CN106729778B - Molecular image nanoparticle probe and preparation and application thereof - Google Patents
Molecular image nanoparticle probe and preparation and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of nuclear medicine molecular imaging probes, and particularly relates to a molecular imaging nanoparticle probe and preparation and application thereof. The molecular imaging nano-particle probe is characterized in that the basic nano-particles are rare earth nano-particles. Compared with the known nuclear medicine molecular imaging probe, the molecular imaging nanoparticle probe has the size of less than 10nm, and is surface modified with a biological reaction active group or a molecular recognition group; the preparation method is simple, the separation and purification are convenient and quick, the F18 adsorption capacity is strong, the probe can be used as a radioactive probe for molecular image detection, diagnosis and tracing, the imaging sensitivity is high, and the specificity is strong.
Description
Technical Field
The invention belongs to the field of nuclear medicine molecular imaging probes, and particularly relates to a molecular imaging nanoparticle probe and preparation and application thereof.
Background
Due to the characteristics of sensitivity, non-invasiveness and the like, the molecular imaging technology is more and more widely applied to the aspects of biomedical research and clinical diagnosis, particularly the Positron Emission Tomography (PET) technology has high in-vivo imaging sensitivity and is widely applied to clinical diagnosis. The probes currently used for clinical PET imaging are mainly F18-labeled glucose analogues based on tissue/cell glucose metabolism: F18-FDG. However, F18-FDG has no molecular specificity, and can only be used for functional imaging based on glucose metabolism, but not for specific molecular events such as detection and tracing of proteins or drugs. At present, in the preparation of nuclide probes, positive electronic nuclide F18 (half-life period of 109 minutes) is mainly connected to probe molecules through a covalent bond, so that the problems of multiple reaction steps, harsh conditions, long time, low yield, difficulty in separation and purification and the like are solved, and the development and application of F18 labeled probes are severely limited. Therefore, it is of great significance to develop an F18 labeled molecular imaging probe which has specificity, high sensitivity, easy labeling, high yield and easy separation.
Disclosure of Invention
In order to overcome the problems in the prior art, the present invention is directed to a molecular imaging nanoparticle probe, and a method for preparing the same.
In order to achieve the above objects and other related objects, the present invention adopts the following technical solutions:
in a first aspect of the present invention, a molecular imaging nanoparticle probe is provided, wherein the base nanoparticle is a rare earth nanoparticle.
Preferably, the rare earth nanoparticles are doped nanoparticles containing one or more rare earth elements.
Preferably, the rare earth element is selected from lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), scandium (Sc), or yttrium (Y).
Preferably, the rare earth nanoparticles are fluoride particles, oxide particles, composite oxide particles, hydroxide particles, sulfide particles, carbonate particles, phosphate particles, titanate particles, borate particles, vanadate particles, tungstate particles, composite cationic compounds or composite anionic compound particles doped with one or more rare earth elements.
Preferably, the rare earth nanoparticles are fluoride particles doped with one or more rare earth elements.
Preferably, the rare earth nanoparticles are selected from REF3、MREF4Or REOF, wherein RE refers to trivalent rare earth element, and M is selected from alkali metal elements Li, Na or K.
Further preferably, the rare earth nanoparticles are NaGdF4And (3) nanoparticles.
Preferably, the surface of the basic nanoparticle is modified with a molecular recognition group, so that the basic nanoparticle can obtain the capability of actively targeting an object to be traced. And the molecular recognition group modified on the surface of the basic nano particle and the molecular recognition group modified on the surface of the object to be traced form a molecular recognition pair.
Preferably, the molecular recognition pair is selected from the group consisting of antibody-antigen, ligand-receptor, protein-substrate, protein-inhibitor, protein/polypeptide-protein/polypeptide, aptamer-protein, complementary oligonucleotide pair, bio-orthogonal reactive group, and clathrate/complex.
Some embodiments of the invention recite the molecular recognition pair as tetrazine and trans-cyclooctene. Namely, the surface of the basic nanoparticle is modified with tetrazine serving as a molecular recognition group, so that the capability of actively targeting and modifying an object to be traced with trans-cyclooctene is given to the molecular imaging nanoparticle probe.
Preferably, the molecular imaging nanoparticle probe is labeled with a positive electron species, making it useful for PET imaging. Some embodiments of the invention recite the positive electron species as F18. That is, the positron species F18 is labeled on the base nanoparticle to form a molecular imaging nanoparticle probe that can be used for PET imaging.
Preferably, the particle size range of the molecular imaging nanoparticle probe is 1-10 nm. Some embodiments of the present invention recite the molecular imaging nanoparticle probe having a particle size of 4nm or less.
In a second aspect of the present invention, there is provided a method for preparing the molecular imaging nanoparticle probe, comprising the steps of:
(1) preparing a base particle; (2) carrying out molecular recognition group modification on the basic nanoparticles obtained in the step (1); (3) and (3) continuously carrying out positron nuclide labeling on the basic nanoparticles modified with the molecular recognition groups obtained in the step (2).
In some embodiments of the invention, the base particle is exemplified by a rare earth nanoparticle-NaGdF4Nanoparticles, in the step (1), preparing base particles-NaGdF by adopting a solvothermal method4Nanoparticles, comprising the steps of: 1) heating rare earth elements gadolinium ion salt, oleic acid and octadecene under vacuum to form transparent solution, cooling to room temperature, and adding NaOH and NH4Stirring the methanol solution of F at room temperature for reaction, heating to remove the methanol, washing with ethanol for centrifugation, collecting precipitate, dispersing in cyclohexane to obtain oil phase rare earth NaGdF4Nanoparticles; 2) oil phase rare earth NaGdF obtained in the step (1)4Adding dichloromethane and trichloroperoxybenzoic acid into nano particles, stirring for reaction, adding L-cysteine, continuing stirring for reaction, centrifuging the obtained solution by using ethanol, collecting precipitate, washing the precipitate, and drying in vacuum to obtain water-phase rare earth NaGdF4Nanoparticles.
In step 1), the rare earth element gadolinium ion salt may be a rare earth gadolinium chloride, such as gadolinium chloride hexahydrate: the molecular formula is H12Cl3GdO 6; the molecular weight is 371.7936; CAS number 13450-84-5; gadolinium chloride: the molecular formula is Cl3 Gd; the molecular weight is 263.61; CAS number 10138-52-0.
Correspondingly, in the step (2), the aqueous phase rare earth NaGdF obtained in the step (1) is subjected to Click chemistry4Reacting the nano particles with a substance shown in a formula I to carry out molecular recognition group-tetrazine modification;
correspondingly, in the step (3), adding the F18 anion solution into the base nanoparticle solution modified with the molecular recognition group obtained in the step (2), and incubating to obtain the positive electron nuclide F18 label.
In a third aspect of the invention, the use of the molecular imaging nanoparticle probe in vivo and in vitro molecular imaging detection, diagnosis and tracing is provided.
Specifically, the molecular imaging nanoparticle probe can be used for biological detection, diagnosis and tracing, including detection, diagnosis and tracing of molecules, viruses, bacteria, cells and materials in vitro, detection, diagnosis and tracing of molecules, viruses, bacteria, cells, organs and tissues in vivo and molecules (including small molecule compounds, high molecular polymers and biological macromolecules such as polypeptides, proteins, nucleic acids and the like), pharmaceutical preparations, nanoparticles, biological materials and the like which are given to the body in a certain way, or detection, diagnosis and tracing of the substances in vivo after in vitro labeling by using the molecular imaging nanoparticle probe.
In some embodiments of the invention, it is exemplified that the preferred biological assays are tumor diagnosis and drug and tissue distribution imaging in animals, wherein the animal is a living animal.
Preferably, the molecular imaging nanoparticle probe can be used for preparing a PET contrast agent.
Compared with the prior art, the invention has the following beneficial effects:
compared with the known nuclear medicine molecular imaging probe, the molecular imaging nanoparticle probe has the size of less than 10nm, and is surface modified with a biological reaction active group or a molecular recognition group; the preparation method is simple, the separation and purification are convenient and quick, the F18 adsorption capacity is strong, the probe can be used as a radioactive probe for molecular image detection, diagnosis and tracing, the imaging sensitivity is high, and the specificity is strong.
Drawings
FIG. 1: TEM representation of oil phase ultra-small rare earth nanoparticles NaGdF 4.
FIG. 2: TEM representation of aqueous phase ultra small rare earth nanoparticles NaGdF 4.
FIG. 3: tz modification characterization of NaGdF 4.
FIG. 4: the stability of NaGdF4-Tz adsorbing F18 in different solutions was determined.
FIG. 5: the NaGdF4-Tz nano-particles adsorbed with F18 are distributed and metabolized in a mouse body.
FIG. 6: Tz-NaGdF4 nanoparticles are used for PET tracing and tumor pre-targeting imaging of TCO-SNP.
FIG. 7: hydrogen spectrum of Ad-PEG.
FIG. 8 shows the hydrogen spectrum of 6-ots- β -CD.
FIG. 9: hydrogen spectra of CD-PEI.
Detailed Description
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Test methods in which specific conditions are not specified in the following examples are generally carried out under conventional conditions or under conditions recommended by the respective manufacturers.
When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.
Unless otherwise indicated, the experimental methods, detection methods, and preparation methods disclosed herein all employ techniques conventional in the art of molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related arts. These techniques are well described in the literature, and may be found in particular in the study of the MOLECULAR CLONING, Sambrook et al: a LABORATORY MANUAL, Second edition, Cold Spring harbor LABORATORY Press, 1989and Third edition, 2001; ausubel et al, Current PROTOCOLS Inmolecular BIOLOGY, John Wiley & Sons, New York, 1987and periodic updates; the series METHODS IN ENZYMOLOGY, Academic Press, San Diego; wolffe, CHROMATINSTRUCUTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998; (iii) Methods Inenzymolygy, Vol.304, Chromatin (P.M. Wassarman and A.P.Wolffe, eds.), academic Press, San Diego, 1999; and METHODS IN MOLECULAR BIOLOGY, Vol.119, chromatography protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999, etc.
Example 1 oil and WaterSex ultra-small NaGdF4Preparation of nanoparticles
Heating 1mmol gadolinium chloride hexahydrate, 4ml oleic acid and 15ml octadecene to 140 deg.C under vacuum to form transparent solution, cooling to room temperature, and dropwise adding 2.5mmol sodium hydroxide and NH4F4 mmol in methanol 10mL, stirred overnight for 15h, the mixture was slowly heated to 70 deg.C, the methanol removed, cooled to room temperature, centrifuged twice at 4500rpm in ethanol, and finally dispersed in 5mL cyclohexane. The obtained oil phase rare earth NaGdF4A TEM image of the nanoparticles is shown in fig. 1.
20mg oil phase rare earth NaGdF4Dispersing the nanoparticles in 4ml cyclohexane, adding 2ml dichloromethane and 5mg 3-chloroperoxybenzoic acid, mixing and stirring for 3h at 40 ℃, cooling to room temperature, adding 0.02g L-cysteine, stirring the mixed solution for 5h at room temperature, centrifuging, washing with ethanol for several times, and vacuum drying to collect the obtained water-phase rare earth nanoparticles. The obtained water phase rare earth NaGdF4A TEM image of the nanoparticles is shown in fig. 2.
Example 2 ultra Small NaGdF4Tetrazine (Tz) functional modification of nanoparticles
Amino groups are arranged on the surface of the nano particles modified by cysteine, and aqueous phase NaGdF is added4Dispersing the nanoparticles in mes buffer solution with pH 7.4, adding a certain amount of DMF solution dissolved with 2mg of Tetrazine-PEG5-NHS Ester, reacting for 3h, dialyzing for three days to remove unreacted Tetrazine-PEG5-NHS Ester, and freeze-drying and collecting. Some of the samples after freeze-drying were dissolved in DMSO for nuclear magnetic characterization, and the nuclear magnetic results are shown in FIG. 3. Existing Tz-PEG in nuclear magnetism peak production5The peak of-NHS, and also of the nanoparticle, indicates that Tz has been successfully attached to the nanoparticle.
In this example, Tetrazine-PEG5-NHS Ester: the molecular formula is C27H36N9O 10; molecular weight is 604.41, and structural formula is:
example 3 ultra-Small Tz-NaGdF4Nanoparticle F18 labeling and stability testing
Adding Tz-NaGdF4Dissolving in physiological saline, adding positive electronic nuclide F18-Incubating in water at room temperature for 10min, dialyzing to remove free F18-. Placing the F18 adsorbed nanoparticles in pure water, normal saline, PBS and serum respectively for a period of time, measuring the radiation dose of the solution in the tube, then dialyzing, and measuring the F18 adsorption efficiency of the nanoparticles in the solution. Observing whether the adsorption efficiency changes after a period of time. As a result, as shown in FIG. 4, F18 adsorbed on the nanoparticles was stable for 4 hours in pure water, physiological saline, and serum.
Example 4F18 labeling ultra-Small Tz-NaGdF4In vivo nanoparticle distribution and clearance PET imaging
The nanoparticles of example 3 labeled F18 were injected into mice via tail vein before PET scanning, and the scanning was performed at 0h, 2h and 4h, respectively, and the scanning results are shown in FIG. 5. Observation of Tz-NaGdF4The clearance of nanoparticles in the organs of mice, we show from FIG. 5, Tz-NaGdF4After 2 hours of blood circulation, the nanoparticles in the viscera can be basically removed.
Example 5F18 labeling ultra-Small Tz-NaGdF4PET tracing imaging and tumor pre-targeting imaging of TCO modified self-assembled drug carrier (TCO-SNP) with tumor pre-targeting distribution by nanoparticles
Preparing adamantane modified polyethylene glycol Ad-PEG: 47mg of adamantane hydrochloride having a molecular weight of 187.74g/mol was dissolved in 10ml of CH2Cl2A stirrer was added and stirred at an appropriate rotation speed so that 1-Ad was dissolved in dichloromethane. 26mg of triethylamine and 50mg of mPEG-NHS are sequentially added, the mixture is stirred for 2 hours at room temperature, dichloromethane is removed by a rotary evaporator, water is added for dissolution, the liquid is placed in a dialysis bag with the molecular weight of 3500 for dialysis for three days, and the dialysis bag is placed in a freeze dryer for overnight freeze-drying.
The structure of the product was characterized, and the characterization data is shown in fig. 7:
the characterization data are as follows:1H NMR(400MHz，DMSO-d6):δ3.42-3.54(440H,OCH2)，1.13-1.18(15H,protons on Ad)。
preparation of 6-O- (p-toluenesulphonic acid) - β -cyclodextrin, which is to add 20g of β -CD (17.6mmol) into 400mL of 0.4mol/L NaOH solution in a 500mL three-necked flask, stir vigorously to be colorless (0-5 ℃ in an ice water bath in advance) after complete dissolution, slowly add 15mL of acetonitrile solution dissolved with 6.723g of p-toluenesulfonyl chloride (35.2mmol) in a constant-pressure funnel within 90.0min under the protection of nitrogen, react in the reactor in the ice water bath for 5h, remove unreacted TsCl by suction filtration, take filtrate, acidify to generate white solid with pH2-3 by using 1mol/L HCl, stand the filtrate for 12h at 4 ℃ overnight, suction filter, recrystallize the white solid twice by using water, and dry in vacuum to obtain white powder.
The structure of the product was characterized, and the characterization data is shown in fig. 8:
the structural characterization data for the product are as follows:1H NMR(400MHz，DMSO),δ3.18-3.78(C-2，-3，-4，-5)；4.79(C-1)；5.74(C-2，-3OH)。
β -preparation of Cyclodextrin-modified polyethyleneimine CD-PEI 100mg of PEI (molecular weight 10KD) was dissolved in 100ml of DMSO, 6-OTs- β -CD prepared in example 4 was added to the solution, reacted at 70 ℃ for 3 days, dialyzed with a dialysis bag having a molecular weight of 10KD for six days, filtered to remove unreacted 6-OTs- β -CD, and lyophilized to collect a sample.
The structure of the product was characterized, and the characterization data is shown in fig. 9:
the structural characterization data for the product are as follows:1h NMR (400MHz, DMSO). delta.4.92 (C on Cyclodextrin)1H) 3.27-3.66 (C on cyclodextrin)2-6H) 2.3-3.0 (OCH on PEI)2)。
Preparation of adamantane-modified PAMAM Ad-PAMAM: the PAMAM used in this example was a first generation polyamide dendrimer with a 1, 4-diaminobutane core and amine ends. The PAMAM is available from DendriticNanotechnologies, Inc (Mount plexant, MI).
A solution of PAMAM (20% wt, 100mg, 0.069mmol) in methanol was added to a round bottom flask. The methanol was evaporated in vacuo and the viscous solid was dissolved in 10ml of dry THF. 1-adamantane isocyanate (244.6mg, 1.38mmol) in 10ml THF was added directly to the PAMAM solution. After the reaction mixture was stirred at room temperature for 2 hours, the solvent was removed in vacuo. Diethyl ether (100ml) was added to the reaction residue to give a white precipitate, which was collected by filtration. The white precipitate (100 ml. times.3) was washed with ether and dried to obtain Ad-PAMAM as a white solid. According to the characterization data analysis, 8 Ad were attached to each PAMAM.
TCO component is connected on the long chain of adamantane modified PEG (Ad-PEG), and the TCO component and cyclodextrin modified PEI (CD-PEI) and adamantane modified PAMAM (Ad-PAMAM) are self-assembled through inclusion complexation between Ad and CD to form nano-particle TCO-SNPs, and the particle size is about 150 nm. The method comprises the following steps: Ad-PEG-TCO (10mg/ml) 52.8 ul; Ad-PAMAM (2.1mg/ml)18.86 ul; vortex the vortex apparatus for 10s, let stand for 3min, add CD-PEI (10mg/ml) and vortex 15ul for 10s and let stand for 20 min.
After injection into mice via the tail vein, the TCO-SNPs can be accumulated at the tumor site by the tumor EPR effect. Labeling of ultra-small Tz-NaGdF by tail vein injection F18 after 24 hours4And (3) carrying out PET scanning on the nanoparticles after 2h, wherein the white dotted circle part in the image is the position of the subcutaneous tumor. As shown in fig. 6, the obtained PET image showed very high radioactive signals in tumors, while there were almost no radioactive signals in organs such as liver, lung, and spleen. The result shows that the ultra-small rare earth nanoparticles combined with the TCO component are remained at the tumor part, and the non-combined nanoparticles are quickly discharged out of the body, so that the in-vivo tracing of TCO-SNPs is realized, and the high tumor/tissue contrast imaging is also obtained. Our imaging method is based on the tumor EPR effect, and the 18F-FDG contrast agent is mostly used clinically at present and is based on the property of high glucose metabolism of tumors. In contrast, our probe is universal and eliminates the possibility of false positives.
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (10)
1. A preparation method of a molecular imaging nanoparticle probe comprises the steps that basic nanoparticles are rare earth nanoparticles, positive electronic nuclides are marked on the molecular imaging nanoparticle probe, and a molecular recognition group is modified on the surface of the basic nanoparticles, so that the basic nanoparticles have the capability of actively targeting an object to be traced; the molecular recognition group modified on the surface of the basic nanoparticle and the molecular recognition group modified on the surface of the object to be traced form a molecular recognition pair, and the molecular recognition pair is tetrazine and trans-cyclooctene, and the method comprises the following steps:
(1) preparing a base particle;
(2) carrying out molecular recognition group modification on the basic nanoparticles obtained in the step (1);
(3) and (3) continuously carrying out positron nuclide labeling on the basic nanoparticles modified with the molecular recognition groups obtained in the step (2).
2. The method of claim 1, wherein the rare earth nanoparticles are doped nanoparticles containing one or more rare earth elements.
3. The method of claim 2, wherein the rare earth nanoparticles are particles of fluoride, oxide, composite oxide, hydroxide, sulfide, carbonate, phosphate, titanate, borate, vanadate, tungstate, cation, or anion doped with one or more rare earth elements.
4. The method of claim 2, wherein the rare earth nanoparticles are fluoride particles doped with one or more rare earth elements.
5. The method of claim 2, wherein the rare earth nanoparticles are selected from the group consisting of REF3、MREF4Or REOF, wherein RE refers to trivalent rare earth element, and M is selected from alkali metal elements Li, Na or K.
6. The method of claim 2, wherein the rare earth nanoparticles are NaGdF4And (3) nanoparticles.
7. The method of claim 1, wherein the particle size of the molecular imaging nanoparticle probe is 1-10 nm.
8. The method of claim 1, wherein when the base particle is a rare earth nanoparticle-NaGdF4When nano particles are used, in the step (1), the solvothermal method is adopted to prepare the base particles NaGdF4The nanoparticles specifically include the steps of: 1) heating rare earth elements gadolinium ion salt, oleic acid and octadecene under vacuum to form transparent solution, cooling to room temperature, and adding NaOH and NH4Stirring the methanol solution of F at room temperature for reaction, heating to remove the methanol, washing with ethanol for centrifugation, collecting precipitate, dispersing in cyclohexane to obtain oil phase rare earth NaGdF4Nanoparticles; 2) oil phase rare earth NaGdF obtained in the step (1)4Adding dichloromethane and trichloroperoxybenzoic acid into nano particles, stirring for reaction, adding L-cysteine, continuing stirring for reaction, centrifuging the obtained solution by using ethanol, collecting precipitate, washing the precipitate, and drying in vacuum to obtain water-phase rare earth NaGdF4Nanoparticles.
9. The method according to claim 8, wherein the aqueous phase rare earth NaGdF obtained in the step (1) is subjected to click chemistry4The nano particles react with the substance shown in the formula I to carry out molecular recognition group-tetrazine modification.
10. The method as claimed in claim 8, wherein in the step (3), F18 anion solution is added into the base nanoparticle solution modified with the molecular recognition group obtained in the step (2), and the base nanoparticle solution is incubated to obtain F18 labeling of positive electron species.
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