CN108864106B - The preparation and application of two area's small organic molecule fluorescence probe of near-infrared - Google Patents
The preparation and application of two area's small organic molecule fluorescence probe of near-infrared Download PDFInfo
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- 239000000523 sample Substances 0.000 title claims abstract description 30
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- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 238000002648 combination therapy Methods 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
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- 150000004867 thiadiazoles Chemical class 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 238000002604 ultrasonography Methods 0.000 claims description 9
- -1 2- octyldodecyl Chemical group 0.000 claims description 6
- 239000006187 pill Substances 0.000 claims description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
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- 238000006396 nitration reaction Methods 0.000 claims description 2
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- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims 1
- 235000009566 rice Nutrition 0.000 claims 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 claims 1
- 229910001948 sodium oxide Inorganic materials 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 13
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- 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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Abstract
The invention discloses a kind of novel two area's small organic molecule fluorescence probe of near-infrared, including specific structure and preparation method and application, main component is pyrrolo-pyrrole-dione (DPP) derivative；The nano particle with good aqueous solubility, biocompatibility and targeting is further prepared by nanometer coprecipitation method, the nano particle has excellent two area's fluorescence imaging of near-infrared and photoacoustic imaging ability, light power and photothermal conversion performance, it can be used for two area's fluorescence imaging of near-infrared, the cancer target photo-thermal under photoacoustic imaging guidance and light power link to treat, to significantly improve therapeutic effect, and it is based on optical dynamic therapy (PDT) and photo-thermal therapy (PTT), the toxic side effect and drug resistance of tumor that reduce normal tissue can be prevented；Its imaging effect is excellent, toxic side effect is small, significant in efficacy, has preferable potential applicability in clinical practice as novel image probe and cancer target combination therapy reagent.
Description
Technical field
The present invention relates to a kind of small-molecule fluorescent probes, and in particular to a kind of two area's small organic molecule fluorescence probe of near-infrared
Preparation and application, belong to bio-pharmaceutical engineer technology domain.
Background technique
Cancer has become one of the major disease for threatening human life, therefore the effective diagnostic reagent of Development of Novel is for swelling
The diagnoses and treatment of tumor is of great significance.
Compared to common imaging technique for example magnetic resonance imaging, Tomography, X-ray imaging, fluorescence imaging due to
Have many advantages, such as noninvasive, real-time, high resolution, is widely used in biotechnology and life science.
In recent years, 2nd area of near-infrared (NIR-II, 1000-1700nm) Imaging-PAM has obtained extensive concern, by
Longer in the wave band launch wavelength, the light scattering of biological tissue itself and autofluorescence are weaker, therefore greatly improve imaging
Penetration depth and imaging effect.
Outer photoacoustic imaging (PAI) combines light as a kind of emerging non-radiative, not damaged Biologic Medical Image technology
The characteristics of studying picture and ultrasonic imaging has the advantages that high contrast, high-resolution and biological tissue's high-penetration, cures in real time
Learning imaging field has huge application prospect.
Traditional oncotherapy means would generally be over the course for the treatment of with various toxic side effects, and development efficacy is good, malicious pair
Low novel therapeutic means are acted on widely to be paid close attention to.Tumor multi-mode combination therapy can generate collaboration or increase effect
It answers, so as to significantly improve therapeutic effect, and the toxic side effect of normal tissue can be prevented to a certain extent and swollen
Tumor drug resistance.The advantages that optical dynamic therapy (PDT) and photo-thermal therapy (PTT) small, therapeutic effect is good with its toxic side effect and by
It widely pays close attention to, gradually the effective means of oncotherapy.
Therefore, light power, photo-thermal are combined together, developing, there is the nano particle of multiple mode combiend therapeutic to be used for tumour
Treatment have important scientific meaning and application prospect.
Summary of the invention
To solve the deficiencies in the prior art, the purpose of the present invention is to provide a kind of for current tumor imaging and treatment
Deficiency, the cancer target photo-thermal/light power link treatment that can be used under two area's fluorescence imaging of near-infrared/photoacoustic imaging guidance are close
Infrared 2nd areas small organic molecule fluorescence probe.
To achieve the goals above, the present invention adopts the following technical scheme that:
Two area's small organic molecule fluorescence probe of near-infrared, structural formula are as follows:
Wherein, R is
The preparation method of above-mentioned two area's small organic molecule fluorescence probe of near-infrared, comprising the following steps:
A1, certain molal weight component ratio is pressed, by bromo- 4- aldehyde radical benzo [c] [1,2, the 5] thiadiazoles (BT) of 7-, to nitro
Benzene acetonitrile or malononitrile, sodium hydroxide are added in methylene chloride, and heating stirring, revolving removes solvent, after pillar layer separation, system
Obtain BT-R；
A2, certain molal weight component ratio is pressed, by 2,5- bis- (2- octyldodecyl) -3,6- bis- (5- tin trimethyl) -
Pyrrolo-pyrrole-dione, BT-R, tetrakis triphenylphosphine palladium are added in dry toluene, and heating stirring, revolving removes solvent, Jing Zhuse
After spectrum separation, small organic molecule fluorescence probe DPP-BT-R is made.
Heating temperature is 40-60 DEG C in above-mentioned steps A1, and the heating stirring time is 4-6h, stirring rate 20-30r/
min；Heating temperature in step A2 is 100-120 DEG C, and the heating stirring time is 20-30h, stirring rate 20-30r/min.
Bromo- 4- aldehyde radical benzo [c] [1,2, the 5] thiadiazoles (BT) of 7- in above-mentioned steps A1 is 1mmol, para orientation nitration
Or malononitrile is 1mmol, sodium hydroxide is 0.1g, methylene chloride 40ml；
2,5- bis- (2- octyldodecyl) -3,6- two (5- tin trimethyl)-pyrrolopyrrole two in the step A2
Ketone is 0.1-0.5mmol, and BT-R is 0.22-1.1mmol, and tetrakis triphenylphosphine palladium is 15mg, and dry toluene is 20ml.
Above-mentioned two area's small organic molecule fluorescence probe of near-infrared is made DPP-BT-R nanometers by nanometer coprecipitation
Particle, comprising the following steps:
B1, the DPP-BT-R drug for weighing certain mass, ultrasound are dissolved in tetrahydrofuran；
B2, the prepared solution of B1 is added in amphiphilic sex pill aqueous solution, after ultrasound, revolving removal tetrahydrofuran, system
Obtain DPP-BT-R nanoparticle aqueous solution.
Above-mentioned two area's small organic molecule fluorescence probe of near-infrared, by nanometer coprecipitation, being made has targeting
The DPP-BT-R nanoparticle of function, comprising the following steps:
C1, the DPP-BT-R drug for weighing certain mass, ultrasound are dissolved in tetrahydrofuran；
C2, the prepared solution of C1 is added in the amphiphilic sex pill aqueous solution containing cancer target, after ultrasound, revolving removal
The DPP-BT-R nanoparticle aqueous solution with target function is made in tetrahydrofuran.
The amphiphilic sex pill includes F127, DSPE-mPEG, PEG-b-PPG-b-PEG.
The cancer target drug includes DSPE-PEG-FA, DSPE-PEG-cRGD.
Above-mentioned two area's small organic molecule fluorescence probe of near-infrared is used for photoacoustic imaging.
Above-mentioned two area's small organic molecule fluorescence probe of near-infrared is used for two area's fluorescence imaging of near-infrared.
Above-mentioned two area's small organic molecule fluorescence probe of near-infrared has photo-thermal and light dynamic under the irradiation of near infrared light
Power effect.
Above-mentioned two area's small organic molecule fluorescence probe of near-infrared, refers to as two area's fluorescence imaging of near-infrared, photoacoustic imaging
The tumor photo-thermal led and light power link treatment.
Above-mentioned two area's small organic molecule fluorescence probe of near-infrared, refers to as two area's fluorescence imaging of near-infrared, photoacoustic imaging
The cancer target photo-thermal led and light power link treatment.
The invention has the beneficial effects that:
Two area's small organic molecule fluorescence probe of near-infrared of the invention, is further prepared by nanometer coprecipitation method
Nano particle with good aqueous solubility, biocompatibility and targeting, the nano particle have excellent 2nd area of near-infrared glimmering
Light imaging and photoacoustic imaging ability, light power and photothermal conversion performance, can be used for two area's fluorescence imaging of near-infrared, photoacoustic imaging
Cancer target photo-thermal and light power link under guidance are treated, to significantly improve therapeutic effect, and are based on optical dynamic therapy
(PDT) and photo-thermal therapy (PTT) it, can prevent to reduce the toxic side effect and drug resistance of tumor of normal tissue；Its imaging effect
It is excellent, toxic side effect is small, significant in efficacy, have as novel image probe and cancer target combination therapy reagent preferable clinical
Application prospect.
Detailed description of the invention
Fig. 1 is the uv atlas of DPP-BT-R2 water soluble nanometer particles；
Fig. 2 is the fluorogram of DPP-BT-R2 water soluble nanometer particles；
Fig. 3 is that the DLS of DPP-BT-R2 water soluble nanometer particles schemes；
Fig. 4 is the two window fluorescence imaging figure of near-infrared of DPP-BT-R2 water soluble nanometer particles；
Fig. 5 is the optoacoustic intensity of DPP-BT-R2 water soluble nanometer particles with concentration trend chart；
Fig. 6 is photo-thermal variation diagram of the various concentration DPP-BT-R2 nanoparticle under same power illumination；
Fig. 7 is a certain concentration DPP-BT-R2 nanoparticle in 1W/m2Under illumination the 414nm UV absorption intensity of DPBF with
Time variation diagram.
Specific embodiment
Specific introduce is made to the present invention below in conjunction with the drawings and specific embodiments.
Reagent used in the embodiment of the present invention be all it is commercially available, used instrument includes:
Two window phosphorimager of near-infrared: NIRvana 640-Princeton instrument；
Photoacoustic imager: Endra Nexus 128；
Infrared thermal imager: TESTO869；
Laser: MDL-IH-730-1.5W-PSU-II-LED；
The abbreviation of part chemical reagent title are as follows:
DSPE-PEG-FA: phosphatide-polyethylene glycol-folic acid；
F127: poloxamer (Poloxamer) is polyoxyethylene poly-oxygen propylene aether block copolymer.
R in the embodiment of the present invention withFor:
1, the synthetic route of DPP-BT-R2:
Specific synthesis step is as follows:
A1, compound BT-R2: by bromo- 4- aldehyde radical benzo [c] [1,2, the 5] thiadiazoles (0.242g, 1mmol) of 7- and to nitre
Base benzene acetonitrile (0.148g, 1mmol) 40ml methylene chloride dissolves, and 0.1g NaOH is added and filters yellow in 50 DEG C of stirring 5h
Color precipitating, with ethanol washing, obtains compound BT-R2 (0.34g, yield: 87%).
A2, DPP-BT-R2: DPP (0.23g, 0.19mmol) and product BT-R2 (0.234g, 0.6mmol) are dissolved in
Catalyst Pd (PPh is added in 20ml dry toluene3)4(15mg) is heated slowly to 110 DEG C, heating is stirred under inert gas protection
It mixes reaction for 24 hours, reaction solution is spin-dried for, column chromatographs to obtain product DPP-BT-R2 (0.18g, yield: 38.7%).
2, the preparation of the DPP-BT-R2 water soluble nanometer particles with target function:
It weighs DPP-BT-R2 (1mg) and is dissolved in 1ml tetrahydrofuran, F127 (15mg) and DSPE-PEG-FA (5mg) are dissolved in 5ml
In ultrapure water, then DPP-BT-R2 solution is slowly added in the ultrapure water containing F127 and DSPE-PEG-FA, the side Bian Chaosheng adds
Enter, continue ultrasound 2 minutes, air-blowing then is carried out to mixed solution with nitrogen, until tetrahydrofuran is removed, finally with 30,000
Super filter tube to solution carry out centrifugation removal part water, finally obtain concentration be 1mg/ml DPP-BT-R2 aqueous solution, it is ultraviolet such as
Shown in Fig. 1, fluorescence spectra is as shown in Fig. 2, the size of obtained nanoparticle is as shown in Figure 3.
(in above step, F127 can be substituted by other amphiphilic sex pills, removed DSPE-PEG-FA, be can be prepared by non-tool
There is the nanometer DPP-BT-R2 aqueous solution of target function).
3, DPP-BT-R2 water soluble nanometer particles are used for two window fluorescence imaging of near-infrared/photoacoustic imaging:
(1), two window fluorescence imaging of near-infrared
Compound concentration is the above-mentioned DPP-BT-R2 aqueous solution 1ml of 0.1mg/ml, is placed in small centrifuge tube, in near-infrared
Under two window phosphorimagers, the laser excitation for being 808nm with wavelength obtains two window fluorescence imaging of near-infrared.As shown in figure 4, knot
Fruit shows that the nanoparticle has excellent infrared two windows fluorescence imaging ability.
(2), photoacoustic imaging
Compound concentration is the DPP-BT-R2 water of 0mg/ml, 0.3mg/ml, 0.6mg/ml, 0.9mg/ml, 1.2mg/ml respectively
Then solution is imaged in small test tube with photoacoustic imager, the trend that optoacoustic intensity changes with solution concentration variation is such as
Shown in Fig. 5, the results showed that photoacoustce signal intensity is linear as nanoparticle concentration increases to be increased.
4, DPP-BT-R2 water soluble nanometer particles are in photo-thermal/application of the light power in oncotherapy:
(1), the test of light thermal property:
Different solutions concentration and different illumination power densities are studied to the photothermal conversion of DPP-BT-R2 nanoparticle aqueous solution
Effect.
The deionized water and concentration that 200 μ L are separately added into the small centrifuge tube of 250 μ L are respectively 400 μ g/ml, 600 μ g/
The DPP-BT-R2 nanoparticle aqueous solution of ml, 800 μ g/ml and 1000 μ g/ml, and with laser (730nm, 1W/cm2) irradiation, by
The trend that infrared thermal imager recording solution temperature changes over time, as shown in fig. 6, identical laser power is irradiated, DPP-BT-
The bigger aqueous temperature of R2 nanoparticle concentration rises higher.
Finally, the solar thermochemical cycle stability of test nanoparticle:
It is 1W/cm with optical power density2730nm laser irradiation concentration be 1000 μ g/ml DPP-BT-R2 nanoparticle
Aqueous solution closes laser when solution temperature rises to maximum temperature, makes solution natural cooling, is cooled to room temperature and is further continued for light
According to moving in circles 5 times, obtain solar thermochemical cycle figure, the results showed that the nanoparticle has good photo and thermal stability.
(2), the test of light power performance:
DPP-BT-R2 nanoparticle aqueous solution (0.25mM, 2mL) is added in cuvette, then is added dropwise to 40 μ L concentration and is
The ethanol solution of the DPBF of 1mM is 1W/m with optical power density2Laser (730nm) interrupted illuminating, each illumination 2min, and
The variation of the ultraviolet absorption peak at DPBF characteristic peak 414nm is monitored, as shown in Figure 7.
Absorption peak of the DPBF at 414nm is substantially reduced with the continuous irradiation of light, to reflect that During Illumination generates
Singlet oxygen.In addition, the amplitude of absorption peak decline of the DPBF at 414nm is bigger as optical power density is bigger, show this
Nanoparticle has preferable light power performance.
Two area's small organic molecule fluorescence probe of near-infrared disclosed by the invention, main component are pyrrolo-pyrrole-dione
(DPP) derivative, benzo [c] [1,2, the 5] thiadiazoles and R functional group for being further introduced into electron deficient can be substantially reduced molecule
It is mobile near infrared region to make molecule absorption for difference in band gap, while fluorescent emission being made to be 2nd area of near-infrared.In near infrared light
Under, which can be absorbed luminous energy and is converted into thermal energy, while oxygen molecule can also be converted into singlet oxygen.Further lead to
It crosses nanometer coprecipitation method and the nano particle with good aqueous solubility, biocompatibility and targeting is prepared, the nanometer
Grain can be used for cancer target photo-thermal/light power link treatment under two area's fluorescence imaging of near-infrared/photoacoustic imaging guidance.
The basic principles, main features and advantages of the invention have been shown and described above.The technical staff of the industry should
Understand, the above embodiments do not limit the invention in any form, all obtained by the way of equivalent substitution or equivalent transformation
Technical solution is fallen within the scope of protection of the present invention.
Claims (8)
1. two area's small organic molecule fluorescence probe of near-infrared, which is characterized in that structural formula is as follows:
2. the preparation method of two area's small organic molecule fluorescence probe of near-infrared according to claim 1, which is characterized in that packet
Include following steps:
A1, certain molal weight component ratio is pressed, by bromo- 4- aldehyde radical benzo [c] [1,2, the 5] thiadiazoles (BT) of 7-, p-nitrophenyl second
Nitrile, sodium hydroxide are added in methylene chloride, and heating stirring, revolving removes solvent, and after pillar layer separation, BT-R is made；
A2, certain molal weight component ratio is pressed, by 2,5- bis- (2- octyldodecyl) -3,6- bis- (5- tin trimethyl)-pyrroles
And pyrroledione, BT-R, tetrakis triphenylphosphine palladium are added in dry toluene, heating stirring, revolving removes solvent, through column chromatography
After separation, small organic molecule fluorescence probe is made.
3. the preparation method of two area's small organic molecule fluorescence probe of near-infrared according to claim 2, which is characterized in that institute
Stating bromo- 4- aldehyde radical benzo [c] [1,2, the 5] thiadiazoles (BT) of the 7- in step A1 is 1mmol, and para orientation nitration is 1mmol, hydrogen
Sodium oxide molybdena is 0.1g, methylene chloride 40ml；
2,5- bis- (2- octyldodecyl) -3,6- two (5- tin trimethyl)-pyrrolo-pyrrole-dione in the step A2 is
0.1-0.5mmol, BT-R are 0.22-1.1mmol, and tetrakis triphenylphosphine palladium is 15mg, and dry toluene is 20ml.
4. the nanoparticle aqueous solution of two area's small organic molecule fluorescence probe of near-infrared according to claim 1, feature
It is, is made by nanometer coprecipitation, comprising the following steps:
B1, a certain amount of small organic molecule fluorescence probe described in claim 1 is weighed, ultrasound is dissolved in tetrahydrofuran；
B2, the prepared solution of B1 is added in amphiphilic sex pill aqueous solution, after ultrasound, revolving removal tetrahydrofuran is made and receives
Rice corpuscles aqueous solution.
5. the nanoparticle with target function of two area's small organic molecule fluorescence probe of near-infrared according to claim 1
Aqueous solution, which is characterized in that be made by nanometer coprecipitation, comprising the following steps:
C1, a certain amount of small organic molecule fluorescence probe described in claim 1 is weighed, ultrasound is dissolved in tetrahydrofuran；
C2, the prepared solution of C1 is added in the amphiphilic sex pill aqueous solution containing cancer target, after ultrasound, revolving removal tetrahydro
The nanoparticle aqueous solution with target function is made in furans.
6. the application of two area's small organic molecule fluorescence probe of near-infrared according to claim 1, which is characterized in that be used for light
Acoustic imaging.
7. the application of two area's small organic molecule fluorescence probe of near-infrared according to claim 1, which is characterized in that for close
Infrared 2nd area fluorescence imaging.
8. the pharmaceutical applications of two area's small organic molecule fluorescence probe of near-infrared according to claim 1, which is characterized in that use
In the preparation of cancer target combination therapy reagent.
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| CN109943319A (en) * | 2019-02-28 | 2019-06-28 | 南京邮电大学 | A kind of two area's fluorescent material of near-infrared and the nano particle and magnetic nanoparticle that can be used for multi-modal diagnosis and treatment |
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