and monoclinic phase Ag2S.

[0064] Test Example 3

[0065] The element mapping patterns were collected by field emission electron microscopy to verify the elemental composition of Ag / Ag2S-GP, such as Figure 4 The element mapping shows that Ag, S, Gd, C, N, and O are evenly distributed, confirming the successful construction of Ag / Ag2S-GP.

[0066] Test Example 4

[0067] The hydrated particle size of Ag / Ag2S-GP is as follows: Figure 5 As shown, the hydrated particle size of Ag / Ag2S-GP is about 21.9 nm.

[0068] The Zeta potential of Ag / Ag2S, Ag / Ag2S-G, and Ag / Ag2S-GP is as follows Figure 6As shown in the figure, during the functional modification process, the Zeta potential gradually decreased from 19.43 mV (Ag / Ag2S) to 5.24 mV (Ag / Ag2S-G), and then to 2.46 mV (Ag / Ag2S-GP).

[0069] The colloidal stability of Ag / Ag2S-GP was evaluated and its hydrated particle size was continuously monitored for 5 days. Figure 7 As shown, the results showed that the particle size did not change significantly, indicating that the probe has good colloidal stability.

[0070] Test Example 5

[0071] The electronic state of Ag / Ag2S was systematically characterized by X-ray photoelectron spectroscopy and compared with pure Ag and Ag2S. Figure 8 As shown, A is the XPS spectrum of Ag 3d signals of Ag and Ag / Ag2S, and B is the XPS spectrum of S2p signals of Ag2S and Ag / Ag2S.

[0072] Ag 3d with pure Ag 5 / 2 and Ag 3d 3 / 2 The binding energy (BE) of the Ag / Ag2S signal (368.2eV and 374.2eV) is negatively shifted compared to that of the Ag / Ag2S signal (367.8eV and 373.8eV), indicating that the Ag part of Ag / Ag2S has a higher electron density. 3 / 2 and S 2p 1 / 2 The BE of the signal (160.3 eV and 161.5 eV) is positively shifted compared to that of Ag2S (160.0 eV and 161.2 eV), indicating a decrease in the electron density of the Ag2S portion of the Ag / Ag2S complex. These changes in binding energy confirm the presence of electron transfer from Ag2S to Ag at the Ag / Ag2S interface, resulting in the enrichment of negative charge on the Ag surface.

[0073] Test Example 6

[0074] The electrochemical impedance spectroscopy test was performed on a standard three-electrode electrochemical workstation (CHI 660D) at 25°C, with platinum (Pt) wire and Ag / AgCl electrodes as counter and reference electrodes, respectively. Before the measurement, the glassy carbon electrode was carefully polished with 0.05 μM alumina powder, then cleaned with ultrasonic waves through Milli-Q water and ethanol, and finally dried at room temperature to prepare for the next experimental operation. Subsequently, the catalyst ink (including Ag, Ag2S and Ag / Ag2S) was drop-coated on the glassy carbon electrode to prepare the working electrode. In 0.5 M KOH solution, the reaction was carried out at 20 mV s −1The cyclic voltammetry and Nyquist curves of the scanning rate records of the catalysts (including Ag, Ag2S and Ag / Ag2S) were recorded. During the whole test, ultrasound was used as an excitation source and focused on the working electrode to improve the signal response sensitivity.

[0075] As shown in the results Figure 9 , electrochemical impedance spectroscopy analysis showed that Ag / Ag2S had the smallest Nyquist circle radius compared with Ag and Ag2S, indicating that it had the lowest charge transfer resistance, which was beneficial to the charge of piezoelectric catalysis.

[0076] Test Example Seven

[0077] First, the dissolved oxygen meter was calibrated for zero oxygen and saturated oxygen, and then the probe was inserted into the zero oxygen water for standby. After mixing Ag / Ag2S-GP with 10 mM H2O2 solution (simulating tumor microenvironment conditions), the amount of O2 generated was monitored and recorded in real time by the dissolved oxygen meter. In addition, photographs were taken at different times after mixing Ag / Ag2S-GP with 10 mM H2O2 solution.

[0078] As shown in the results Figure 10 , where A is the dissolved oxygen content generation curve of Ag / Ag2S-GP treated with H2O2 for different times, and B is the picture of the dissolved oxygen generation process. The results show that after mixing Ag / Ag2S-GP with 10 mM H2O2 solution, the reaction process is accompanied by the generation of a large number of bubbles and the increase of dissolved oxygen concentration, which confirms that Ag / Ag2S-GP can spontaneously catalyze the decomposition of H2O2 to produce O2 molecules.

[0079] Test Example Eight

[0080] Micro-tumor cell spheres were prepared by liquid overlay method. 0.16 g of agarose was dissolved in 10 mL of DMEM medium under stirring in a 100°C water bath, and then subjected to high-temperature sterilization treatment. After sterilization, the dissolved agarose was quickly added to a 96-well plate and left to cool to a solid state. After the agarose solidified, pancreatic cancer cells PANC-1, pancreatic stellate cells HSPC and matrigel suspension were inoculated into the 96-well plate pre-coated with agarose (8000 cells / well). After inoculation, the cells were cultured in a cell culture incubator until spheres with a diameter of about 300 μm were formed. Ag / Ag2S-GP or Ag / Ag2S-GP+H2O2 (10 mM) complex solution was co-incubated with micro-tumor cell spheres in a constant-temperature incubator for 6 hours. After incubation, the cell spheres were washed slowly with PBS and then transferred to a confocal dish. The micro-tumor spheres were subjected to Z-stack tomography under a confocal laser microscope, and a fluorescence image was taken every 15 μm. The acquired images were quantitatively analyzed by Image J software.

[0081] The results are shown in the following tableFigure 11 As shown, part A is a Z-stack tomographic fluorescence photograph of Ag / Ag2S-GP with or without H2O2 after co-incubation with micro-tumor spheres for 6 hours, and part B is the distribution of Ag / Ag2S-GP along the white dotted line at 150 μm.

[0082] The results showed that within the depth range of 0-150 μm, the micro-tumor spheres containing H2O2 showed stronger fluorescence signals within the same depth range, which confirmed that Ag / Ag2S-GP could enhance the tumor interstitial penetration ability through "self-propelling" behavior in the tumor microenvironment.

[0083] Test Example 9

[0084] Free radical generation was assessed using a reactive oxygen species detection kit. Pancreatic cancer cells PANC-1 in the logarithmic growth phase were seeded in confocal microplates and, after adherence, were treated according to the experimental groups. After treatment, cells in each group were stained with a DCFH-DA probe, and nuclei were labeled with Hoechst stain. After staining, images were captured using a fluorescence microscope to observe the generation of hydroxyl radicals by Ag / Ag2S-GP under piezoelectric catalysis. Subsequently, image quantification was performed to analyze the differences in free radical generation intensity among the experimental groups to assess the piezoelectric catalytic efficiency of Ag / Ag2S-GP and its potential to induce oxidative stress in tumor cells.

[0085] The results are as follows Figure 12 As shown in the figure, A is the fluorescence image of PANC-1 cells stained with DCFH-DA after different treatments, and B is the quantification of the fluorescence image in A. The results showed that compared with other control groups, the level of intracellular hydroxyl radicals in the Ag / Ag2S-GP+US group was significantly increased, confirming that Ag / Ag2S-GP can efficiently generate hydroxyl radicals under ultrasound excitation.

[0086] Test Example 10

[0087] A series of Ag / Ag2S-GP solutions with a concentration gradient were prepared and sequentially placed into centrifuge tubes. The frequency and pulse sequence for measuring T1 relaxation time were set on a 9.4T magnetic resonance imaging system. The system collected and analyzed the relaxation signal data and calculated the longitudinal relaxation rate (r1).

[0088] The results are as follows Figure 13 As shown, A is the MRI image of Ag / Ag2S-GP and B is the T1WI relaxation rate. The results show that with the increase of Gd ion concentration, the MR image signal intensity of Ag / Ag2S-GP is significantly enhanced, and its longitudinal relaxation rate (r1) value is 3.9614mM -1 S -1 , indicating that Ag / Ag2S-GP has good MRI enhancement performance.

[0089] Test Example XI

[0090] Ag / Ag2S-GP (200 μg / mL) was injected into healthy mice through the tail vein. The mice were sacrificed on the 7th day after administration, and the main organs such as heart, liver, spleen, lung, kidney, etc. were completely taken out for H&E staining. The pathological changes of the tissues were observed, and the in vivo biological safety of Ag / Ag2S-GP was systematically evaluated.

[0091] As shown in FIG. 14, H&E staining of the tissue sections of the important organs (heart, liver, spleen, lung, and kidney) of the mice on the 7th day after tail vein injection of Ag / Ag2S-GP showed that there was no obvious pathological damage in each organ.

[0092] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application rather than limiting them, although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that: the technical solutions of the present application can still be modified or replaced by equivalents, and these modifications or equivalent replacements cannot make the modified technical solutions deviate from the spirit and scope of the technical solutions of the present application.

Claims

1. A method for preparing a magnetic resonance imaging nanoprobe capable of penetrating pancreatic cancer tumor stroma, characterized in that: The steps include: S1. Prepare Ag / Ag2S solution using silver acetylacetonate and thioacetamide as raw materials; S11, dissolving silver acetylacetonate and trisodium citrate in ethylene glycol, adding polyethyleneimine, and stirring to react for 2 hours to obtain solution A; The volume mass ratio of silver acetylacetonate: trisodium citrate: ethylene glycol: polyethyleneimine is 0.186 mg: 0.882 mg: 15 mL: 150 mg; S12. 0.05 M thioacetamide and 0.5 mL triethanolamine were sequentially added to solution A under stirring to obtain a mixture; the mixture was reacted by a solvothermal method at 200° C. for 1 hour to obtain an Ag / Ag2S solution; The volume ratio of thioacetamide: triethanolamine: solution A is 1.5 mL: 0.5 mL: 15 mL; S2. Dissolve SH-PEG-NHS and Gd-DOTA in deionized water and stir under ice bath for 6 hours to obtain a Gd-DOTA-PEG-SH solution; S3, mixing the pancreatic cancer targeting peptide KTLLPTP and SH-PEG-NHS, and stirring under ice bath for 6 hours to obtain a PTP-(CO-NH)-PEG-SH solution; S4, Ag / A g2 The S solution, Gd-DOTA-PEG-SH solution and PTP-(CO-NH)-PEG-SH solution were mixed, stirred in an ice bath, and washed with pure water to obtain the final product, magnetic resonance imaging nanoprobe Ag / Ag2S-Gd-PTP.

2. The method for preparing a pancreatic cancer tumor stroma-penetrating magnetic resonance imaging nanoprobe according to claim 1, characterized in that: In S2, the mass volume ratio of SH-PEG-NHS:Gd-DOTA:deionized water is 3 mg:0.5 mg:4 mL.

3. The method for preparing a pancreatic cancer tumor stroma-penetrating magnetic resonance imaging nanoprobe according to claim 1, characterized in that: In S3, the mass ratio of KTLLPTP:SH-PEG-NHS is 20 μg:1 mg.

4. The method for preparing a pancreatic cancer tumor stroma-penetrating magnetic resonance imaging nanoprobe according to claim 1, characterized in that: In S4, the volume ratio of Ag / Ag2S solution:Gd-DOTA-PEG-SH solution:PTP-(CO-NH)-PEG-SH solution is 17 mL:4 mL:4 mL.

5. A magnetic resonance imaging nanoprobe Ag / Ag2S-Gd-PTP capable of penetrating pancreatic cancer tumor stroma prepared by the preparation method according to any one of claims 1 to 4.

6. Use of the nanoprobe Ag / Ag2S-Gd-PTP according to claim 5 in the preparation of pancreatic cancer active targeting, interstitial penetration, piezoelectric catalysis and magnetic resonance imaging drugs.

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