CN111892645B - Organic coordination compound, preparation method and application thereof, and probe - Google Patents
Organic coordination compound, preparation method and application thereof, and probe Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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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
- A61K49/001—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
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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
- A61K49/001—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
- A61K49/0052—Small organic molecules
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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
- A61K49/001—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
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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
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
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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
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/18—Metal complexes
- C09K2211/182—Metal complexes of the rare earth metals, i.e. Sc, Y or lanthanide
Abstract
The invention relates to an organic coordination compound, a preparation method, application and a probe thereof, wherein the organic coordination compound has a structure shown as the following formula (I):
the organic coordination compound can emit near-infrared two-region fluorescence, can realize near-infrared two-region fluorescence and magnetic resonance bimodal imaging compound, has higher relaxation and good biological stability, and has small toxic and side effects on biological cells; the Angiopep-2 polypeptide structure can enable the organic coordination compound to pass through a blood brain barrier, and the RGD polypeptide structure enables the organic coordination compound to target glioma, so that when the organic coordination compound is used for brain surgery, the spatial imaging resolution of the brain glioma and the tumor boundary surgery precision can be effectively improved.
Description
Technical Field
The invention relates to the field of magnetic resonance/fluorescence bimodal imaging probes, in particular to an organic coordination compound, a preparation method and application thereof, and a probe.
Background
The brain tumor is a primary tumor of a central nervous system with extremely high malignancy degree, has the characteristics of high morbidity, high recurrence rate, high mortality rate, low cure rate and the like, and is the key for treating the brain tumor by surgical excision. Brain tumor surgery typically requires preoperative stereotactic localization using magnetic resonance imaging to locate the focal site of the brain, and intraoperative navigation with ultrasound, microscopic white light, and visible or near infrared one-zone fluorescence probes. However, biological tissues of human bodies have strong attenuation effect on visible light or near infrared region fluorescence and strong autofluorescence interference, so that the sensitivity and signal-to-noise ratio of probe navigation are reduced, and the spatial imaging resolution of brain glioma and the tumor boundary operation precision are reduced.
Compared with visible light and near-infrared first-region fluorescence (NIR-I, 750-950nm), the near-infrared second-region fluorescence (NIR-II, 1000-1400nm and 1500-1700nm), the method has weaker biological tissue absorption and scattering effect, higher penetration depth and lower background fluorescence effect, has higher signal-to-noise ratio and sensitivity when being used for in-vivo imaging, and can greatly improve the spatial imaging resolution and the boundary operation precision of glioma in brain tumor operation navigation. At present, most of the probes for magnetic resonance/near-red two-zone imaging are nano probes, and then are small molecular probes; the nano-type probe has the advantages of good EPR effect (namely high tumor permeability and long retention effect), drug slow release and the like, but has the defects of easy liver and spleen accumulation (endothelial network tissue enrichment), low tumor uptake rate, long in-vivo retention time and the like, so that the nano-type probe is approved by the Food and Drug Administration (FDA) of the United states and only has dozens of types when being applied to clinical nano-type probes, and the clinical transformation of most of the nano-type probes has a bottleneck which is difficult to break through; compared with a nano probe, the small molecular probe has the advantages of small molecular weight, difficulty in liver and spleen aggregation, easiness in kidney metabolism, capability of flexibly performing functional modification and the like, and is a hot spot of current domestic and foreign researches.
Therefore, the design and synthesis of the small molecular probe with high relaxation rate, safety and stability have great significance for improving the accuracy of brain tumor surgery.
Disclosure of Invention
Therefore, it is necessary to provide an organic coordination compound with high relaxation rate, high quantum yield, safety and stability, a preparation method and application thereof, and a probe.
In one aspect, the present invention provides an organic complex compound having a structure represented by the following formula (I):
wherein L is1And L2Each independently selected from a single bond or an alkyl group containing an ether bond and having 1 to 20 carbon atoms;
L3one or more of alkyl with 1-20 carbon atoms and aryl with 5-20 ring atoms or a single bond;
L4selected from single bond or alkyl with 1-20 carbon atoms;
a is a group containing an Angiopep-2 polypeptide structure;
d is a group containing an RGD polypeptide structure.
In some of these embodiments, the organic complex compound has the structure shown in formula (I-2):
wherein n1 is more than or equal to 0 and less than or equal to 10, n2 is more than or equal to 0 and less than or equal to 10, n3 is more than or equal to 0 and less than or equal to 20, n4 is more than or equal to 0 and less than or equal to 20, and n1, n2, n3 and n4 are integers.
In some of these embodiments, 1 ≦ n1 ≦ 5, 1 ≦ n2 ≦ 5, 1 ≦ n3 ≦ 8, 1 ≦ n4 ≦ 5, n1, n2, n3, n4 are integers.
In some embodiments, the organic coordination compound has a structure according to formula (I-3):
in some of these embodiments, A has the structure shown in formula (I-4):
wherein n5 is more than or equal to 1 and less than or equal to 20, and n5 is an integer; are attachment sites.
In some embodiments, the organic coordination compound has a structure according to formula (I-5):
in another aspect, the present invention provides a method for preparing any one of the above organic complex compounds, comprising the steps of:
carrying out coordination reaction on the compound 1 and neodymium salt to obtain a compound 3;
carrying out coordination reaction on the compound 2 and gadolinium salt to obtain a compound 4;
carrying out coupling reaction on the compound 3, the compound 4, the Angiopep-2 polypeptide compound and the RGD polypeptide compound to obtain an organic coordination compound;
the structural formula of the compound 1-4 is as follows:
the Angiopep-2 polypeptide compound contains at least one carboxyl group; the RGD polypeptide compound contains at least one carboxyl group.
In some embodiments, the Angiopep-2 polypeptide compound has the structure shown in formula (3-a):
wherein n6 is more than or equal to 1 and less than or equal to 19, and n6 is an integer.
The invention also provides application of any organic coordination compound or the organic coordination compound prepared by any preparation method in magnetic resonance imaging and/or fluorescence imaging.
The invention also provides an application of any one of the organic coordination compounds or the organic coordination compound prepared by any one of the preparation methods in preparing a probe.
Further, the present invention provides a probe comprising any of the above-mentioned organic complex compounds or the organic complex compound produced by any of the above-mentioned production methods.
Advantageous effects
1. The invention provides an organic coordination compound shown as a structural general formula (I), wherein an element neodymium and an element gadolinium in the organic coordination compound are respectively coordinated with a 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetracarboxylic acid structure to obtain a chelate, and an Angiopep-2 polypeptide structure and a glioma targeting RGD polypeptide structure which can penetrate through a blood brain barrier are modified.
The small molecular organic coordination compound can emit near-infrared two-region fluorescence, can realize near-infrared two-region fluorescence and magnetic resonance bimodal imaging compound, and has higher relaxation rate; meanwhile, the element neodymium and the element gadolinium are chelated in the compound, so that the generation of free neodymium atoms and gadolinium atoms is avoided, the biological stability of the compound is improved, and the toxic and side effects of the compound on biological cells are reduced; the Angiopep-2 polypeptide structure can enable the compound to cross a blood brain barrier, and the RGD polypeptide structure enables the compound to target glioma, so that when the compound is used for brain surgery, the spatial imaging resolution of the brain glioma and the tumor boundary surgery precision can be effectively improved.
2. In the preparation method of the organic coordination compound, neodymium salt and gadolinium salt are respectively subjected to coordination reaction with a compound containing a 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetracarboxylic acid structure to obtain a compound 3 and a compound 4, and finally the compound 3, the compound 4, an Angiopep-2 polypeptide compound and an RGD polypeptide compound are subjected to coupling reaction to obtain the organic coordination compound.
3. The present invention provides a probe comprising any of the above organic complex compounds or an organic complex compound produced by any of the above production methods. The probe can emit near-infrared two-zone fluorescence, can realize near-infrared two-zone fluorescence and magnetic resonance bimodal imaging compounds, and has high relaxation rate; the biological tissue of the human body has weaker attenuation effect on near-infrared two-region fluorescence and weak interference of autofluorescence, so that the sensitivity and signal-to-noise ratio of the probe for surgical navigation are improved, and the spatial imaging resolution of brain glioma and the tumor boundary surgical precision are further improved.
Drawings
FIG. 1 is a fluorescence emission spectrum of a probe according to example 1 of the present invention;
FIG. 2 is a graph showing the results of the cytotoxicity test in example 1 of the present invention.
Detailed Description
The compounds of the present invention, their preparation methods and uses, and probes are described in further detail below with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
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. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
Unless otherwise stated or contradicted, terms or phrases used herein have the following meanings:
the term "alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. The phrase including the term, for example, an alkyl group having 1 to 20 carbon atoms. Suitable examples include, but are not limited to: methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) 1-propyl (n-Pr, n-propyl, -CH)2CH2CH3) 2-propyl (i-Pr, i-propyl, -CH (CH)3)2) 1-butyl (n-Bu, n-butyl, -CH)2CH2CH2CH3) 2-methyl-1-propyl (i-Bu, i-butyl, -CH)2CH(CH3)2) 2-butyl (s-Bu, s-butyl, -CH (CH)3)CH2CH3) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)3)3) 1-pentyl (n-pentyl, -CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) 1-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3And octyl (- (CH)2)7CH3)。
The term "alkyl group containing an ether bond having 1 to 20 carbon atoms" means that any of the above alkyl groups contains an ether bond, and the position and number of the ether bond are not particularly limited.
The term "single bond" refers to a linkage of two moieties directly to form a bond.
The term "aryl" refers to an aromatic hydrocarbon group derived by removing one hydrogen atom from the aromatic ring compound and may be a monocyclic aryl group, or a fused ring aryl group, or a polycyclic aryl group, at least one of which is an aromatic ring system for polycyclic ring species. The number of ring atoms in the aryl group having 1 to 20 ring atoms is the number of ring-forming atoms, and for example, the number of ring atoms in benzene is 6 and the number of ring atoms in biphenyl is 12. Suitable examples include, but are not limited to: benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and derivatives thereof.
It will be appreciated that a plurality of aryl groups may also be interrupted by short non-aromatic units (e.g. < 10% of non-H atoms, such as C, N or O atoms), such as in particular acenaphthene, fluorene, or 9, 9-diarylfluorene, triarylamine, diarylether systems should also be included in the definition of aryl groups. One embodiment of the present invention provides an organic complex compound having a structure represented by the following formula (i):
wherein L is1And L2Each independently selected from a single bond or an alkyl group containing an ether bond and having 1 to 20 carbon atoms;
L3one or more of alkyl with 1-20 carbon atoms and aryl with 5-20 ring atoms or a single bond;
L4selected from single bond or alkyl with 1-20 carbon atoms;
a is a group containing an Angiopep-2 polypeptide structure;
d is a group containing an RGD polypeptide structure.
In the organic coordination compound with the structure shown in the formula (I), an element neodymium and an element gadolinium are respectively coordinated with a 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetracarboxylic acid structure to obtain a chelate, and a polypeptide Angiopep-2 polypeptide structure capable of passing through a blood brain barrier and a glioma targeting RGD polypeptide structure are modified.
The small molecular organic coordination compound not only can realize near-infrared two-region fluorescence and magnetic resonance bimodal imaging, but also has higher relaxation rate; meanwhile, the element neodymium and the element gadolinium are chelated in the compound, so that free neodymium atoms and gadolinium atoms are avoided, the biological stability of the compound is improved, and the toxic and side effects of the compound are reduced; and the Angiopep-2 polypeptide structure can enable the organic coordination compound to pass through a blood brain barrier, and the RGD polypeptide structure enables the organic coordination compound to target glioma, so that the spatial imaging resolution and the tumor boundary operation precision of brain glioma can be effectively improved, and the cure rate is further improved.
In some of these embodiments, L1And L2The same is true.
In some of these embodiments, L3A combination of a plurality of alkyl groups having 1 to 20 carbon atoms and aryl groups having 6 to 12 ring atoms. Further, the above organic complex compound has a structure represented by the following formula (I-2):
wherein n1 is more than or equal to 0 and less than or equal to 10, n2 is more than or equal to 0 and less than or equal to 10, n3 is more than or equal to 0 and less than or equal to 20, n4 is more than or equal to 0 and less than or equal to 20, and n1, n2, n3 and n4 are integers.
In some of these embodiments, 1 ≦ n1 ≦ 5, 1 ≦ n2 ≦ 5, 1 ≦ n3 ≦ 8, 1 ≦ n4 ≦ 5, n1, n2, n3, n4 are integers.
In some of these embodiments, n1 and n2 are the same, and further n1 and n2 are both 2.
In some embodiments, n3 and n4 are different, and further n3 is 2 and n4 is 1.
In some embodiments, the organic coordination compound has a structure according to formula (I-3):
in some of these embodiments, A has the structure shown in formula (I-4):
wherein n5 is more than or equal to 1 and less than or equal to 20, and n5 is an integer; are attachment sites.
Further, 1. ltoreq. n 5. ltoreq.10, and further, n5 is 3.
In some of these embodiments, D is an RGD polypeptide molecule.
In some embodiments, the organic coordination compound has a structure according to formula (I-5):
in still another aspect, the present invention provides a method for preparing any one of the above organic complex compounds, comprising the following steps S100 to S300.
S100, carrying out coordination reaction on the compound 1 and a neodymium salt to obtain a compound 3.
Wherein, the structural formula of the compound 1 and the compound 3 is shown as follows:
in some of the embodiments, the coordination reaction of step 100 is performed in an alkaline environment, and further, the reaction system is adjusted to be alkaline by adding sodium hydroxide.
In some of the embodiments, the coordination reaction of step S100 is performed in an alkaline environment with a pH of 8.5.
In step S100, neodymium ions in a neodymium salt are coordinated with compound 1, wherein the neodymium salt is selected from salts capable of ionizing neodymium ions, including but not limited to: chloride, sulfate, nitrate, and the like.
In some of these embodiments, the neodymium salt is neodymium chloride. Further, in the coordination reaction of step S200, neodymium chloride is added to the reaction system in the form of an aqueous neodymium chloride solution.
In some of these embodiments, the molar ratio of neodymium ions in the neodymium salt to compound 1 is 1: (1-3); the reaction conditions are as follows: reacting for 12-24 h at room temperature.
In some of these embodiments, the molar ratio of neodymium ions in the neodymium salt to compound 1 is 1: 3; the reaction conditions are as follows: the reaction was carried out at room temperature for 24 h.
In some of these embodiments, step S100 further comprises a post-processing step: after the reaction is completed, the reaction product is concentrated and then precipitated with ethyl ether to obtain pure compound 3.
Elemental neodymium is chelated in the compound through coordination reaction, so that free toxic neodymium atoms are avoided, and the formed compound 3 can realize near-infrared two-region fluorescence imaging.
Further, in step S100, free neodymium ions in the reaction system may further coordinate with neodymium in the compound 3, and the content of neodymium element in the compound 3 may be adjusted by adjusting the amount of neodymium ions in step S200, so that the content of neodymium element in the compound (i) may be adjusted, and the intensity of fluorescence emission of the compound (i) may be further adjusted. When the molar ratio of neodymium to gadolinium is 1:1, the concentration of neodymium is 0.3W/cm under the excitation of 808nm laser2Under irradiation, the number of emission intensity photons at 1064nm is 45432, and the number of emission intensity photons at 1345nm is 12563; when the molar ratio of neodymium to gadolinium is 2:1, the concentration of neodymium is 0.3W/cm under the excitation of 808nm laser2The number of emission intensity photons at 1064nm was 58186 and the number of emission intensity photons at 1345nm was 27651 under irradiation.
And S200, carrying out coordination reaction on the compound 2 and gadolinium salt to obtain a compound 4.
Wherein, the structural formulas of the compound 2 and the compound 4 are shown as follows:
in some embodiments, the coordination reaction of step S200 is performed in an alkaline environment, and further, the reaction system is adjusted to be alkaline by adding sodium hydroxide.
In some of the embodiments, the coordination reaction of step S200 is performed in an alkaline environment with a pH of 8.5.
In step S200, gadolinium ions in gadolinium salt are subjected to coordination reaction with compound 2, wherein gadolinium salt is selected from salts capable of ionizing gadolinium ions, including but not limited to: chloride, sulfate, nitrate, and the like.
In some of these embodiments, the gadolinium salt is gadolinium chloride. Further, in the coordination reaction of step 200, gadolinium chloride is added to the reaction system in the form of an aqueous solution of gadolinium chloride.
In some of these embodiments, the molar ratio of gadolinium ions in the gadolinium salt to compound 2 is 1: (2-10); the reaction conditions are as follows: reacting for 12-24 h at room temperature.
In some of these embodiments, the molar ratio of gadolinium ions in the gadolinium salt to compound 2 is 1: 5; the reaction conditions are as follows: the reaction was carried out at room temperature for 24 h.
The element neodymium is chelated in the compound through coordination reaction, so that the generation of free toxic neodymium atoms is avoided, and the formed compound 4 can realize magnetic resonance imaging.
In some of these embodiments, step S200 further comprises a post-processing step: after the reaction is completed, the reaction product is concentrated under low pressure, and then ether is precipitated to obtain the pure compound 4.
Further, in step S200, free gadolinium ions in the reaction system may further coordinate with gadolinium in the compound 4, and the content of gadolinium element in the compound 4 may be adjusted by adjusting the amount of gadolinium ions in step S200, so that the content of gadolinium element in the compound (i) may be adjusted, and further the relaxation rate of the compound may be adjusted.
In some embodiments, compound 1 above is represented by formula (1-a); compound 2 is represented by formula (2-a):
wherein n1 is more than or equal to 0 and less than or equal to 10, n2 is more than or equal to 0 and less than or equal to 10, n3 is more than or equal to 0 and less than or equal to 20, n4 is more than or equal to 0 and less than or equal to 20, and n1, n2, n3 and n4 are integers.
In some embodiments, compound 1 above is represented by formula (1-b); compound 2 is represented by formula (2-b):
L1～L4the meaning of (A) is as defined above.
It is understood that step S100 and step S200 have no specific order of precedence. Can be carried out sequentially or simultaneously.
S300, carrying out coupling reaction on the compound 3, the compound 4, an Angiopep-2 polypeptide compound and an RGD polypeptide compound to obtain the organic coordination compound;
the Angiopep-2 polypeptide compound contains at least one carboxyl group; the RGD polypeptide compound contains at least one carboxyl group.
And performing coupling reaction on the compound 3, the compound 4, the Angiopep-2 polypeptide compound and the RGD polypeptide compound to obtain an organic coordination compound capable of emitting near-infrared two-region fluorescence, wherein the organic coordination compound can realize near-infrared two-region fluorescence and magnetic resonance bimodal imaging. The Angiopep-2 polypeptide structure enables the organic coordination compound to pass through a blood brain barrier, the RGD polypeptide structure can target glioma, and when the RGD polypeptide structure is used for brain surgery, the space imaging resolution and the tumor boundary surgery precision of brain glioma can be further improved, and the cure rate is improved
It should be noted that: the Angiopep-2 polypeptide compound can be natural high-efficiency polypeptide molecule Angiopep-2 which can cross blood brain barrier, and also can be polypeptide molecule Angiopep-2 with modified functional group.
Further, in one embodiment, the Angiopep-2 polypeptide compound has the structure shown in formula (3-a):
wherein n6 is more than or equal to 1 and less than or equal to 19, and n6 is an integer. Further, the structure of the Angiopep-2 polypeptide compound is shown as a formula (3-b).
In some embodiments, the RGD polypeptide compound may be a native RGD polypeptide molecule, or may be a functional group-modified RGD polypeptide molecule.
In some of these embodiments, the coupling reaction of step S300 is carried out under the influence of EDC/NHS.
EDC is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, NHS is N-hydroxysuccinimide (NHS), carboxyl can be activated, the reaction rate is accelerated, and byproducts generated in the process of reaction stay can be avoided, so that the coupling reaction efficiency is improved.
Specifically, in step S300, compound 3, compound 4, Angiopep-2 polypeptide compound and RGD polypeptide compound are added first, then EDC is added to activate carboxyl, and NHS is added finally, so as to avoid generating by-products and improve the yield.
Further, step S300 is performed in an aqueous solution.
In some of these embodiments, step S300 further includes a post-processing step: after the reaction is finished, the reaction product is dialyzed for 48 hours by a dialysis membrane with the dalton of 5000, and then the final product compound (I) is obtained by concentration.
The invention also provides application of any organic coordination compound or the organic coordination compound prepared by any preparation method in magnetic resonance and/or near-infrared two-zone fluorescence imaging.
The organic coordination compound can emit near-infrared two-region fluorescence, can realize near-infrared two-region fluorescence and magnetic resonance bimodal imaging, and has higher relaxation rate; the method can integrate the advantages of high tissue resolution and qualitative diagnosis of preoperative nuclear magnetic imaging and the advantage of real-time imaging of near-infrared fluorescence in the operation process, avoids the defects of respective single detection, and shows good clinical application prospect. Meanwhile, the organic coordination compound has the advantages of biological stability and small toxic and side effects; and the Angiopep-2 polypeptide structure can enable the organic coordination compound to pass through a blood brain barrier, and the RGD polypeptide structure enables the organic coordination compound to target glioma, so that when the coordination compound is used for brain surgery, the spatial imaging resolution and tumor boundary surgery precision of brain glioma can be effectively improved, and the cure rate is further improved.
An embodiment of the present invention provides an application of any one of the above organic complex compounds or the organic complex compound obtained by any one of the above preparation methods to the preparation of a probe.
Further, an embodiment of the present invention provides a probe containing any of the above organic complex compounds or the organic complex compounds produced by any of the above production methods.
The probe includes any one of the above organic complex compounds or the organic complex compound prepared by any one of the above preparation methods. The probe can emit near-infrared two-zone fluorescence, can realize near-infrared two-zone fluorescence and magnetic resonance bimodal imaging compounds, and has high relaxation rate; the biological tissue of the human body has weaker attenuation effect on near-infrared two-region fluorescence and weak interference of autofluorescence, so that the sensitivity and signal-to-noise ratio of the probe for surgical navigation are improved, and the spatial imaging resolution of brain glioma and the tumor boundary surgical precision are further improved.
The probe is a small molecular probe, is not easy to gather in the liver and spleen, and is easy to be discharged out of an organism through renal metabolism.
While the present invention will be described with respect to particular embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but is intended to cover by the appended claims the scope of the invention, and that certain changes in the embodiments of the invention will be suggested to those skilled in the art and are intended to be covered by the appended claims.
The following are specific examples.
The organic complex compound according to the present invention, its preparation method and use, and probe are exemplified herein, but the present invention is not limited to the following examples.
Example 1
1) 1mL of 0.1mol/L neodymium chloride aqueous solution is mixed with 4mL of 0.5mol/L compound 1-b aqueous solution, the pH value of the system is adjusted to 8.5 by using 0.4mol/L NaOH solution, after stirring for 24 hours at room temperature, the reaction product is concentrated and precipitated by using ether, and the compound 3-b is obtained. The structures of compound 1-b and compound 3-b are shown below.
2) Taking 1mL of 0.1mol/L gadolinium chloride solution, mixing with 4mL of 0.5mol/L compound 2-b aqueous solution, adjusting the pH value of the system to 8.5 by using 0.4mol/L NaOH solution, stirring at room temperature for 24 hours, concentrating the reaction product, and precipitating with diethyl ether to obtain the compound 4-b. The structures of compound 2-b and compound 4-b are shown below.
3) Weighing 1mg of AP-2, 0.5mg of RGD, 1mg of compound 4-b and 1mg of compound 3-b, dissolving the above compounds in 5ml of water, weighing 2mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 1.25mg of N-hydroxysuccinimide (NHS) into the above aqueous solution, mixing, stirring at room temperature for 6 hours, dialyzing with a dialysis membrane of 5000 daltons for 48 hours, and concentrating to obtain the final product, namely, the organic coordination compound 5.
The structures of AP-2 and organic complex 5 are shown below:
wherein the amino acid sequence of RGD is: Arg-Gly-Asp-D-Phe-Lys;
the amino acid sequence of Angiopep-2 is: TFFYGGSRGKRNNFKTEEY are provided.
4) The relaxation rate of the organic complex 5 was measured using it as a probe, and the result showed that the relaxation rate r1 was 10.2mM-1·s-1The relaxation rate and the sensitivity of the probe are high.
5) Taking the organic coordination compound 5 as a probe, performing fluorescence test under the excitation of 808nm laser, and referring to fig. 1, the abscissa of the graph represents the generation Wavelength (recorded as Wavelength) and the ordinate represents the fluorescence intensity (fluorescence), as can be seen from fig. 1: the emission wavelengths of the probe are 1064nm and 1345nm respectively under the excitation of 808nm laser, and the fluorescence of the compound is near-infrared two-region fluorescence and has high fluorescence emission intensity.
6) Cytotoxicity experiments to study the chemical stability of the probes, the specific steps were as follows:
respectively planting fibroblasts NIH/3T3 in a 96-well plate, adding materials (compound 3-b or compound 4-b or neodymium ion or gadolinium ion) with different concentrations into each well, incubating for 30min (6 multiple wells per concentration) to serve as an experimental group, wherein the material solvent is PBS buffer solution; setting a PBS buffer solution group as a blank control group; after 24h of culture, the cell viability was determined by the MTT method to verify the degree of toxicity of the probe to the cells. The test data are shown in FIG. 2.
In FIG. 2, the abscissa represents the Concentration of the added material (Concentration) and the ordinate represents the Cell Viability (Cell Viability). (a) Results of NIH-3T3 fibroblast cytotoxicity MTT assay with neodymium ion and compound 3-b (noted DOTA-Nd), (b) results of NIH-3T3 fibroblast cytotoxicity MTT assay with gadolinium ion and compound 4-b (noted DOTA-Gd).
As shown in FIGS. 2 (a) and (b), the complex-forming compounds 3-b and 4-b are substantially non-biotoxic; and gadolinium and neodymium in ionic states have strong biological toxicity.
The above results indirectly demonstrate that the organic complex compound 5 having a gadolinium complex and a neodymium complex has good stability and biosafety.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. An organic complex compound, characterized in that the organic complex compound has a structure represented by the following formula (I):
wherein L is1And L2Each independently selected from a single bond or an alkyl group containing an ether bond and having 1 to 20 carbon atoms;
L3one selected from alkyl with 1-20 carbon atoms and aryl with 5-20 ring atoms, or the combination of alkyl with 1-20 carbon atoms and aryl with 5-20 ring atoms, or a single bond;
L4selected from single bond or alkyl with 1-20 carbon atoms;
a is a group containing an Angiopep-2 polypeptide structure;
d is a group containing an RGD polypeptide structure, and the amino acid sequence of the RGD polypeptide structure is as follows: Arg-Gly-Asp-D-Phe-Lys.
2. The organic complex compound according to claim 1, wherein the organic complex compound has a structure represented by the following formula (i-2):
wherein n1 is more than or equal to 0 and less than or equal to 10, n2 is more than or equal to 0 and less than or equal to 10, n3 is more than or equal to 0 and less than or equal to 20, n4 is more than or equal to 0 and less than or equal to 20, and n1, n2, n3 and n4 are integers.
3. The organic complex compound according to claim 2, wherein 1. ltoreq. n 1. ltoreq.5, 1. ltoreq. n 2. ltoreq.5, 1. ltoreq. n 3. ltoreq.8, 1. ltoreq. n 4. ltoreq.5, and n1, n2, n3, n4 are integers.
4. The organic complex compound according to claim 1, wherein the organic complex compound has a structure represented by formula (i-3):
5. the organic complex compound according to any one of claims 1 to 4, wherein A has a structure represented by the formula (I-4):
wherein n5 is more than or equal to 1 and less than or equal to 20, and n5 is an integer; are attachment sites.
6. The organic complex compound according to claim 1, wherein the organic complex compound has a structure represented by formula (i-5):
7. the method for producing an organic complex compound according to any one of claims 1 to 6, comprising the steps of:
carrying out coordination reaction on the compound 1 and neodymium salt to obtain a compound 3;
carrying out coordination reaction on the compound 2 and gadolinium salt to obtain a compound 4;
carrying out coupling reaction on the compound 3, the compound 4, an Angiopep-2 polypeptide compound and an RGD polypeptide compound to obtain an organic coordination compound; the amino acid sequence of the polypeptide structure in the RGD compound is: Arg-Gly-Asp-D-Phe-Lys;
the structural formula of the compound 1-4 is as follows:
said Angiopep-2 polypeptide compound contains at least one carboxyl group; the RGD polypeptide compound at least contains one carboxyl, and the amino acid sequence of the RGD polypeptide compound is as follows: Arg-Gly-Asp-D-Phe-Lys.
8. The method for preparing an organic complex compound according to claim 7, wherein the Angiopep-2 polypeptide compound has a structure represented by formula (3-a):
wherein n6 is more than or equal to 1 and less than or equal to 19, and n6 is an integer.
9. Use of the organic complex compound according to any one of claims 1 to 6 for preparing a probe.
10. A probe comprising the organic complex compound according to any one of claims 1 to 6.
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