CN110025794A - Purposes of the metal iridium complex in the long Phosphorescence imaging reagent of preparation medicine or drug - Google Patents
Purposes of the metal iridium complex in the long Phosphorescence imaging reagent of preparation medicine or drug Download PDFInfo
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- CN110025794A CN110025794A CN201910377897.2A CN201910377897A CN110025794A CN 110025794 A CN110025794 A CN 110025794A CN 201910377897 A CN201910377897 A CN 201910377897A CN 110025794 A CN110025794 A CN 110025794A
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- iridium complex
- metal iridium
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- long phosphorescence
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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
- A61K49/0015—Phosphorescence
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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
- C09K2211/185—Metal complexes of the platinum group, i.e. Os, Ir, Pt, Ru, Rh or Pd
Abstract
The invention discloses metal iridium complexes in the purposes for preparing the long Phosphorescence imaging reagent of medicine or drug, its metal iridium complex is using 2- phenylpyridine as C^N ligand, with Phen, 3,8- dibromo Phen or thiophene are as N^N ligand, after extraneous laser excitation, long phosphorescence afterglow imaging signal is generated under the conditions of no exciting light.The present invention, in solution and in vivo without the optical imagery excited in real time, realizes the medical optics imaging application of the high background signal-to-noise ratio of metal iridium complex by metal iridium complex.
Description
Technical field
The present invention relates to metal complex nano materials and molecular image imaging field, and in particular to metal iridium complex exists
Prepare the purposes of the long Phosphorescence imaging reagent of medicine or drug.
Background technique
The diagnosis of optical imagery Biologic Medical Image has had very extensive application.However, due in imaging process
Tissue autofluorescence can just be generated by needing the excitation of Real-Time Optical, seriously affect the sensibility and specificity of chemiluminescence assay.It is remaining
Brightness (Afterglow) persistently shines (Persistent Luminescence) because having the continuous illumination after removing light source,
And can realize that zero background without exciting in real time is imaged in vivo, become the new focus of optical imaging field concern.From theory
On say, afterglowing material it is luminous both can in the energy trapping heat shock of hole and electronics it is compound, can also be from normal
Long-life excitation state under temperature, but the excitation state of high activity causes the luminescent lifetime of luminous organic material usually shorter.Inorganic gold
Belong to (such as Ir3+、Pt2+) singlet state in organic molecule can be enhanced to the transition of triplet in complex, it is lacked by generating energy
It falls into extend its fluorescent lifetime.Metal complex reported at present usually require nitrogen atmosphere, solid crystal state and
Long phosphorescence is realized under ultralow temperature, there are application limitations.
Summary of the invention
The purpose of the present invention is to provide metal iridium complex the long Phosphorescence imaging reagent of preparation medicine or drug purposes,
Metal iridium complex is using 2- phenylpyridine as C^N ligand, with Phen, 3,8- dibromo Phen or thiophene as N^N
Ligand generates long phosphorescence afterglow imaging signal after extraneous laser excitation under the conditions of no exciting light in solution or in vivo, uses
It is detected in medical imaging.
For achieving the above object, the present invention adopts the following technical scheme:
Metal iridium complex is in the purposes of the long Phosphorescence imaging reagent of preparation medicine or drug, and the metal iridium complex is with 2-
Phenylpyridine is as C^N ligand, with Phen, 3,8- dibromo Phen or thiophene as N^N ligand.
Further, the metal iridium complex is selected from the structural formula as shown in following formula (I), formula (II) or formula (III):
Further, the metal iridium complex generates more than long phosphorescence after extraneous laser excitation under the conditions of no exciting light
Brightness imaging signal.
Further, the metal iridium complex generates long phosphorescence afterglow imaging signal in solution, and more than the long phosphorescence
The intensity of brightness imaging signal and the solution are in a linear relationship.
Further, the method that the metal iridium complex generates the imaging of long phosphorescence afterglow in solution includes:
The metal iridium complex is protected from light in advance and is made into the acetonitrile or methanol solution of 0.1~5mM by (I), in no excitation
The optical signal intensity that solution is acquired under the conditions of light, as background signal value；
(II) metal iridium complex solution described in extraneous excitation light irradiation step (I), irradiation time are 1~2min；
After (III) stops 10~60s of irradiation, optical signal intensity is acquired under the conditions of without real-time exciting light, when acquisition interval
Between be 5~30s, the acquisition duration be 0.5~10min.
Further, in step (I), the metal iridium complex solution is the acetonitrile solution of 1mM, and/or
In step (II), the ambient light be ultraviolet lamp, excitation wavelength 365nm, and/or
In step (III), the acquisition time is 2min.
Further, the metal iridium complex in vivo generates long phosphorescence afterglow imaging signal.
Further, the metal iridium complex is configured to the water soluble nanometer particles that concentration is 0.1~0.5mg/mL, made
Dosage is 30~60 μ L.
Further, the water soluble nanometer particles the preparation method comprises the following steps: take 10mg F127 be added 3mL water in, ultrasound
Dissolution, add metal iridium complex described in 1mg, under 20% power, with after cell disruptor ultrasound 10min pass through 0.22 μm
Water-soluble filter membrane and obtain.
Further, the long Phosphorescence imaging reagent of the medicine or drug are using the metal iridium complex as active constituent, or go back
Including pharmaceutically acceptable carrier.
In the inventive solutions, in uv-visible absorption spectra, metal iridium complex GOLD FROM PLATING SOLUTION category-match
Between body charge migration (1MLCT 350~450nm) is concentrated on, wavelength is used to shine for the ultraviolet lamp of 365nm as excitation light source
1~2min is penetrated, after stopping irradiation 30s, its optical signal intensity, acquisition time 2min are acquired under the conditions of no exciting light.With
Comparison before original excitation, intensity are remarkably reinforced, and illustrate that the metal iridium complex solution generates twilight sunset phosphorescence through excitation.In addition,
After removing light source, optical signal intensity value still has enhancing than before, and possible cause is the transmitting generated in excitation process
Energy still has luminous energy sustained release after removing light source through energy storage.By every the optics letter in 30s continuous acquisition 10min
Number intensity, it is found that the optical signal intensity of the metal iridium complex extends at any time and decays, further illustrate it is this slowly
Exergonic generation.
Compared with prior art, the beneficial effects of the present invention are:
1. the present invention is by the design metal iridium complex that C^N ligand is identical and N^N ligand is different, through excitation a period of time
It removes excitation light source to remain to shine, illustrates that it has the property of energy storage and slow release energy after exciting, realize that nothing swashs
Luminous is imaged without background optical, and changing original complex of iridium can only be expanded by way of exciting realize optical imagery in real time
Its application in long phosphorescence has broad application prospects in molecular image field.
2. 3,8- dibromo Phen is prepared into water-soluble nano grain by the present invention
Son realizes being imaged without background optical without real-time exciting light in back of mice, improves metal using its long Phosphorescence imaging property
Complex of iridium signal-to-noise ratio in optical imagery application, and its application in chemiluminescence assay.
Detailed description of the invention
Fig. 1 is the acetonitrile solution of tri- kinds of metal iridium complexes of 1mM before ultraviolet lamp, and after ultraviolet light irradiation 1min
Solution signal strength comparison diagram and intensity contrast value.
Three kinds of complex methanol solutions of three kinds of complex acetonitrile solutions and 5mM that Fig. 2 is 1mM are in ultraviolet light irradiation
Before, and through ultraviolet light irradiation 1min, it is strong every a 30s solution signal of acquisition under without excitation optical mode after removing light source
Degree, acquires 8min altogether.
Fig. 3 is iridium (II) complex acetonitrile solution of 0.067mM, 0.1mM, 0.2mM, 0.5mM, 1mM, with 365nm wavelength
Ultraviolet lamp excitation 1min is moved back except light source, and the solution signal strength in its 2min is acquired under without excitation optical mode.
Iridium (II) the complex nanoparticle and iridium (II) that Fig. 4 is the 0.05mg/mL and 0.1mg/mL of same concentrations cooperate
The acetonitrile solution of object after removing light source, under without excitation optical mode, acquires the solution letter in 2min through ultraviolet light irradiation 1min
Number intensity.Wherein, the preparation process of nanoparticle is as follows: taking the F127 of 10mg to be added in 3mL water, ultrasonic dissolution adds 1mg
Iridium (II) complex.Under 20% power, pass through 0.22 μm of water-soluble filter membrane after ten minutes with cell disruptor ultrasound.
Fig. 5 is long Phosphorescence imaging of iridium (II) the complex nanoparticle in back of mice, first by mouse anesthesia, then small
Mouse back specific position is subcutaneously injected iridium (II) complex nanoparticle (0.2mg/mL, 50 μ L).After injection, ultraviolet radiator is used
2min is irradiated, light source is then removed, back of mice is imaged.
Specific embodiment
Below with reference to embodiment, the invention will be further described:
Embodiment 1
In this example, the acetonitrile solution for preparing tri- kinds of complexs of 1mM respectively, being mentioned the last week or more is kept in dark place.
Its initial optical signal value is first acquired under the conditions of no exciting light.Then, using ultraviolet light irradiation 1min, light source is then removed,
Continue to acquire the optical signalling value after its irradiation under the conditions of no exciting light.It is found by quantitative analysis, complex (I) solution exists
Irradiation front and back signal value is respectively 0.459 × 105、1.333×105p/sec/cm2/ sr becomes initial 2.9 times after irradiation；Match
Closing object (III) solution signal value before and after irradiation is respectively 0.6592 × 105、2.278×105p/sec/cm2/ sr becomes after irradiation
It is initial 3.5 times；And complex (II) solution signal value before and after irradiation is respectively 0.5172 × 105、5.413×105p/
sec/cm2/ sr, signal value become initial 10.5 times, and it is 3~4 times of other two kinds that the signal value of complex 2, which increases at most,
As shown in Fig. 1.
Embodiment 2
In this example, three kinds of complex methanol solutions for testing 5mM are moved back except light source, often through ultraviolet lamp excitation 1min
Change every the signal value of 30s.As the signal value of Fig. 2,1,2,3 solution of complex are followed successively by 1.34 × 105、4.38×105、2.75
×105p/sec/cm2/ sr, the signal value highest of 2 solution of complex.The results show that methanol solution signal value is 0.25 × 105p/
sec/cm2/ sr, and at any time without significant change.And the signal value of three kinds of complex solutions is gradually reduced as time went on, and
Reach stabilization in 90s, 270s, 120s respectively to remain unchanged, and three's signal value is close.
Similar test, such as Fig. 2 have been carried out with same procedure in the acetonitrile solution of 1mM, after ultraviolet light irradiation, has been matched
The signal value for closing 1,2,3 solution of object is followed successively by 2.16 × 105、4.45×105、2.77×105p/sec/cm2/ sr, three kinds of cooperations
The signal value of object solution is gradually reduced as time went on, and reaches stable in 90s, 210s, 120s respectively, and signal value is kept
It is constant.And acetonitrile solution signal value is 0.2795 × 105p/sec/cm2It/sr and hardly follows time change and changes, it is undamped
Process illustrates that three kinds of complex phosphorescence properties have universality.
Embodiment 3
In this example, as shown in figure 3, complex (II) acetonitrile of 0.067mM, 0.1mM, 0.2mM, 0.5mM, 1mM concentration
For solution with after ultraviolet light irradiation 1min, long phosphorescence intensity is followed successively by 1.215 × 105、1.285×105、1.749×105、
2.589×105、3.993×105p/sec/cm2/sr.With the increase of material concentration, phosphorescence afterglow intensity also increases.Warp
Property fitting after, the relationship of the long phosphorescence intensity of complex (II) and concentration is y=2.9684x+1.0577 (R2=0.996), explanation
Phosphorescence afterglow effect and complex concentration are in a linear relationship.
Embodiment 4
In this example, iridium (II) complex is prepared into nanoparticle, process is as follows: takes the F127 of 10mg that 3mL is added
In water, ultrasonic dissolution adds 1mg iridium (II) complex, under 20% power, with cell disruptor ultrasound 10 minutes, then
Pass through 0.22 μm of water-soluble filter membrane.
As shown in figure 4, being matched by iridium (II) the complex nanoparticle of comparison 0.05mg/mL and 0.1mg/mL with iridium (II)
The acetonitrile solution for closing object, finds the solution and nanoparticle of 0.05mg/mL, phosphorescent signal value is respectively 1.974 × 105p/
sec/cm2/sr、4.907×105p/sec/cm2/ sr, the signal value of nanoparticle are about 2.5 times of solution；And 0.1mg/mL
Solution and nanoparticle, phosphorescent signal value are respectively 2.2 × 105p/sec/cm2/sr、5.935×105p/sec/cm2/sr；
The signal value of nanoparticle is about 2.7 times of solution, is illustrated under various concentration, and iridium (II) complex nanoparticle can increase
The phosphorescent signal intensity of strong solution.
Embodiment 5
In this example, using nude mice as model, in dorsal sc injection 0.2mg/mL, iridium (II) complex nanometer of 50 μ L
Particle then removes light source with 1min is irradiated at ultraviolet lamp above it 1cm, under without excitation optical mode, acquires its back
Signal value, while its back signal intensity is also acquired by fluorescence imaging.As shown in figure 5, by long Phosphorescence imaging and fluorescence at
As comparison, long Phosphorescence imaging is this it appears that its dorsal injection positions of materials, the position and other muscle parts compare very
Obviously, the intensity rate of imaging clearly, signal and muscle region is higher (1.47 ± 0.31).And in fluorescence imaging, back of mice
Other regions have very strong background fluorescence, cause us the signal in injection material region to be not obvious, signal-to-noise ratio it is low (0.14 ±
0.05).Contrastingly from numerical value, the signal-to-noise ratio of long Phosphorescence imaging is about 10.5 times of fluorescence imaging, sufficiently confirm by using
Without the twilight sunset imaging mode excited in real time, signal and muscle of the complex of iridium nanoparticle in living imaging can be greatly improved
The ratio of tissue.
The above is presently preferred embodiments of the present invention, but the present invention should not be limited to disclosed in the embodiment
Content.So all do not depart from the lower equivalent or modification completed of spirit disclosed in this invention, the model that the present invention protects is both fallen within
It encloses.
Claims (10)
1. metal iridium complex is in the purposes of the long Phosphorescence imaging reagent of preparation medicine or drug, the metal iridium complex is with 2- benzene
Yl pyridines are as C^N ligand, with Phen, 3,8- dibromo Phen or thiophene as N^N ligand.
2. purposes according to claim 1 or 2, which is characterized in that the metal iridium complex is selected from such as following formula (I), formula
(II) and structural formula shown in formula (III):
3. purposes according to claim 1 or 2, which is characterized in that the metal iridium complex after extraneous laser excitation,
Long phosphorescence afterglow imaging signal is generated under the conditions of no exciting light.
4. purposes according to claim 3, which is characterized in that the metal iridium complex is generated in solution more than long phosphorescence
Brightness imaging signal, and the intensity of the long phosphorescence afterglow imaging signal and the solution are in a linear relationship.
5. purposes according to claim 3, which is characterized in that the metal iridium complex in vivo generates more than long phosphorescence
Brightness imaging signal.
6. purposes according to claim 4, which is characterized in that the metal iridium complex is generated in solution more than long phosphorescence
Brightness imaging method include:
The metal iridium complex is protected from light in advance and is made into the acetonitrile or methanol solution of 0.1~5mM by (I), without excitation striation
The optical signal intensity of solution is acquired under part as background signal value；
(II) metal iridium complex solution described in extraneous excitation light irradiation step (I), irradiation time are 1~2min；
After (III) stops 10~60s of irradiation, optical signal intensity is acquired under the conditions of without real-time exciting light, the acquisition interval time is
5~30s, acquisition duration are 0.5~10min.
7. purposes according to claim 6, which is characterized in that
In step (I), the metal iridium complex solution is the acetonitrile solution of 1mM, and/or
In step (II), the ambient light be ultraviolet lamp, excitation wavelength 365nm, and/or
In step (III), the acquisition time is 2min.
8. purposes according to claim 5, which is characterized in that by the metal iridium complex be configured to concentration be 0.1~
The water soluble nanometer particles of 0.5mg/mL, usage amount are 30~60 μ L.
9. purposes according to claim 8, which is characterized in that the water soluble nanometer particles the preparation method comprises the following steps: taking
The F127 of 10mg is added in 3mL water, and ultrasonic dissolution adds metal iridium complex described in 1mg, uses cell powder under 20% power
0.22 μm of water-soluble filter membrane is crossed after broken machine ultrasound 10min and is obtained.
10. -9 described in any item purposes according to claim 1, which is characterized in that the long Phosphorescence imaging reagent of the medicine or medicine
Object is using the metal iridium complex as active constituent, or further includes pharmaceutically acceptable carrier.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009067603A1 (en) * | 2007-11-21 | 2009-05-28 | Bio-Rad Laboratories, Inc. | Photoluminescent metal complexes for protein staining |
| CN103881700A (en) * | 2014-03-14 | 2014-06-25 | 上海师范大学 | Thienyl phosphorescent iridium complex as well as preparation method and application thereof |
| CN103936794A (en) * | 2014-03-18 | 2014-07-23 | 上海师范大学 | Water-soluble cationic phosphorescent iridium complex, preparation method and application thereof |
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- 2019-05-06 CN CN201910377897.2A patent/CN110025794B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009067603A1 (en) * | 2007-11-21 | 2009-05-28 | Bio-Rad Laboratories, Inc. | Photoluminescent metal complexes for protein staining |
| CN103881700A (en) * | 2014-03-14 | 2014-06-25 | 上海师范大学 | Thienyl phosphorescent iridium complex as well as preparation method and application thereof |
| CN103936794A (en) * | 2014-03-18 | 2014-07-23 | 上海师范大学 | Water-soluble cationic phosphorescent iridium complex, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| RUI CAO 等: ""Membrane Localized Iridium(III) Complex Induces Endoplasmic Reticulum Stress and Mitochondria-Mediated Apoptosis in Human Cancer Cells"", 《J. MED. CHEM》 * |
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