CN113797361A - Active targeting PET/MR bimodal imaging nanoprobe and preparation method thereof - Google Patents
Active targeting PET/MR bimodal imaging nanoprobe and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an active targeting PET/MR bimodal imaging nanoprobe and a preparation method thereof. The active targeting PET/MR bimodal imaging nanoprobe comprises a nanoparticle kernel, radionuclide and targeting short peptide; the inner core of the nano-particle is a manganese ferrite nano-particle modified by carboxyl; the radionuclide is68Ga. The active targeting type bimodal imaging probe provided by the invention has higher sensitivity and specificity for detecting prostate cancer positive by Prostate Specific Membrane Antigen (PSMA), and canCan be effectively enriched at the prostate tumor part, improves the contrast ratio of tumor tissues and normal tissues, and is expected to be used as a novel PET/MRI bimodal imaging probe for accurate diagnosis of clinical prostate cancer.
Description
Technical Field
The invention relates to the technical field of medical application of nano materials, in particular to an active targeting type PET/MR bimodal imaging nanoprobe and a preparation method thereof.
Background
Early diagnosis of tumors is of great significance for effective treatment and prognosis of patients, single-mode imaging detection may be considered, and multi-mode images are expected to realize advantage complementation between modes, thereby improving the accuracy of tumor diagnosis. For example, Magnetic Resonance Imaging (MRI) technology has the advantages of no limitation of signal penetration depth, no ionizing radiation, high soft tissue resolution, wide clinical application range and the like, and plays an important role in clinical tumor diagnosis and staging. However, MRI has problems such as low sensitivity, difficulty in whole-body scanning, and inability to obtain quantitative images, and thus has limited its application to molecular imaging. The Positron Emission Tomography (PET) imaging technology has the characteristics of high sensitivity and capability of providing functional and metabolic information on a molecular level, but has the problem of low spatial resolution. If the two imaging modes are effectively combined, both functional and anatomical information can be taken into consideration, the sensitivity, accuracy and quantification capability of disease diagnosis are improved, a more comprehensive image analysis result is obtained, and the micro lesion is expected to be identified in the early stage of cancer development, so that the development of a high-resolution and high-sensitivity PET/MRI bimodal imaging probe is particularly important.
The magnetic nano material with ultra-small size is widely applied to the research of T1 magnetic resonance contrast agent due to the characteristics of unique magnetic characteristics, adjustable relaxation performance, excellent in-vivo stability, easy surface modification, good biological safety and the like on the nano scale, and mainly has the following advantages: (1) the safety is high. When injected intravenously, iron oxide nanoparticles are normally naturally degraded in the liver and spleen, and then enter the iron metabolic pathway, becoming part of the essential iron elements of the human body. (2) The repairability is strong. Different surface modifications can control the cellular uptake and biodistribution of the nanoparticles by influencing the interaction between the nanoparticles and the biomolecules. In addition, the higher specific surface area at the nanometer scale provides more sites for the modification of the surface ligand. (3) The preparation process is simple. The synthesis method is diversified, the crystallinity is obviously improved, and the size and the performance of the materials are adjustable and controllable.
The Prostate Specific Membrane Antigen (PSMA) is a transmembrane protein which is overexpressed in prostate cancer, and the expression level of the PSMA in the cell membrane of the prostate cancer is 100-1000 times that of normal cells, so that the PSMA is regarded as an important target of the prostate cancer. The glutamic acid urea analogue (Glu-urea-Lys, Glu) is proved to be capable of being specifically combined with PSMA, is successfully applied to clinical diagnosis, and has high targeting property and safety. In clinical PET imaging examination, 18F-FDG is a small molecule positron emission imaging agent which is most widely used, and reacts to the site of tumor tissue by utilizing the high metabolic activity of tumor cells and thus being taken up by the tumor cells, but lacks effective targeting and is difficult to distinguish malignant lesions from inflammatory lesions to cause misdiagnosis, 68Ga (T1/2 ═ 67.7min) is receiving attention of more and more researchers as a nuclide replacement for 18F (T1/2 ═ 109.8min), and has the advantages that: (1) high positron yield (89%); (2) the product is relatively easy to obtain, can be produced by a radionuclide generator, and has lower cost and simple and easy preparation process compared with the traditional heavy cyclotron; (3) the half-life is relatively short (67.7 min. t 1/2), effectively reducing the radiation dose to the patient while ensuring the need for clinical examination. (4) The metal ions are more easily and stably and efficiently connected to the chelating agent, and the radiochemical yield is higher.
According to literature reports, in recent years, the key links are the selection of imaging targets and the synthesis of efficient specific molecular probes when the accurate diagnosis and treatment of malignant tumors are explored. The inventor finds that the ultra-small manganese ferrite nanoparticles (UMFNPs) are coupled with tumor-targeting pentapeptide CREKA (cys-arg-glul-lysa-ala), so that chemotactic targeting activation capacity is shown, breast cancer metastasis can be accurately detected, and the minimum detection limit for detecting the breast cancer metastasis is 0.39mm, which is obviously higher than the detection limit of a previously reported MRI probe (A Bioamplified Nanoprobe with multiple response T1-Weighted MR Signal-Amplification chemicals ultra Materials [ J ]. Advanced Materials,2020,32 (4)). At present, the diagnosis of prostate cancer has the problems of low lesion detection rate, insufficient sensitivity and the like, so that a novel imaging probe applied to the accurate diagnosis of clinical prostate cancer is urgently needed.
Disclosure of Invention
The invention aims to overcome the problems of low detection rate, insufficient sensitivity and the like of prostate cancer focus, and provides an imaging nanoprobe with active targeting of prostate cancer and T1-MR and PET bimodal imaging and a preparation method thereof.
A first object of the present invention is to provide a method for preparing manganese ferrite nanoparticles.
The second purpose of the invention is to provide the manganese ferrite nano-particles prepared by the preparation method of the manganese ferrite nano-particles.
The third purpose of the invention is to provide the application of the manganese ferrite nanoparticles in preparing nano-drugs or imaging nanoprobes.
The fourth purpose of the invention is to provide an active targeting type PET/MR bimodal imaging nanoprobe.
The fifth purpose of the invention is to provide the application of the active targeting type PET/MR bimodal imaging nanoprobe in the preparation of a prostate cancer PET/MR imaging diagnosis product.
In order to achieve the purpose, the invention is realized by the following technical scheme:
the invention provides a preparation method of manganese ferrite nanoparticles, which comprises the following steps:
s1, FeCl3·6H2O, erucic acid and methanol by mass volumeThe ratio is (2-3 g): (9-11 g): (40-60 ml), heating to 40-50 ℃ for reaction, then adjusting the pH value until precipitate is separated out, and washing and purifying the obtained precipitate solid to obtain an erucic acid iron complex;
s2, uniformly mixing the erucic acid iron complex obtained in the step S1 with manganese oleate, oleic acid, oleyl alcohol and benzyl ether, heating to 100-110 ℃ under an inert atmosphere, heating the system to 250-270 ℃ at a reaction rate of 4-6 ℃/min, and performing reflux reaction to obtain a brown product;
s3, dispersing the brown product obtained in the step S2 in chloroform, adding an organic solvent, centrifuging, and re-suspending the centrifuged precipitate to obtain manganese ferrite nanoparticles; wherein the volume ratio of the trichloromethane to the organic solvent is 1: (1-1.5);
the molar ratio of the erucic acid iron complex to manganese oleate, oleic acid, oleyl alcohol and benzyl ether in the step S2 is (0.5-1.5): (0.5-1.5): (1-2): (5-6): (40-50).
Preferably, the FeCl is obtained in step S13·6H2The mass-volume ratio of O, erucic acid and methanol is 2.7 g: 10.2 g: 50 ml; the molar ratio of the erucic acid iron complex to manganese oleate, oleic acid, oleyl alcohol and benzyl ether in the step S2 is 1: 1: 2: 6: 50.
more preferably, FeCl is added3·6H2O, erucic acid and methanol in a mass-volume ratio of 2.7 g: 10.2: and (3) uniformly mixing 50ml of the solution, heating the solution to 40 ℃ to form a clear and transparent solution, then dropwise adding a sodium hydroxide solution, reacting for 15-20 minutes, and after the reaction is finished, alternately washing reddish brown precipitates by using methanol and deionized water to obtain the iron erucic acid complex.
Preferably, in step S1, the manganese oleate is synthesized by mixing tetrahydrate manganese dichloride and oleic acid in a molar ratio of 1: 2 in methanol solvent.
Preferably, in the step S2, the iron erucic acid complex in the step S1 is uniformly mixed with manganese oleate, oleic acid, oleyl alcohol and benzyl ether, after the mixture is heated to 110 ℃ under an inert atmosphere, the system is heated to 265 ℃ at a reaction rate of 5 ℃/min and is refluxed for 30min, and then is rapidly cooled to room temperature, so as to obtain a brown product.
Preferably, in step S3, dispersing the brown product in chloroform, adding methanol as a precipitant to perform centrifugation, and redispersing the centrifuged precipitate with chloroform to obtain manganese ferrite nanoparticles; wherein the volume ratio of the trichloromethane to the methanol is 1: 1.
the invention claims a manganese ferrite nanoparticle prepared by the preparation method of the manganese ferrite nanoparticle.
The application of the manganese ferrite nanoparticles in the preparation of nano-drugs or imaging nanoprobes also falls within the protection scope of the invention.
The invention also provides an active targeting PET/MR bimodal imaging nanoprobe, which is characterized in that the composition of the nanoprobe comprises the manganese ferrite nanoparticle of claim 4, a radionuclide and a targeting short peptide; the manganese ferrite nano-particles are also modified with carboxyl; the targeting short peptide is glutamic acid urea analogue Glu-urea-Lys.
Preferably, the manganese ferrite nanoparticles are modified to have carboxyl groups through reaction with 3, 4-dihydroxyphenyl propionic acid, and the mass ratio of the 3, 4-dihydroxyphenyl propionic acid to the manganese ferrite nanoparticles is 4-6: 2.
more preferably, the mass ratio of 3, 4-dihydroxyphenylpropionic acid to manganese ferrite nanoparticles is 5: 2.
preferably, the radionuclide is68Ga。
The invention claims application of the active targeting PET/MR bimodal imaging nanoprobe in preparation of a PET/MR imaging diagnosis product for prostatic cancer.
The preparation method of the active targeting PET/MR bimodal imaging nanoprobe comprises the following steps:
s11, 3, 4-dihydroxyphenyl propionic acid, the manganese ferrite nanoparticles and tetrahydrofuran are mixed according to the mass-volume ratio of (4-6 mg): 2 mg: mixing and heating 0.7ml for reaction, adjusting pH until precipitation is separated out, centrifugally collecting the precipitate, and then suspending to obtain the manganese ferrite nanoparticles modified with carboxyl;
s12, activating the carboxyl of the manganese ferrite nanoparticles obtained in the step S11, then carrying out covalent reaction with targeting short peptides and a metal chelating agent, and dialyzing and purifying to obtain the manganese ferrite nanoparticles with targeting capability;
s13, combining the manganese ferrite nano-particles with targeting ability in the step S12 with radioactivity68GaCl3And (3) carrying out solution mixing reaction, and purifying a reaction product by adopting a desalting column to obtain the active targeting PET/MR bimodal imaging nanoprobe.
Preferably, in step S11, the mass-to-volume ratio of the 3, 4-dihydroxyphenyl propionic acid, the manganese ferrite nanoparticles, and the tetrahydrofuran is 5 mg: 2 mg: 0.7 ml.
Preferably, in the step S11, after dissolving the 3, 4-dihydroxyphenyl propionic acid in tetrahydrofuran, dropwise adding the manganese ferrite nanoparticle solution dissolved in tetrahydrofuran, and heating and refluxing at 50-55 ℃ for 2-3 hours; and then dropwise adding 0.5-0.6 mM sodium hydroxide solution to precipitate the nano particles, centrifugally collecting the precipitate, and then suspending the precipitate to obtain the carboxyl-modified manganese ferrite nano particles.
More preferably, the centrifugation is performed under conditions of 5000r/min for 10 min.
Preferably, in step S12, the manganese ferrite nanoparticles are first subjected to carboxyl activation through EDC/NHS reaction, and then the targeting short peptide, the metal chelator and the nanoparticles after carboxyl activation are mixed in a mass-to-volume ratio of (1-2 mg): (15-20 mg): (15-20 mg) carrying out covalent coupling, dialyzing and purifying the reaction product, then adding a metal chelating agent into the dialyzed product, adjusting the pH value to 7-9, and dialyzing and purifying to obtain the manganese ferrite nanoparticles with targeting ability; the metal chelating agent is a macrocyclic chelating agent NOTA-NHS-ester.
Preferably, the targeting short peptide, the metal chelator and the carboxyl activated nanoparticle are in a mass-to-volume ratio of 1 mg: 20 mg: 20 mg.
More preferably, the method of adjusting the pH is: and adjusting the pH value to 7-9 by using 1M sodium hydroxide aqueous solution, and carrying out shaking table reaction at room temperature for 24 hours.
More preferably, the dialysis purification method is: dialyzed against a 3kDa dialysis bag for 48 hours.
As described aboveThe manganese ferrite nanoparticles are ultra-small manganese ferrite nanoparticles, namely UMFNPs for short, and the size of the manganese ferrite nanoparticles is 2-4 nm; the PET/MR bimodal imaging nanoprobe is referred to as a PET/MR bimodal imaging nanoprobe for short68Ga-NOTA-UMFNPs-Glu with the size of 10-20 nm and the relaxation rate of 8.18mM-1s-1The radiochemical purity is 97%.
Compared with the prior art, the invention has the following beneficial effects:
(1) the ultra-small manganese ferrite nanoparticles (UMFNPs) prepared by the method have the size of 2-4 nm; taking ultra-small manganese ferrite nanoparticles as a platform, selecting a prostate cancer targeting molecule glutamic acid urea analogue (Glu-urea-Lys) to carry out functional modification on the nanoparticles, and finally carrying out radionuclide by using a specific metal chelating agent NOTA-NHS-ester68Ga is marked on manganese ferrite nano particles, so that the PET/MR bimodal imaging capability is realized, and the specificity receptor binding can be utilized, so that the diagnosis accuracy of the prostatic cancer is improved. The invention uses the manganese ferrite nano-particles with ultra-small size, has long circulation time in blood, can effectively increase the enrichment amount of tumor parts, and has low biological toxicity and good safety compared with the traditional clinical gadolinium-based T1 magnetic resonance contrast agent.
(2) The bimodal imaging nanoprobe prepared by the invention68Ga-NOTA-UMFNPs-Glu has a lower r2/r1 value of 2.9 and a higher r1 relaxation rate of 8.32mM-1s-1Twice as much as the commercial gadolinium-based T1 contrast agent. Meanwhile, the radiochemical yield is as high as 97%, and after the solution is placed in PBS and FBS for 4 hours, the radiochemical yield is still over 90%, and good stability is shown. The image nanoprobe of the invention68Ga-NOTA-UMFNPs-Glu can be phagocytized by LNCaP cells with high PSMA expression in a large quantity, and shows good tumor cell targeting effect.
(3) The active targeting bimodal imaging probe provided by the invention has higher sensitivity and specificity for detecting prostate cancer with positive Prostate Specific Membrane Antigen (PSMA), can be effectively enriched at prostate tumor parts, improves the contrast ratio of tumor tissues and normal tissues, and can be used as a novel PET/MRI bimodal imaging probe to be applied to accurate diagnosis of clinical prostate cancer.
Drawings
FIG. 1 is a schematic view of an embodiment68Schematic synthesis diagram of Ga-NOTA-UMFNPs-Glu;
FIG. 2 is a graph showing the results of characterization and identification of UMFNPs in example 1; a is a Transmission Electron Microscope (TEM) image of oil phase UMFNPs and a corresponding particle size distribution diagram; b is an XRD pattern of oil phase UMFNPs; c is a VSM diagram of oil phase UMFNPs;
FIG. 3 is a graph showing the results of characterization and identification of NOTA-UMFNPs-Glu in example 2; a is a TEM image of water-phase nano-particles NOTA-UMFNPs-Glu modified with Glu-urea-Lys and NOTA; b is a hydrated particle size analysis chart of NOTA-UMFNPs-Glu; c is an infrared spectrum comparison schematic diagram before and after the UMFNPs surface modification (a black curve represents UMFNPs of an oil phase, a red result diagram, a water phase UMFNPs-DHCA modified by DHCA, a blue result diagram, a water phase NOTA-UMFNPs-Glu modified by targeting molecules and metal chelating agents); d is a thermogravimetric graph before and after the surface modification of UMFNPs (black represents UMFNPs-DHCA, blue represents UMFNPs-Glu modified by DHCA, and red represents NOTA-UMFNPs-Glu modified by targeting molecules and metal chelating agents);
FIG. 4 is a graph showing the results of characteristics of NOTA-UMFNPs-Glu in example 2; a is a T1 magnetic resonance two-dimensional imaging graph and r1 relaxation rate of NOTA-UMFNPs-Glu; b is an r2 relaxation rate analysis chart of NOTA-UMFNPs-Glu;
FIG. 5 is a photograph of confocal fluorescence images of NOTA-UMFNPs-Glu of example 2 co-cultured with prostate cancer (LNCaP) cells (PSMA positive) and PC3 cells (PSMA negative), respectively, for 0.5 h;
FIG. 6 shows the in vitro stability test results of the PET/MR bimodal nano-imaging probe of example 3; a is68Paper chromatography chromatograms of Ga-NOTA-UMFNPs-Glu at different time points; b is68A radiation stability curve chart of Ga-NOTA-UMFNPs-Glu;
FIG. 7 shows a schematic view of a liquid crystal display device of example 368An in vivo imaging map of Ga-NOTA-UMFNPs-Glu; a is in vivo68Micro-PET image display of Ga-NOTA-UMFNPs-Glu; b is the 3T-MR visualization of NOTA-UMFNPs-Glu in vivo.
Detailed Description
The invention is described in further detail below with reference to the drawings and specific examples, which are provided for illustration only and are not intended to limit the scope of the invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1 preparation and characterization of ultra-small manganese ferrite nanoparticles (UMFNPs)
First, experiment method
1. Preparation of UMFNPs
(1) Accurately weighing ferric chloride hexahydrate (FeCl)3·6H2O)2.70g and erucic acid 10.20g, which are dissolved in 50mL of methanol solution, mixed evenly and heated to 40 ℃ to form clear and transparent solution A, 1.2g of sodium hydroxide is added into another 100mL beaker and dissolved by methanol ultrasound till no precipitate is formed, and the solution is added into the solution A drop by drop and reacted for 15 minutes.
(2) And after the reaction is finished, alternately washing the mixture by using methanol and deionized water until no impurity is separated out, obtaining a reddish brown precipitate, namely the erucic acid iron complex, and drying the obtained product in vacuum and storing the product for later use.
(3) Accurately weighing 2.0g of manganese chloride tetrahydrate and 5.7g of oleic acid, dissolving the manganese chloride tetrahydrate and the oleic acid in 50mL of methanol solution, uniformly mixing, heating to 40 ℃ to form clear and transparent solution B, adding 0.8g of sodium hydroxide into another 100mL beaker, ultrasonically dissolving the sodium hydroxide with methanol until no precipitate exists, dropwise adding the solution into the solution B, and reacting for 15 minutes to obtain manganese oleate.
(4) 1mmol (1.07g) of iron erucate complex, 1mmol (0.62g) of manganese oleate, 2mmol (0.57g) of oleic acid and 6mmol (1.61g) of oleyl alcohol are weighed out accurately, 50mmol (10g) of benzyl ether is added for ultrasonic dissolution, and the mixture is placed in a 50mL round-bottom three-neck flask and heated to 110 ℃ under the protection of argon for 30 minutes of reaction. Further, the system was warmed to 265 ℃ at a reaction rate of 5 ℃/min and maintained under reflux for 30min, and then rapidly cooled to room temperature to give a brown product.
(5) The resulting brown product was dispersed in chloroform using a 1: repeatedly centrifuging with 1 volume of anhydrous ethanol as precipitant for 3 times (8000r/min, 10min), discarding supernatant, and re-dispersing with chloroform to obtain ultra-small manganese ferrite nanoparticles (UMFNPs), and storing at 4 deg.C.
2. Characterization and characterization of UMFNPs
Characterization of UMFNPs using Transmission Electron Microscopy (TEM): diluting UMFNPs to 0.3-15 mg/ml by using deionized water, ultrasonically dispersing for 5-10 minutes at 30-80W, then dropwise adding the UMFNPs onto a copper mesh, drying, and observing the forms of the UMFNPs by using a TEM. The susceptibility and magnetization of UMFNPs were measured by a vibrating sample magnetometer. Second, experimental results
As a result, as shown in FIG. 2, FIG. 2A is a TEM Image of UMFNPs, in which the particles were observed to be spherical and monodisperse, and the size of the particles was about 3.1. + -. 0.2nm by statistically analyzing different regions of the sample using Image J; FIG. 2B is an XRD diagram of UMFNPs whose peak positions correspond to (111), (220), (311), (400), (422), (511), (440), and (622) crystal planes in a manganese ferrite standard card (JCPDS 10-0319), respectively, showing that the prepared sample is spinel-phase manganese ferrite, high in crystallinity, and free from other impurity peaks; FIG. 2C is a magnetic hysteresis loop of UMFNPs, and it can be seen that the magnetization value increases with the increase of the applied magnetic field, and when the applied magnetic field reaches 20000Oe, the saturation magnetization value close to the sample is 22.2emu/g, and it can be seen from the figure that when the applied magnetic field is removed at room temperature, the particles have no obvious remanence and coercive force, showing superparamagnetism.
Example 2 preparation and characterization of NOTA-UMFNPs-Glu
First, experiment method
1. Preparation of NOTA-UMFNPs-Glu
The general flow chart of the preparation is shown in figure 1, and the specific steps are as follows:
(1) first, 20mg of the oil-phase manganese ferrite nanoparticles (UMFNPs) prepared in example 1 were dissolved in 1mL of tetrahydrofuran as a solution a.
(2) Further, 50mg of 3, 4-dihydroxyphenylpropionic acid (DHCA) was accurately weighed and dissolved in 6mL of tetrahydrofuran, magnetic stirring was turned on under an argon atmosphere and slowly warmed to 50 ℃, after DHCA was completely dissolved, solution A was added dropwise to the DHCA solution, and the mixture was maintained under reflux for 3 hours.
(3) After the reaction is finished, cooling to room temperature, dripping 0.5mL (0.5mM) of sodium hydroxide solution to precipitate the nano particles, centrifuging at 5000r/min for 10min, collecting precipitation products, and dispersing in 2mL of deionized water again for standby, and marking as UMFNPs-DHCA.
(4) 20mg of DHCA-modified UMFNPs-DHCA nanoparticles were weighed into 2mL of PBS, and 2mL (20mM) of freshly prepared EDC solution was added thereto, and mixed well for 15min to activate the carboxyl group.
(5) 2mL (24mM) of freshly prepared NHS solution and 1mg of Glu-urea-Lys were added to the solution of step (4), and after mixing well, 1.2mL (10mM) of ethylenediamine was added and the mixture was subjected to shaking reaction at room temperature for 4 hours.
(6) And (5) dialyzing the product for 48h by using a 3kDa dialysis bag after the reaction in the step (5) is finished so as to remove unreacted small molecular compounds.
(7) And (3) accurately weighing 20mg of NOTA-NHS-ester (New Biotech Co., Ltd., Seisan Kay) and dissolving in 2ml of deionized water, adding the solution into the dialysis product obtained in the step (6), adjusting the pH value to 7-9 by using 1M of sodium hydroxide aqueous solution, and carrying out shaking table reaction at room temperature for 24 hours.
(8) And (4) dialyzing the product for 48 hours by using a 3kDa dialysis bag after the reaction is finished, and collecting the product NOTA-UMFNPs-Glu.
2. Characterization and identification of NOTA-UMFNPs-Glu
Taking 1-2 drops of NOTA-UMFNPs-Glu nano particles to be suspended, and dropping the suspension on a copper net covered with a supporting film. After the sample is naturally dried, observing the surface morphology and the particle size of the nano particles under a Transmission Electron Microscope (TEM); the surface modification of the nanoparticles was analyzed using fourier infrared spectroscopy and thermogravimetry. 1mM, 0.5mM, 0.25mM, 0.125mM, 0.07mM and 0mM of nanoparticles were placed in a 3.0T MRI imaging device, and the T1 and T2 magnetic relaxation rates of NOTA-UMFNPs-Glu nanoparticles were examined using T1 and T2 weighted imaging sequences, respectively.
3. Cellular phagocytosability of NOTA-UMFNPs-Glu
Human prostate cancer (LNCaP) cells (PSMA +) and PC3 cells (PSMA-) at 3X 104Inoculating the concentration into a confocal culture dish, performing overnight culture, washing with PBS, and performing co-culture with NOTA-UMFNPs-Glu nanoparticles for 30 minutes; cells were carefully washed with PBS, using 4% moreFixing the cells for 15 minutes by polyformaldehyde, and staining by DAPI; followed by observation using a laser confocal fluorescence microscope.
Second, experimental results
FIG. 3A is a TEM image of NOTA-UMFNPs-Glu, and it can be observed that there is no significant change in particle size and dispersibility after water transfer (conversion of oil-soluble nanoparticles to water-soluble nanoparticles). Fig. 3B shows the hydrodynamic diameter change of the particles after two-step functionalization, the particle diameter after the first step modification of DHCA is 7.1nm, and after the modification of Glu-urea-Lys and NOTA by EDC/NHS reaction, the hydrodynamic diameter of the ultra-small manganese ferrite nanoparticles is increased to 13.4nm, which indirectly proves the successful modification of Glu-urea-Lys and NOTA, and the manganese ferrite nanoparticles dispersed in the aqueous solution are clear and transparent as can be observed from the optical photograph. FIG. 3C is a schematic diagram showing comparison of infrared spectra before and after surface modification of UMFNPs, wherein three curves respectively correspond to oil-phase UMFNPs, DHCA-modified aqueous-phase UMFNPs, and glutamic acid urea-and NOTA-modified aqueous-phase UMFNPs, and 2925cm is shown in the curves of oil-phase UMFNPs-1And 2851cm-1Two sharp absorption peaks appear, which respectively correspond to asymmetric and symmetric stretching vibration peaks of-CH 2 in oleic acid, and the two characteristic absorption peaks of-CH 2 stretching vibration can be obviously weakened after the oleic acid is converted into a water phase through a ligand exchange reaction, which indicates that DHCA successfully replaces oleic acid molecules on the surface of particles. 1682cm can be seen in the spectrum of NOTA-UMFNPs-Glu-1，1556cm-1，1039cm-1New peaks appeared, which are respectively derived from C ═ O (amide I bond), N-H (amide II bond) and C-N stretching vibration, indicating that NOTA and Glu-urea-Lys are successfully modified on the surface of the ultra-small manganese ferrite nanoparticles. FIG. 3D is a thermogravimetric result analysis of NOTA-UMFNPs-Glu, wherein the thermal weight loss of the ultra-small manganese ferrite modified by the glutamic acid urea is increased by 8.1% compared with that of the ultra-small manganese ferrite modified by DHCA, and the thermal weight loss of the NOTA-UMFNPs-Glu is increased by 7.5% compared with that of the UMFNPs-Glu, and it can be found through calculation that 17 pieces of glutamic acid urea and 14 pieces of NOTA molecules are modified on the surface of each ultra-small manganese ferrite particle on average.
FIG. 4A is a top view of a T1 weighted two-dimensional image of NOTA-UMFNPs-Glu at different concentrations, which is seen as the sample concentration increases compared to the blank aqueous solutionThe bright signal gradually becomes strong, the r1 relaxation rate of NOTA-UMFNPs-Glu is represented below, and the r1 relaxation rate is 8.32mM as obtained by linear fitting-1s-1(ii) a FIG. 4B is a T2 relaxation rate test of NOTA-UMFNPs-Glu, and a fitted curve drawn from the measured T2 intensities revealed that r2 relaxation rate of the probe was 23.75mM-1s-1For the performance evaluation of the T1 magnetic resonance contrast agent, the ratio of r2 to r1 is another important parameter in addition to the r1 value, where the value of r2/r1 is 2.9, much less than 5, exhibiting excellent T1 contrast performance of NOTA-UMFNPs-Glu.
FIG. 5 is a photograph of confocal fluorescence images of NOTA-UMFNPs-Glu co-cultured with LNCaP cells (PSMA positive) and PC3 cells (PSMA negative) for 0.5h, respectively; in the figure, a is LNCaP cells, and B is PC3 cells, wherein green color represents FITC fluorescein-stained nanoparticles, and blue color represents DAPI-stained nuclei, and it can be observed that green fluorescence in LNCaP cells is much stronger than that of PC3 cells, indicating that NOTA-UMFNPs-Glu can be effectively phagocytosed by LNCaP cells through PSMA.
EXAMPLE 3 determination and in vivo imaging of PET/MR bimodal imaging nanoprobes
First, experiment method
1. Preparation of PET/MR bimodal imaging nanoprobe
1mg (1mg/ml) of NOTA-UMFNPs-Glu prepared in example 2 was added to 180 to 200MBq68GaCl3To the solution, 150. mu.l (1.0mol/L) of an aqueous sodium acetate solution was added to adjust the pH to 3 to 3.5, and the mixture was subjected to oil bath at 70 ℃ with light shielding for 10 minutes. After the reaction is cooled to room temperature, a PD-10 desalting column is adopted for purification operation, and the PET/MR bimodal nano imaging probe is obtained68Ga-NOTA-UMFNPs-Glu。
2. In-vitro stability of PET/MR bimodal imaging nanoprobe
The nuclide labeling rate and in vitro stability of the nanoparticles are determined by using a paper chromatography method, and the specific activity of the nuclide is detected by using a counter.
(1) Stability testing in PBS buffer (pH 7.4): 0.5mL (about 100. mu. Ci) of68Ga-NOTA-UMFNPs-Glu is put into 0.4mL PBS buffer solution, incubated for 0.5h, 1h, 1.5h, 2h and 4h at constant temperature of 37 ℃,separately, 1. mu.L of the labeled product was pipetted by capillary, and then subjected to spotting by paper chromatography, followed by radiochemical yield test by a gamma-counter, and stability change in PBS buffer was observed, and each group was repeated 3 times.
(2) Stability testing in Fetal Bovine Serum (FBS): 0.5mL (about 100. mu. Ci) of68Ga-NOTA-UMFNPs-Glu is put into 0.4mL FBS solution, incubated for 0.5h, 1h, 1.5h, 2h and 4h at constant temperature of 37 ℃, 1 mu L of marked product is sucked by a capillary tube and spotted by a paper chromatography method, then an gamma-counter is used for carrying out an radiochemical yield test, and the stability change of the marked product in the serum of a fetal calf is observed.
4. Imaging of mouse prostate cancer tumor sites
Selecting male NOD-SCID mouse pairs with the weight of about 20g68Ga-NOTA-UMFNPs-Glu bimodal probes were used for in vivo PET/MR imaging, and all animal studies were performed with approval from the institutional animal protection and use committee at Zhongshan university.
(1) PET imaging: mice were first anesthetized with 4% chloral hydrate solution (10mL/kg) and then injected intravenously via the tail of the mice68And (3) respectively adopting a Siemens Iveon micro PET/micro CT scanner to carry out transverse position image acquisition on Ga-NOTA-UMFNPs-Glu nanoprobe (about 100 mu Ci or 2.7MBq) at 10min, 20min, 30min and 40min after injection, and analyzing and processing the obtained image at a Siemens workstation.
(2) MRI imaging: mice were first anesthetized with 4% chloral hydrate solution (10mL/kg) and then injected intravenously via the tail of the mice68Ga-NOTA-UMFNPs-Glu(5mg[Fe+Mn]And/kg), acquiring transverse position images by adopting a clinical 3T magnetic resonance scanner at 10min, 20min, 30min and 40min after injection respectively, wherein the specific parameters are as follows: TR is 2250 ms; TE is 13 ms; matrix size 256 × 256; NEX ═ 1.
Second, experimental results
FIG. 6A shows the in vitro stability test results of PET/MR bimodal nano-imaging probe, which was subjected to the radiochemical yield determination of samples at different time points by clinical PET scanner using paper chromatography, and it was observed that free nano-imaging probe was free at the same time of chromatography68Ga3+Distributed at the upper end of the chromatographic filter paper along with the development of the mobile phase, and chelated with the manganese ferrite nanoparticles68Ga-NOTA-UMFNPs-Glu still stays at the sample application position and does not move along with the time, which proves that68Successful preparation of Ga-NOTA-UMFNPs-Glu. FIG. 6B is a quantification curve of FIG. 6A, and the results of radioactivity counting samples at various time points using a gamma counter, are observed to show that the probe still has an radiochemical yield of greater than 90% after incubation for 4 hours at 37 ℃ in 0.01mol/L PBS (pH 7.4) and 10% FBS, which indicates that68Ga-labeled NOTA-UMFNPs-Glu has good in vitro stability in serum.
FIG. 7A shows the tail vein injection of the model mice68Micro-PET cross section position significant map behind Ga-NOTA-UMFNPs-Glu nanoprobe can be seen, the radioactive signal of the tumor position is obviously enhanced along with the time, and the peak value is reached after 30min, which shows that the radioactive tracer has excellent targeting effect on prostate cancer. Meanwhile, the enhancement effect of the probe on MRI T1 imaging of tumor parts before and after mouse tail vein injection is also researched: the result is shown in fig. 7B, after the nanoprobe is injected, the brightness of the tumor part is obviously enhanced, the tumor boundary is clearly outlined, and the MRI enhancement effect of the tumor part reaches the best after the nanoprobe is injected for 30min, which is consistent with the PET imaging result, and shows that the nanoprobe has good selective PET and MRI dual-mode enhanced imaging capability; 50 male NOD-SCID mice were imaged with a detection rate of 90% and the sensitivity and specificity of prostate cancer detection in the peripheral zone were 92.68% and 84.37%, respectively. .
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A preparation method of manganese ferrite nanoparticles is characterized by comprising the following steps:
s1, FeCl3·6H2O, erucic acid and methanol in a mass-volume ratio of (2-3 g): (9-11 g): (40-60 ml), heating to 40-50 ℃ for reaction, then adjusting the pH value until precipitate is separated out, and washing and purifying the obtained precipitate solid to obtain an erucic acid iron complex;
s2, uniformly mixing the erucic acid iron complex obtained in the step S1 with manganese oleate, oleic acid, oleyl alcohol and benzyl ether, heating to 100-110 ℃ under an inert atmosphere, heating the system to 250-270 ℃ at a reaction rate of 4-6 ℃/min, and performing reflux reaction to obtain a brown product;
s3, dispersing the brown product obtained in the step S2 in chloroform, adding an organic solvent, centrifuging, and re-suspending the centrifuged precipitate to obtain manganese ferrite nanoparticles; wherein the volume ratio of the trichloromethane to the organic solvent is 1: (1-1.5);
the molar ratio of the erucic acid iron complex to manganese oleate, oleic acid, oleyl alcohol and benzyl ether in the step S2 is (0.5-1.5): (0.5-1.5): (1-2): (5-6): (40-50).
2. The method of claim 1, wherein the FeCl is FeCl in step S13·6H2The mass-volume ratio of O, erucic acid and methanol is 2.7 g: 10.2 g: 50 ml; the molar ratio of the erucic acid iron complex to manganese oleate, oleic acid, oleyl alcohol and benzyl ether in the step S2 is 1: 1: 2: 6: 50.
3. the method of claim 1, wherein the manganese ferrite nanoparticles are prepared by heating to 110 ℃ under argon protection, reacting for 30 minutes, heating the system to 265 ℃ at a reaction rate of 5 ℃/min, refluxing for 30 minutes, and rapidly cooling to room temperature to obtain a brown product in step S2.
4. The manganese ferrite nanoparticles prepared by the method for preparing manganese ferrite nanoparticles according to any one of claims 1 to 3.
5. Use of the manganese ferrite nanoparticles of claim 4 in the preparation of nano-drugs or imaging nanoprobes.
6. An active targeting PET/MR bimodal imaging nanoprobe, wherein the nanoprobe comprises the manganese ferrite nanoparticle of claim 4, a radionuclide and a targeting short peptide; the manganese ferrite nano-particles are also modified with carboxyl; the targeting short peptide is glutamic acid urea analogue Glu-urea-Lys.
7. The active targeting type PET/MR bimodal imaging nanoprobe according to claim 6, wherein the manganese ferrite nanoparticles are modified with carboxyl groups by reaction with 3, 4-dihydroxyphenylpropionic acid, and the mass ratio of the 3, 4-dihydroxyphenylpropionic acid to the manganese ferrite nanoparticles is 4-6: 2.
8. use of the actively targeted PET/MR bimodal imaging nanoprobe of claim 6 or 7 for the preparation of PET/MR imaging diagnostic products for prostate cancer.
9. The method for preparing the active targeting PET/MR bimodal imaging nanoprobe as claimed in claim 6, wherein the method comprises the following steps:
s11, mixing 3, 4-dihydroxyphenyl propionic acid, the manganese ferrite nano-particles as claimed in claim 4 and tetrahydrofuran in a mass-to-volume ratio of (4-6 mg): 2 mg: mixing and heating 0.7ml for reaction, adjusting pH until precipitation is separated out, centrifugally collecting the precipitate, and then suspending to obtain the manganese ferrite nanoparticles modified with carboxyl;
s12, activating the carboxyl of the manganese ferrite nanoparticles obtained in the step S11, then carrying out covalent reaction with targeting short peptides and a metal chelating agent, and dialyzing and purifying to obtain the manganese ferrite nanoparticles with targeting capability;
s13, combining the manganese ferrite nano-particles with targeting ability in the step S12 with radioactivity68GaCl3And (3) carrying out solution mixing reaction, and purifying a reaction product by adopting a desalting column to obtain the active targeting PET/MR bimodal imaging nanoprobe.
10. The method for preparing an active targeting PET/MR bimodal imaging nanoprobe according to claim 9, wherein in step S12, the manganese ferrite nanoparticles are firstly activated by carboxyl through EDC/NHS reaction, and then the targeting short peptide, the metal chelating agent and the nanoparticles after carboxyl activation are mixed according to the mass-to-volume ratio of (1-2 mg): (15-20 mg): (15-20 mg) carrying out covalent coupling, dialyzing and purifying the reaction product, then adding a metal chelating agent into the dialyzed product, adjusting the pH value to 7-9, and dialyzing and purifying to obtain the manganese ferrite nanoparticles with targeting ability; the metal chelating agent is a macrocyclic chelating agent NOTA-NHS-ester.
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