CN111317829B - SPECT/FI bimodal molecular imaging probe and preparation method thereof - Google Patents
SPECT/FI bimodal molecular imaging probe and preparation method thereof Download PDFInfo
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- CN111317829B CN111317829B CN201811533501.0A CN201811533501A CN111317829B CN 111317829 B CN111317829 B CN 111317829B CN 201811533501 A CN201811533501 A CN 201811533501A CN 111317829 B CN111317829 B CN 111317829B
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- 238000003384 imaging method Methods 0.000 title claims abstract description 38
- 238000002603 single-photon emission computed tomography Methods 0.000 title claims abstract description 27
- 230000002902 bimodal effect Effects 0.000 title claims abstract description 24
- 239000000523 sample Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- DGYHPLMPMRKMPD-UHFFFAOYSA-N L-propargyl glycine Natural products OC(=O)C(N)CC#C DGYHPLMPMRKMPD-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001540 azides Chemical class 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 6
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 5
- 229960005055 sodium ascorbate Drugs 0.000 claims description 5
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000003068 molecular probe Substances 0.000 abstract description 12
- 239000002243 precursor Substances 0.000 abstract description 5
- 238000012650 click reaction Methods 0.000 abstract description 4
- BXRLWGXPSRYJDZ-UHFFFAOYSA-N 3-cyanoalanine Chemical compound OC(=O)C(N)CC#N BXRLWGXPSRYJDZ-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002738 chelating agent Substances 0.000 abstract description 2
- 239000007850 fluorescent dye Substances 0.000 abstract 1
- 238000000799 fluorescence microscopy Methods 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002086 nanomaterial Substances 0.000 description 3
- -1 propargyl glycine modified RGD Chemical class 0.000 description 3
- 238000010171 animal model Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000013170 computed tomography imaging Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/082—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being a RGD-containing peptide
Abstract
The invention discloses a preparation method of a SPECT/FI bimodal molecular imaging probe, which is characterized in that a biological target molecule is connected with a fluorescence signal through click reaction of azide and propargyl glycine, and the probe can be used for preparing a fluorescent probe99mTc-labeled chelating agent, thereby completing the precursor of the SPECT/FI bimodal molecular probe in one step. On the basis of this precursor by simple99mTc marks to obtain the SPECT/FI bimodal molecular probe.
Description
Technical Field
The invention relates to a SPECT/FI bimodal molecular imaging probe and a preparation method thereof based on click reaction.
Background
Molecular imaging techniques play an increasingly important role in the accurate medical treatment of tumors. However, the size of the imaging system is short, the size of the imaging system is long, each molecular imaging technology has different advantages and disadvantages, and a single molecular imaging technology cannot meet the requirement of precise medicine due to the fact that the single molecular imaging technology cannot cope with complex tumor problems. The fusion of two or more different molecular imaging technologies exerts respective advantages to complement respective disadvantages, can provide as much accurate information as possible for complex tumors from multiple aspects, achieves the purposes of accurate medical treatment and personalized diagnosis and treatment, and provides medical service fitting to the patient. Throughout the fusion of various image modalities, nuclear medicine imaging and Fluorescence Imaging (FI), which have similar sensitivities, show perfect complementarity in spatial resolution and tissue penetrability, have received much attention and have been rapidly developed.
The molecular probe is a cornerstone of molecular imaging technology, and the fusion of various molecular imaging technologies depends on the development of multi-modal molecular probes. Most of the multi-modal molecular imaging probes currently being researched are constructed on the basis of nano materials, but the in vivo compatibility of the nano materials is still unsatisfactory, and the conversion application of the nano materials in biomedicine, particularly in vivo imaging is obstructed. To date, nanoparticle-based molecular probes have remained limited to preclinical studies, with a long clinical transformation road. The molecular probe for practical clinical application is still based on the traditional small molecular compound with biological activity, but the biggest problem in constructing the multi-modal molecular imaging probe based on the traditional small molecule is that the small molecule generally lacks an active group which is easy to modify and is difficult to link a plurality of imaging signal units. Therefore, clinical transformation of multi-modal molecular imaging probes is not always feasible.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defect that small molecular biological target molecules lack active groups which are easy to modify, constructing a precursor of a SPECT/FI bimodal molecular probe by a click reaction one-step method on the basis of only occupying one active group, and performing radioactivity99mTc mark is applied to tumor imaging, and a simple, rapid and low-demand SPECT/FI bimodal molecular probe synthesis method is established.
On one hand, the invention provides a preparation method of a SPECT/FI bimodal molecular imaging probe, which comprises the following steps:
1) propargylglycine-modified RGD (RGD-Pra) is reacted with azido Cy7(Cy 7-N) in the presence of copper sulfate and sodium ascorbate3) Reacting to generate RGD-click-Cy 7; the reaction formula of the step is as follows:
synthesis of RGD-ckick-Cy7 compound of formula I
2) Mixing the RGD-click-Cy7 obtained in the step 1) with99mTc(CO)3Reacting, adjusting the pH value of the reaction to 4-9, and reacting to generate99mTc(CO)3-RGD-click-Cy 7; the reaction formula of the step is as follows:
a compound of formula II99mTc(CO)3Synthesis of-RGD-click-Cy 7
Wherein, in step 1), propargylThe ratio of the amount of the substance of the reaction between the glycine-modified RGD and the azido Cy7 is 1:1, and every 1-10 mu g of RGD-click-Cy7 in the step 2) corresponds to 1-10mCi99mTc(CO)3The reaction is carried out.
Preferably, in the step 1), mixing the propargyl glycine modified RGD aqueous solution with an azido Cy7 aqueous solution for reaction; wherein the concentration of the propargyl glycine modified RGD aqueous solution is 1-10mM, and the volume of the solution is 0.01-10 mL; the concentration of the aqueous solution of the azido Cy7 is 1-10mM, and the volume of the solution is 0.01-10 mL.
Further, adding CuSO in the step 1)4The amount of sodium ascorbate is 1-20% molar equivalent, and the amount of sodium ascorbate added is also 1-20% molar equivalent.
Further, the reaction temperature of the step 1) is 25-50 ℃, and the reaction time is 1-6 hours.
Further, the reaction temperature of the step 2) is 50-90 ℃, and the reaction time is 10-100 minutes.
Preferably, step 1) further comprises: after the reaction is finished, the reaction solution is concentrated, and the product RGD-click-Cy7 is obtained after column separation and purification.
In another aspect, the invention provides a SPECT/FI bimodal molecular imaging probe prepared by the method, and a product prepared by the method99mThe Tc mark rate is more than 95%.
The method for preparing the SPECT/FI bimodal molecular imaging probe forms a probe which can be used for connecting a biological target molecule and a fluorescence signal through click reaction of azide and propargyl glycine99mTc-labeled chelating agent, thereby completing the precursor of the SPECT/FI bimodal molecular probe by one-step construction, and the precursor is simply processed99mTc marks to obtain the SPECT/FI bimodal molecular probe. The method is simple, rapid and easy to operate, the reaction yield is high, the labeling rate is high, the imaging effect of the prepared probe is reliable, and the method has a very good application prospect.
Drawings
FIG. 1 is a mass spectrum of RGD-click-Cy 7;
FIG. 2 is an HPLC UV spectrum of RGD-click-Cy 7;
FIG. 3 is a schematic view of99mTc(CO)3-radioactive HPLC profile of RGD-click-Cy 7;
FIG. 4 shows a molecular probe prepared in example 299mTc(CO)3SPECT/CT visualization of RGD-click-Cy7 on tumor mice;
FIG. 5 shows the molecular probe prepared in example 299mTc(CO)3FI visualization of RGD-click-Cy7 on tumor mice.
Detailed Description
The conception, the specific structure and the technical effects of the present invention will be further described with reference to the accompanying drawings to fully understand the objects, the features and the effects of the present invention, but the present invention is not limited thereto.
The first embodiment is as follows: synthesis of RGD-click-Cy7
Taking 0.01-10mL of Propargylglycine (Propargylglyceine, Pra) modified RGD (RGD-Pra) aqueous solution (1-10mM) and 0.01-10mL of azido Cy7(Cy 7-N)3) Mixing the aqueous solutions (1-10mM), and then adding 1% -20% molar equivalent of CuSO4And sodium ascorbate at 25-50 deg.C for 1-6 hr (formula I). After the reaction is finished, the reaction solution is concentrated, and the product RGD-click-Cy7 is obtained after column separation and purification, wherein the yield is 40-95%. ESMS m/z 1590.3, theoretical molecular weight 1591.73. The compound characterization spectra are shown in figure 1 and figure 2.
Synthesis of RGD-ckick-Cy7 compound of formula I
The second embodiment:99mTc(CO)3synthesis of-RGD-click-Cy 7
Taking RGD-click-Cy 71-10 μ g, adding 100 μ L of freshly synthesized99mTc(CO)3The solution (about 1-10mCi) is adjusted to pH 4-9 and allowed to react at 50-90 ℃ for 10-100 minutes (formula II). The product is analyzed by high performance liquid chromatography, and the marking rate is high>95 percent. The device is99mThe emission spectrum of the Tc complex is shown in FIG. 3.
A compound of formula II99mTc(CO)3Synthesis of-RGD-click-Cy 7
Effect embodiment: SPECT/FI imaging experiment of tumor mice
BALB/c nude mice, female, with a weight of 18-20 g, were bred in SPF-level animal laboratories of the laboratory animals division of the university of Compound denier, supplied by Shanghai Slek laboratory animals Co. Two days after the animal room is adaptively fed, U87MG glioma cells are injected into the armpit of a nude mouse in a subcutaneous injection mode, and the injection amount is 0.2mL (1 multiplied by 10)7cells/mL). Culturing for 4-6 weeks after injection until the solid tumor mass grows to 500-3It is used for imaging experiment.
1mCi/0.2mL by tail vein injection99mTc(CO)3RGD-click-Cy7 to tumor mice. The experimental animals were subjected to imaging experiments with small animal SPECT/CT 4 hours after injection, and the image is shown in FIG. 4. The PECT/CT imaging is immediately followed by the fluorescence imaging, and the imaging picture is shown in figure 5.
The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
Claims (10)
1. A preparation method of a SPECT/FI bimodal molecular imaging probe is characterized by comprising the following steps:
1) in the presence of copper sulfate and sodium ascorbate, propargyl glycine modified RGD reacts with azido Cy7 to generate RGD-click-Cy 7; the structural formula of the propargyl glycine modified RGD is shown as follows:
2) combining the RGD-click-Cy7 obtained in the step 1) with99mTc(CO)3Reacting, adjusting the pH value of the reaction to 4-9, and reacting to generate99mTc(CO)3-RGD-click-Cy7。
2. The method for preparing the SPECT/FI bimodal molecular imaging probe as claimed in claim 1, wherein the ratio of the amount of the substance reacting the propargyl glycine modified RGD and the azido Cy7 in the step 1) is 1: 1.
3. The method for preparing the SPECT/FI bimodal molecular imaging probe as claimed in claim 1, wherein the propargyl glycine modified RGD aqueous solution is mixed with an azide Cy7 aqueous solution for reaction in the step 1); wherein the concentration of the propargyl glycine modified RGD aqueous solution is 1-10mM, and the volume of the solution is 0.01-10 mL; the concentration of the aqueous solution of the azido Cy7 is 1-10mM, and the volume of the solution is 0.01-10 mL.
4. The method for preparing the SPECT/FI bimodal molecular imaging probe according to claim 1, wherein CuSO is added in the step 1)4In an amount of 1% to 20% molar equivalents.
5. The method for preparing the SPECT/FI bimodal molecular imaging probe of claim 1, wherein the amount of sodium ascorbate added in step 1) is 1% to 20% molar equivalents.
6. The method for preparing the SPECT/FI bimodal molecular imaging probe according to claim 1, wherein the reaction temperature in the step 1) is 25-50 ℃ and the reaction time is 1-6 hours.
7. The method of preparing the SPECT/FI bimodal molecular imaging probe of claim 1, wherein each 1-10 μ g of RGD-click-Cy7 in step 2) corresponds to 1-10mCi99mTc(CO)3The reaction is carried out.
8. The method for preparing the SPECT/FI bimodal molecular imaging probe as claimed in claim 1, wherein the reaction temperature in the step 2) is 50-90 ℃ and the reaction time is 10-100 minutes.
9. The method for preparing a SPECT/FI bimodal molecular imaging probe of claim 1, wherein step 1) further comprises: after the reaction is finished, the reaction solution is concentrated, and the product RGD-click-Cy7 is obtained after column separation and purification.
10. A SPECT/FI bimodal molecular imaging probe prepared by the method of preparation of a SPECT/FI bimodal molecular imaging probe according to any one of claims 1 to 9.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276688A (en) * | 2011-05-19 | 2011-12-14 | 江苏省原子医学研究所 | Modified peptide chain segment and application thereof in modification of peptide molecular imaging probe |
| CN104511030A (en) * | 2013-09-29 | 2015-04-15 | 复旦大学 | Dual-modal nano imaging drug Dex-Rho-99mTc based on glucan |
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| WO2012040108A2 (en) * | 2010-09-20 | 2012-03-29 | Caliper Life Sciences | Multivalent fluorescent probes |
| US9631096B2 (en) * | 2012-01-20 | 2017-04-25 | Cornell University | Dye compositions, methods of preparation, conjugates thereof, and methods of use |
| WO2014055253A1 (en) * | 2012-10-04 | 2014-04-10 | The General Hospital Corporation | Methods of synthesizing and using peg-like fluorochromes |
| AU2014232907B2 (en) * | 2013-03-15 | 2017-12-21 | Cornell University | Multimodal silica-based nanoparticles |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276688A (en) * | 2011-05-19 | 2011-12-14 | 江苏省原子医学研究所 | Modified peptide chain segment and application thereof in modification of peptide molecular imaging probe |
| CN104511030A (en) * | 2013-09-29 | 2015-04-15 | 复旦大学 | Dual-modal nano imaging drug Dex-Rho-99mTc based on glucan |
Non-Patent Citations (1)
| Title |
|---|
| Radiolabeling and evaluation of 188Re-RGD as an agent for αvβ3 receptor expression;Yufei MA et al;《Nuclear Science and Techniques》;20121231;第23卷;第47-51页 * |
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