CN115607690B - Molecular probe and preparation method and application thereof - Google Patents

Molecular probe and preparation method and application thereof Download PDF

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CN115607690B
CN115607690B CN202110803387.4A CN202110803387A CN115607690B CN 115607690 B CN115607690 B CN 115607690B CN 202110803387 A CN202110803387 A CN 202110803387A CN 115607690 B CN115607690 B CN 115607690B
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molecular probe
probe
reagent
nanobody
molecular
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CN115607690A (en
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张茜
侯征
王璐瑶
胡荣军
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Guangdong Jingguan Biomedical Technology Co ltd
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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
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0058—Antibodies
    • 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
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention relates to the technical field of disease detection reagents, in particular to a CD47 nano molecular probe and a preparation method and application thereof. The multi-modal nanobody molecular probe comprises a radioactive element E, a CD47 nanobody and a T connection with a- (M) M-structural formula, wherein G is respectively connected with L 1 ‑R 1 And L 2 ‑R 2 Are connected in turn. The molecular probe provided by the invention can realize near infrared fluorescence single imaging, nuclide single imaging and two-mode combined imaging, and can be used for simultaneously carrying out tumor treatment by combining specific nuclides besides tumor diagnosis.

Description

Molecular probe and preparation method and application thereof
Technical Field
The invention belongs to the technical field of molecular probes, and particularly relates to a CD47 nano molecular probe and a preparation method and application thereof.
Background
In vivo imaging of specific targets requires specific molecular probes in addition to high resolution, high sensitivity, and rapid imaging techniques. Molecular probes are key to successful imaging, and their synthesis and detection are one of the hottest and foremost problems in molecular imaging studies. However, in all the current molecular imaging technologies, no perfect imaging technology can provide all information about the detected object, and any imaging technology has advantages and disadvantages of itself; none of the conventional molecular probes provides information about all structures, functions and molecules of a tissue. In order to overcome these defects, research on a bi-modal or multi-modal molecular probe is started, and the advantages of two or more modal probes are combined, so that the molecular probe can obtain brand new information in aspects of diagnosis, treatment, monitoring and the like. At present, various molecular probes with different modes are effectively combined to initially form various novel dual-mode probes including PET-optical, SPECT-optical, PET-MRI and the like. These "integrated" bimodal molecular imaging probes must be an important tool for future in vivo imaging. The multi-mode molecular imaging not only requires advanced imaging equipment, but also requires development of novel and efficient molecular probes. The existing molecular imaging technology has defects in resolution, detection limit, availability, energy extensibility and the like, and the construction of a novel multi-mode molecular probe which is safe, effective and has detection and treatment functions is an important direction of future development.
CD47 is a widely expressed membrane protein, also known as integrin-associated protein (IAP). As a ligand for signal regulatory protein alpha (Signal regulatory protein alpha, sirpa) on the surfaces of macrophages and myeloid cells, its interaction with sirpa provides a negative regulatory signal to phagocytes, inhibiting phagocytosis of macrophages. CD47 is a multifunctional receptor involved in interactions including between tumors, tumor and interstitium, and tumor and immune cells. In recent years, CD47 has been found to be overexpressed in a variety of human tumors. The overexpression of CD47 in human tumors and its "do-it-yourself" signaling as a tumor makes the CD 47-sirpa pathway an ideal target for various tumor immunotherapies. Currently, a more studied therapeutic approach is blocking antibodies that target CD47 directly. Nanobodies are variable region fragments of heavy chain antibodies that naturally lack a light chain in camels, and are currently the smallest single domain antibodies with complete antigen binding function. Compared with the traditional monoclonal antibody, the nano antibody has the advantages of small molecular volume, strong tissue penetrating capacity, higher stability, easy combination of protein cleft epitope, low production cost and the like, and has become a promising candidate molecule for developing new generation therapeutic antibodies.
Disclosure of Invention
Accordingly, it is an object of the present invention to provide a novel multi-modal molecular probe based on CD47 nanobody. The molecular probe has targeting property on various tumors over-expressing CD47, and can perform living imaging in radionuclide and/or optical two modes.
It is another object of the present invention to provide a method for preparing the CD 47-targeting multi-modal molecular probe.
The invention also aims to provide an application of the multi-mode molecular probe targeting CD47 in preparing a medicine for diagnosing and treating colon cancer.
In order to achieve the above object, the present invention provides the following technical solutions:
a multi-modal nanobody molecular probe having the structure:
d is a CD47 nanobody;
e is a radioactive element 125 I, 126 I, 130 I, 131 I or H;
t is selected from the following structures:
the L is 1 And L 2 Has the formula- (M) M-where M represents a monomer which is identical to or different from each other and may be-CH 2 -、-CH 2 CH 2 O-、-C(＝O)-、-C(＝O)O-、-C(＝O)NH 2 -, -S-, -O-, -S-, -NH-; -NH-C (SC) -C (=o) -or-hc=ch-, SC are residues of 20 natural amino acids, M is the number of monomer repeats, is an integer between 0 and 60, and can be selected from the following structures:
R 1 is a metal ion complexing group or a fluorescent group, and is selected from the following structures:
R 2 can be combined with R 1 Identical or different, when R 2 And R is R 1 When different, R 2 Is metal ionA daughter complexing group, a fluorescent group, a steroid group, or a PEG group.
For targeted fluorescent probes, sufficient TBR (tumor background ratio, T/B) is achieved, requiring sufficient binding time of the probe molecule to the target. Studies have shown that the binding time is largely dependent on the dissociation rate of the probe-target complex, i.e. k off . The effectiveness of the probe depends on the dissociation process, the probe-target binding rate constant k on Limited by concentration and diffusion rate, and thus difficult to control. And k is off It is entirely dependent on the specific interaction between the probe and its target binding. Monovalent ligand-receptor interactions are primarily enthalpy-driven processes in which the ligand diffuses in solution to the target and binds to the receptor with the free energy of interaction Δg=Δh-tΔs, where Δg is the free energy binding force, which is the sum of the enthalpy (Δh) and entropy (-tΔs) contributions. There are only two states of bound and unbound in the monovalent system. In multivalent systems, the scaffold itself and the multiple ligands attached to the scaffold, the entropy penalty required for multivalent probe binding to the target can be reduced by rational design of the linker.
The invention aims at designing a novel fluorescent molecular probe, and the effective method for increasing TBR (tumor background ratio, T/B) to increase TBR, increase T or decrease B is to prolong the action time of the probe and a target point and the effective method for prolonging the action time of the probe and the target point is to decrease k off . The linker in the monovalent probe of the invention enhances the affinity between the targeted fluorescent molecular probe and the target, while the multivalent probe may further enhance the affinity. (multivalent vs. monovalent, k) off Greatly reduced, see multitvalency: peptides, research and Applications, edited by Jurriaan Huskens, leonard J.Prins, rainer Haag, bart Jan Ravoo, pp 209).
As a preferred embodiment, the fluorescent molecular probe has a structure shown in formula I:
the invention also provides a preparation method of the fluorescent molecular probe, which comprises the following steps:
the CD47 nano antibody reacts with the reagent 1 to generate an intermediate 2, the intermediate 2 further reacts with the reagent 3 to generate an intermediate 4, and the intermediate 4 reacts with the reagent 5 to generate a molecular probe 6:
wherein A is one of the following structural formulas:
wherein B is one of the following structural formulas:
in reagent 2, c has the following structural formula:
said E, L 1 、L 2 、R 1 、R 2 As defined above.
The invention also provides a nuclide imaging agent, which comprises the molecular probe, wherein R 1 And R is 2 At least one of which is a metal ion complexing agent, and 65 Ga、 64 cu or 89 Zr ions are combined.
The invention also provides a near infrared fluorescent tracer, which comprises the molecular probe, wherein at least one of R1 and R2 is a near infrared fluorescent group.
The invention also provides a multi-mode probe, which has the structure, wherein R 1 And R is 2 Respectively is with 65 Ga、 64 Cu or 89 Zr ion combined metal ion complex groupA group, and a near infrared fluorescent group.
The invention also provides a multi-mode probe, which has the structure as described above, R 1 And R is 2 Is a near-infrared fluorescent group, and is a fluorescent group, 125 i replaces the hydrogen on CD47 nano antibody tyrosine.
The molecular probe provided by the invention is applied to preparation of tumor diagnosis and treatment reagents.
The nuclide imaging agent, the near infrared fluorescent tracer and the multi-mode probe are applied to preparation of tumor diagnosis and treatment reagents.
The invention also provides a composition comprising a molecular probe as defined in any one of the above and a pharmaceutically acceptable carrier.
The carrier may be selected as desired by one skilled in the art, and may be selected from, for example, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, citric acid, sodium citrate, polysorbate 20, polysorbate 80, water for injection, and the like.
Compared with the prior art, the invention has the following beneficial effects:
1) The molecular probe provided by the invention can realize near infrared fluorescence single imaging, nuclide single imaging and two-mode combined imaging, and can simultaneously treat tumors by combining specific nuclides besides tumor diagnosis;
2) The CD47 nano antibody is used, so that the target binding specificity is high; the nanobody has higher imaging speed because of the advantages in the aspects of volume, tissue permeability and the like.
Drawings
Fig. 1 is a near infrared fluorescence imaging map of nanobody probe HCT116 subcutaneous tumor model.
Figure 2 is a SPECT/CT scan map of nanobody probe HCT116 subcutaneous tumor model imaging.
Detailed Description
The invention discloses a molecular probe with a novel structure, a preparation method and application thereof, and a person skilled in the art can properly improve the technological parameters by referring to the content of the invention. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the methods and applications described herein, and in the practice and application of the techniques of this invention, without departing from the spirit or scope of the invention. The following is a description of the embodiments. Wherein the equivalent is molar equivalent in the examples.
Example 1
CD47 nano antibody and isomerism function crosslinking reagent DBCO-NHS coupling synthesis intermediate product 1
At room temperature, 25mgCD47 nano-antibody is dissolved in normal saline to prepare 1mLCD47 nano-antibody solution, 1mL 1.0M PBS with pH of 8.5 is added to be uniformly mixed to prepare CD47 nano-antibody solution; 4 equivalents of DBCO NHS were dissolved in 20. Mu.L of DMSO, added to the CD47 nanobody solution, and incubated in warm water at 20℃for 2h with several shaking. After the reaction was completed, the mixture was centrifuged 4 times at 1200rpm using a desalting column (Pierce Zebra,5 mL) with 0.01M PBS as a mobile phase; the filtrate was collected and freeze-dried to give 15mg of compound 3.
Example 2
Synthesis of intermediate compound 4:
25mg,0.165mmol of Compound 2 and 98mg,0.33mmol of Compound 3 are dissolved in 2mL of DMF and 57mg,0.42mmol of K are added 2 CO 3 Heating to 80 ℃ for 4 hours, adding 2ml of water for cooling, purifying by high performance liquid chromatography, and freeze-drying the solvent to obtain 45mg of compound in a fluffy state, wherein the detection conditions are as follows: chromatographic column model: agela C18 (10 μm,50X 250mm, chromatographic operating conditions: mobile phase a was 0.05% trifluoroacetic acid and mobile phase B was 90% acetonitrile/water, acetonitrile: water = 90%:10%, flow rate 25 ml/min, UV detection wavelength 254 nm, and freeze drying to obtain 45mg of Compound 4 (yield: 41%, purity 95.5%).
Example 3
Synthesis of intermediate compound 5:
45mg,0.068mmol of Compound 4 was dissolved in 1mL of DCM, and to this solution was added trifluoroacetic acid in dichloromethane (TFA/CH 2 Cl 2 Volume ratio = 1:3,0.4 mL), at room temperature for 45min, volatiles were removed under reduced pressure, and 2mL water was added to dry to give 16mg of compound 5 in 50.9% yield, 95% purity).
Example 4
Synthesis of intermediate compound 7:
2mg,0.004mmol of Compound 5 was dissolved in 0.5mL of PBS (pH=8.4) buffer, 0.5mL of PBS (pH=8.4) buffer in which IR Dye 800CW NHS (Compound 6) (10 mg) had been dissolved was added, reacted at room temperature for 60 minutes, purified by high performance liquid chromatography, and freeze-dried to obtain 6mg of Compound 7 (yield 57%. Purity 94.6%). Wherein, the operating conditions for high performance liquid phase purification are as follows: mobile phase a was 0.05% trifluoroacetic acid and mobile phase B was 90% acetonitrile/water (acetonitrile: water=90%: 10%), flow rate was 25 ml per minute, and uv detection wavelength was 254 nm.
Example 5
Synthesis of intermediate compound 8:
10mg of Compound 3 obtained in example 1 was dissolved to prepare 1mL of an aqueous solution, 2mg of Compound 7 was dissolved in 100. Mu.L of DMSO, and the above two solutions were mixed uniformly, shaken for 30 seconds, and reacted at room temperature for 45 minutes. After the reaction was completed, the mixture was centrifuged 3 times at 1200rpm using a desalting column (Pierce Zebra,5 mL) with 0.01M PBS as a mobile phase. The filtrate was collected and lyophilized to give 6mg of compound 8.
Example 6
Synthesizing a multi-mode probe:
100. Mu.L (2 mg/mL) of Compound 8 was taken, 100. Mu.L of 0.02mol/L of pH7.4 phosphate buffer solution and 15. Mu.L of Na125I (2.54 mCi) solution were added, mixed well, 20. Mu.L of 5mg/mL chloramine T solution was added, reacted at room temperature on a mixer for 70 seconds, 200. Mu.L of sodium metabisulfite solution (5 mg/mL) was added, then 2.06mL of 0.02mol/L of pH7.4 phosphate buffer solution was added, and the reaction was continued for 5 minutes, separation was performed by PD10 column, eluent was 0.02mol/L of pH7.4 phosphate buffer solution, and the elution was collected by a separate tube to obtain a multi-modal probe.
Test examples
1. Establishing a tumor model
All animal experiment procedures were performed with the university of su laboratory animal center and the university of su animal protection and use committee approval. To establish a subcutaneous tumor model of HCT-116 colon cancer, experiments were performed using healthy Balb/C nude mice (18-22 g) injected with 50. Mu.L of HCT-116 cell suspension (5X 10) at the right inguinal site of the mice 6 Individual cells). To the extent that the tumor volume reaches about 200mm 3 And (3) starting living near infrared fluorescence imaging and microSPECT-CT scanning imaging.
2. Near infrared fluorescence imaging
The 9 nude mice of the HCT-116 subcutaneous tumor model were randomly divided into 3 groups of 3 mice each. The CD47 nanobody multi-modal molecular probe obtained in example 6 was injected by tail vein at doses of 2.5mg/kg, 5mg/kg, 10mg/kg, respectively, with an injection volume of 200. Mu.L. The IVIS specrum small animal three-dimensional living body imager of Perkin elmer is turned on, and the CCD lens is initialized to reach-90 ℃. The gas anesthesia instrument for the small animals is opened, the concentration of isoflurane is adjusted to 5%, and after the mice are anesthetized, the concentration of isoflurane is adjusted to 3% until the scanning is finished. The anesthetized mice are orderly placed in a scanning area, and the nose tip is placed in the vent hole. The scan excitation and emission wavelengths were set (theoretical em=789, ex=774; actual em=840, ex=745) and scanned 2, 4, 8, 24, 48 hours post-dose, the results of the mouse imaging are shown in fig. 1.
MicroSPECT-CT scanning imaging
3 HCT-116 subcutaneous tumor model mice were injected with the CD47 nanobody multi-modal molecular probe obtained in example 6 at a dose of 5mg/kg and an injection volume of 200. Mu.L by tail vein. Mice were anesthetized in a mixture of isoflurane and oxygen at a ratio of 1.5% and a flow rate of 0.6L/min. Scanning is carried out in 2, 4, 8, 24 and 48 hours by using a microSPECT-CT, wherein CT imaging parameters are bulb tube current (615 mu A), bulb tube voltage (55 kV), an accurate scanning mode and an omnibearing scanning mode, and the scanning time is 12 minutes. SPECT scan time was 15min. The imaging effect is shown in fig. 2.
Near infrared and microSPECT-CT results show that the embodiment 6 starts to enrich at the tumor part after 2 hours of injection, shows that the probe has good targeting to HCT-116 colon cancer tumor, can realize accurate positioning of tumor, and the tumor enrichment can be up to 48 hours, and shows that the multi-mode molecular probe based on the CD47 nano antibody has fast imaging and long duration. Molecular probes based on full-length monoclonal antibodies generally need to be imaged obviously only about 72 hours after injection, and compared with the molecular probes based on nanoantibodies, the molecular probes based on nanoantibodies have obvious advantages in imaging time, can be more suitable for clinical application scenes, and have more clinical transformation advantages.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (10)

1. A multi-modal nanobody molecular probe characterized by the following structure:
；
d is a CD47 nanobody;
e is a radioactive element 125 I；
T has the following structure:
；
the L is 1 And L 2 Has the formula- (M) M-, wherein M represents CH 2 CH 2 O-, m is the number of monomer repetition and is an integer between 0 and 60;
R 1 is a metal ion complexing group, and has the following structural formula:
；
R 2 and R is R 1 The same applies.
2. The molecular probe of claim 1, wherein the molecular probe has the structure as follows:
。
3. the method for preparing a molecular probe according to any one of claims 1 to 2, comprising the steps of:
reacting the CD47 nano antibody with a reagent DBCO-NHS to generate an intermediate 2, further reacting the intermediate 2 with a reagent 3 to obtain an intermediate 4, and reacting the intermediate 4 with a reagent 5 to generate a molecular probe 6:
；
in reagent 3, c has the following structural formula:
；
said E, L 1 、L 2 、R 1 、R 2 The scope is as defined in claim 1.
4. A nuclide imaging agent comprising the molecular probe of claim 1, wherein R 1 And R is 2 And (3) with 65 Ga、 64 Cu or 89 Zr ions are combined.
5. A near infrared fluorescent tracer comprising the molecular probe of claim 1, wherein R 1 And R is 2 Is a near infrared fluorescent group.
6. A multi-modal probe having the structure of claim 1 wherein R 1 And R is 2 Is in combination with 65 Ga、 64 Cu or 89 Zr ion combined metal ion complexing group and near infrared fluorescent group.
7. A multi-modal probe having the structure as claimed in claim 1, R 1 And R is 2 Is a near-infrared fluorescent group, and is a fluorescent group, 125 i replaces the hydrogen on CD47 nanobody tyrosine.
8. Use of a molecular probe according to any one of claims 1-2 in the preparation of a reagent for tumour diagnosis and treatment.
9. Use of the nuclide imaging agent of claim 4, the near infrared fluorescent tracer of claim 5, the multi-modal probe of claim 6 or 7 in the preparation of a diagnostic reagent for tumor.
10. A composition comprising the molecular probe of any one of claims 1 to 2 and a pharmaceutically acceptable carrier.
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