CN110393811A - A kind of acid response nano probe and the preparation method and application thereof - Google Patents
A kind of acid response nano probe and the preparation method and application thereof Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/221—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by the targeting agent or modifying agent linked to the acoustically-active agent
Abstract
The invention discloses a kind of sour response nano probes and the preparation method and application thereof, wherein the acid response nano probe, comprising: acid response organic molecule and the distearoylphosphatidylethanolamine-polyethylene glycol being coated on the acid response organic molecule；The structural formula of the acid response organic molecule is as follows:Acid response nano probe of the present invention can be realized by photoacoustic imaging is monitored internal gastric acid secretion, has safety, stablizes, high sensitivity, the advantages such as good biocompatibility, gastric acid secretion imaging side face has a good application prospect in vivo.
Description
Technical field
The present invention relates to optoacoustic nano-probe field more particularly to a kind of sour response nano probe and preparation method thereof with answer
With.
Background technique
Functional dyspepsia FD (FD) is one of most common disease of digestive system, affects the people in the whole world 10% -20%
Group.Recent research indicate that reduce internal acid concentration can it is significant reduce FD symptom generation, this show gastric acid excessively point
Secreting is one of important behaviour of FD patient.Therefore, in real-time monitoring body the secretion of gastric acid have to the diagnosing and treating of FD it is important
Meaning.
Traditional gastric acid detection technique needs complicated and time-consuming sample collection, and with serious side effect.For example,
Endoscope check, which is widely used, monitors internal gastric acid secretion.Endoscope is a kind of invasive tool, endoscope check side
Method is easy to cause human body mechanical injuries, and is not suitable for being applied to detect pregnant woman and infant.Therefore, it is necessary to
Develop a kind of safer, more effective gastric acid secretion monitoring method.
Photoacoustic imaging (PAI) is a kind of non-invasive imaging technique for being based on optoacoustic (PA) effect.With other imaging modes
It compares, PAI has many advantages, such as contrast abundant, and high-resolution and deep tissues penetrate.With the development of PA probe, optoacoustic inspection
It surveys (PAD) and has been widely used for diagnosing tumor, metal ion detection, enzyme detection, pH detection etc..But it is possible to be enough in monitoring body
The PA probe of interior gastric acid level is still to be developed.Before this, Gao Hu seminar, Washington, DC university develops a kind of polyaniline
Enwrapping ferric oxide nanoparticle, the PA probe are made of organic and inorganic multicomponent hybrid material, can be used in the PA of internal gastric acid
Imaging.Existing PA probe is metabolized slow and biocompatibility in vivo and still has deficiency, and preparation process is complicated.
Therefore, the existing technology needs to be improved and developed.
Summary of the invention
In view of above-mentioned deficiencies of the prior art, the purpose of the present invention is to provide a kind of sour response nano probe and its preparations
Method and application, it is intended to which solving existing PA probe, accretion rate is slow in vivo and biocompatibility still has deficiency, and makes
The problem of standby complex process.
A kind of acid response nano probe, wherein include: that acid responds organic molecule and is coated on the acid response organic molecule
On distearoylphosphatidylethanolamine-polyethylene glycol；
Wherein, the structural formula of the acid response organic molecule is as follows:
A kind of preparation method of sour response nano probe as described above, wherein include:
Substitution reaction is occurred into for infrared cyanine dye and 3- butene-1-amine, acid response organic molecule is prepared；
The acid response organic molecule is co-precipitated with distearoylphosphatidylethanolamine-polyethylene glycol, is prepared
Obtain sour response nano probe；
The infrared cyanine dye has the following structure formula:
The preparation method of the sour response nano probe, wherein described to carry out infrared cyanine dye and 3- butene-1-amine
Substitution reaction is prepared acid response organic molecule and specifically includes:
Infrared cyanine dye and 3- butene-1-amine is miscible in the first solvent, it is stirred under the conditions of 25 DEG C-45 DEG C,
Acid response organic molecule is prepared.
The preparation method of the sour response nano probe, wherein described by the acid response organic molecule and distearyl
Acylphosphatidyl ethanolamine-polyethylene glycol is co-precipitated, and sour response nano probe is prepared and specifically includes:
The acid response organic molecule and distearoylphosphatidylethanolamine-polyethylene glycol is miscible in the second solvent
In, it is ultrasonically treated after adding deionized water, then removes the second solvent, sour response nano probe is prepared.
The preparation method of the sour response nano probe, wherein first solvent is amine solvent.
The preparation method of the sour response nano probe, wherein first solvent is n,N-Dimethylformamide, 2-
One of aminoethyle alcohol, isopropanolamine.
The preparation method of the sour response nano probe, wherein the acid response organic molecule and the distearyl
Base phosphatidyl-ethanolamine-polyethylene glycol mass ratio is 1:5.
The preparation method of the sour response nano probe, wherein second solvent is methylene chloride, petroleum ether, second
One of ether.
The preparation method of the sour response nano probe, wherein the second solvent of the removing is to be removed by nitrogen stream
Second solvent.
A kind of application of sour response nano probe as described above in the nano-probe pharmaceutical preparation of preparation detection gastric acid.
The utility model has the advantages that acid response nano probe of the present invention can be realized by photoacoustic imaging to internal gastric acid secretion into
Row monitoring, has safety, stablizes, high sensitivity, the advantages such as good biocompatibility, and gastric acid secretion imaging side face has good in vivo
Good application prospect.Meanwhile the synthetic method of sour response nano probe of the present invention is simple, and it is easy to operate, do not need complexity
Expensive equipment, it is easy to accomplish industrialized production.
Detailed description of the invention
Fig. 1 is the gastric acid response mechanism schematic diagram of heretofore described sour response nano probe LET-4.
Fig. 2 is high resolution mass spectrum figure of the present invention in the acid response organic molecule IR-pH.
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of heretofore described acid response organic molecule IR-pH.
Fig. 4 is the carbon-13 nmr spectra figure of acid response organic molecule IR-pH in the present invention.
Fig. 5 is the transmission electron microscope picture of sour response nano probe LET-4 in the present invention.
Fig. 6 is the water particle diameter dynamic scattering figure of sour response nano probe LET-4 in the present invention.
The external sour response diagram that Fig. 7 is sour response nano probe LET-4 in the embodiment of the present invention 4.
Fig. 8 is acid response nano probe LET-4 in the embodiment of the present invention 5 to the detection figure of in vivo gastric acid.
Fig. 9 is the stomach photo-acoustic detection figure in the embodiment of the present invention 6.
The performance test figure that Figure 10 is sour response nano probe LET-4 in embodiment 7 in the present invention.
Figure 11 is the nude mouse tissue slice map in the embodiment of the present invention 8.
Specific embodiment
The present invention provides a kind of sour response nano probe and the preparation method and application thereof, to make the purpose of the present invention, technology
Scheme and effect are clearer, clear, and the present invention is described in more detail below.It should be appreciated that described herein specific
Embodiment is only used to explain the present invention, is not intended to limit the present invention.
A kind of acid response nano probe (LET-4), wherein include: that acid responds organic molecule (IR-pH) and is coated on institute
State the distearoylphosphatidylethanolamine-polyethylene glycol on acid response organic molecule；
Wherein, the structural formula of the acid response organic molecule is as follows:
It is reproducible that the present invention utilizes small organic molecule dyestuff to have, and convenient for modification, preparation method is simple, internal metabolism is fast
A kind of PA probe is obtained with advantages, designs such as good biocompatibilities, meets the requirement for detecting and being imaged to internal gastric acid.The acid
Response nano probe LET-4 in acid condition, occurs proton translocation and structure changes, solution colour becomes blue-green, and real
The synchronous of existing photoacoustic signal is opened.LET-4 substantially enhances with the secretion photoacoustic signal of gastric acid.
The LET-4 has following reaction in different pH environment:
Based on this principle, as shown in Figure 1, the nano-probe can successfully monitor the secretion shape of gastric acid solution in living tissue
State.LET-4 is very sensitive to the response of gastric acid, and response condition is milder, meets organism physiological environment.
The acid response nano probe LET-4, in gastric acid environment, photoacoustic signal of the LET-4 at 808nm significantly increases
By force, and in gastric acid solution can exist steadily in the long term.
It is described acid response nano probe LET-4, LET-4 aqueous solution be in acid condition brown, under alkaline condition for
Blue-green has apparent color change in different pH environment.
The acid response nano probe LET-4, LET-4 can be stabilized in gastric juice environment in vivo, and can be passed through
The variation of photoacoustic signal realizes dynamic monitoring to physiology courses such as internal gastric emptying-gastric acid secretion-probe metabolism.
A kind of preparation method of acid response nano probe, wherein include:
Step A, infrared cyanine dye (IR1061) and 3- butene-1-amine are subjected to substitution reaction, acid response, which is prepared, to be had
Machine molecule (IR-pH)；
Step B, the acid response organic molecule is carried out with distearoylphosphatidylethanolamine-polyethylene glycol coprecipitated
It forms sediment, sour response nano probe (LET-4) is prepared；
Wherein, the infrared cyanine dye has the following structure formula:
The preparation method of acid response nano probe of the present invention is first using infrared cyanine dye as parent, with 3- butene-1-
Amine occurs substitution reaction and acid response small organic molecule (IR-pH) is made, then IR-pH and distearoylphosphatidylethanolamine-
Sour response nano probe is made in polyethylene glycol co-precipitation.Sour response nano probe increases photoacoustic signal significantly in gastric acid environment
By force, to realize the specific detection to gastric acid.Acid response nano probe of the present invention can be realized by photoacoustic imaging to body
The dynamic monitoring of interior gastric acid secretion has with high security, the advantages such as stability is good, high sensitivity and good biocompatibility
Clinical Transformation Application prospect.
The structural formula of infrared cyanine dye of the present invention is as follows:
The infrared cyanine dye (IR1061) is
Near-infrared cyanine dye, the absorption peak with 2nd area of near-infrared, i.e. the ultraviolet-visible characteristic absorption peak of the dyestuff are located at 1061nm
Place, and active site can be modified, and be a kind of ideal near-infrared precursor structure.The IR1061 as parent with
3- butene-1-amine carries out substitution reaction and makes acid response small organic molecule (IR-pH) is prepared have sensitive sour responding ability,
And its absorption peak is monitored when being more advantageous to gastric acid secretion detection at 1061nm.3- butene-1-amine of the present invention,
Its molecular formula is C4H9N, skeleton symbol CH2=CHCH2CH2NH2。
Heretofore described acid response small organic molecule IR-pH is typically only capable to be dissolved in organic solvent, is unfavorable for biologic applications,
There is no good biocompatibility.The present invention is coated on IR-pH by using distearoylphosphatidylethanolamine-polyethylene glycol
Surface makes it have good water solubility.Especially by by IR-pH and distearoylphosphatidylethanolamine-polyethylene glycol into
The method of row co-precipitation, is coated on the surface IR-pH for distearoylphosphatidylethanolamine-polyethylene glycol, to be prepared
Sour response nano probe with good biocompatibility.
The distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) is a kind of amphiphilic surfactant.
Specifically, the distearoylphosphatidylethanolamine-polyethylene glycol can be the poly- second two of distearoylphosphatidylethanolamine-
Alcohol 2000 (DSPE-PEG2000), the surfaces such as distearoylphosphatidylethanolamine-polyethylene glycol 5000 (DSPE-PEG5000)
Activating agent.
Wherein, the structural formula of DSPE-PEG2000 is as follows:
Preferably, LET-4 is that IR-pH reacts under the mass ratio of 1:5 with DSPE-PEG, can be prepared
Optoacoustic nano-probe partial size is about 65nm, and absorption peak is blue shifted at 808nm.The present invention probed into IR-pH and DSPE-PEG by
According to the synthetic method of 1:1,1:2,1:5,1:10 and 1:15 ratio, show that 1:5 is best synthesis ratio.
Preferably, the step A is specifically included:
Infrared cyanine dye and 3- butene-1-amine is miscible in the first solvent, it is stirred under the conditions of 25 DEG C-45 DEG C,
Acid response organic molecule is prepared.
That is, a kind of preferred reaction conditions of substitution reaction of the present invention are by infrared cyanine dye and 3- butylene-
1- amine is dissolved in solvent appropriate, carries out reaction 2-4h under temperature appropriate (such as 40 DEG C).The temperature of substitution reaction in the present invention
Degree can be 25 DEG C -45 DEG C.Under the same terms, the temperature of substitution reaction is higher, and reaction speed is faster, but reaction temperature is more than
45 DEG C will lead to IR-pH decomposed metamorphic.The time of substitution reaction of the present invention is about 2-4h.The too short meeting of the time of substitution reaction
Lead to reaction not exclusively, and the reaction time is too long, will lead to IR-pH decomposed metamorphic.
Preferably, the step B is specifically included:
The acid response organic molecule and distearoylphosphatidylethanolamine-polyethylene glycol is miscible in the second solvent
In, it is ultrasonically treated after adding deionized water, then removes the second solvent, sour response nano probe is prepared.
In step B of the present invention, by being ultrasonically treated the acid response organic molecule and distearyl acyl group phosphatidyl second
Hydramine-polyethylene glycol is evenly dispersed while being conducive to improve the homogeneity of nano particle, in the method by removing the second solvent
Cause the co-precipitation of acid the response organic molecule and distearoylphosphatidylethanolamine-polyethylene glycol, described two is hard at this time
Fatty acyl group phosphatidyl-ethanolamine-coated with polyethylene glycol is on the surface of the acid response organic molecule.Wherein it is preferred to described super
The time of sonication is 2-5 minutes, and the dispersion of dyestuff caused by avoiding ultrasonic time too short is uneven, and nano particle size is uneven
One the problem of.
First solvent of the present invention specifically can be amine solvent for dissolving infrared cyanine dye and 3- butene-1-amine.
Preferably, first solvent is one of n,N-Dimethylformamide (DMF), 2 hydroxy ethylamine, isopropanolamine.Wherein,
The n,N-Dimethylformamide is infrared cyanine dye and 3- butene-1-amine good solvent, while chemical property is more stable,
It can be removed later by the method vacuumized.
Second solvent of the present invention is one of methylene chloride, petroleum ether, ether；The second solvent of the removing is logical
It crosses nitrogen stream and removes the second solvent.Methylene chloride of the present invention is solvent used in coprecipitation process, especially by nitrogen
Air-flow removes the second solvent, so that sour response nano probe be prepared.It is described to be specifically by nitrogen stream the second solvent of removing
By entering nitrogen, accelerate solvent volatilization, to achieve the purpose that remove solvent.
More specifically, the preparation method of the acid response nano probe, includes the following steps:
The preparation of acid response molecular probe IR-pH:
IR1061 and 3- butene-1-amine is miscible in amine solvent, and stirring is to 3h at 40 DEG C, after being cooled to room temperature,
Vacuum decompression removes solvent, by silica flash column method purification of crude product, uses petrol ether/ethyl acetate as elution
Agent obtains brown solid IR-pH.Wherein, the amine solvent is anhydrous n,N-Dimethylformamide.
Near-infrared cyanine dye IR1061 and IR-pH structural formula and reaction process are as follows:
The preparation of gastric acid imaging nano-probe LET-4:
IR-pH and DSPE-PEG is miscible in methylene chloride, deionized water is added, passes through ultrasound under the conditions of nitrogen protection
Reaction removes methylene chloride using nitrogen stream, after membrane filtration, centrifugation washing three times, it is molten to finally obtain bottle green to 2min
Liquid.
Further, IR-pH and DSPE-PEG2000 is dissolved in methylene chloride, addition 4mL deionized water, at ultrasound
After managing 2min, methylene chloride is removed under nitrogen flowing, obtains clear solution；By aqueous solution by 0.22 μm of pvdf membrane filtering, and
Three times using super filter tube centrifugation 5min washing；LET-4 solution is obtained finally by ultrafiltration concentration.
It further include being carried out to reaction product after substitution reaction is complete in the preparation of above-mentioned acid response molecular probe IR-pH
Purification removal of impurities.The purification cleans particular by vacuum decompression removing solvent, silica flash column method purification of crude product,
It is a kind of preferably method of purification.
In the preparation of gastric acid imaging nano-probe LET-4, after the completion of co-precipitation, then pass through membrane filtration and centrifugal water
The method washed improves the purity of sour response nano probe and the homogeneity of granular size.
Near-infrared (NIR) the PA nano-probe (LET-4) of the response of pH prepared by the present invention, for the real-time of internal gastric acid
Monitoring.Specifically, in acid condition, Protonation effect occurs for nano-probe LET-4, causes its absorption at 808nm aobvious
It writes and increases, to generate strong PA signal (PA808) output under the excitation of 808nm laser.And in neutral and alkaline conditions,
Absorption decline at 808nm, PA blackout.Using PAI technology, nano-probe LET-4 can be effectively used for point of living body gastric acid
Secrete assessment.
Further, sour response nano probe application as described above is detected into gastric acid in preparation the present invention also provides a kind of
Nano-probe pharmaceutical preparation.Acid response nano probe of the present invention can be used in or be prepared into drug together with other raw materials
Preparation.The pharmaceutical preparation can be used for gastric acid detection, pass through gastric acid secretion process in photoacoustic imaging real-time dynamic monitoring animal body.
Gastric acid state is of great significance to the diagnosing and treating of gastrointestinal disease in real-time monitoring body.Acid of the present invention is rung
Nano-probe (LET-4) is answered, the photoacoustic imaging (PAI) for internal gastric acid.In acid condition, LET-4 nano-probe is close
Infrared region influx and translocation, and there is the output of strong PA signal at 808nm.The PA of LET-4 when pH 3808The letter of signal ratio pH 7
It is number 3.45 times high.It is commented importantly, LET-4 nano-probe can monitor the internal gastric acid secretion in animal model by PAI
Estimate.This probe synthesis based on small organic molecule NIR dyestuff is simple, and easily prepared, biocompatibility is good, disappears in functionality
Changing bad (FD) diagnosis aspect has very big potentiality.
Technical solution of the present invention is illustrated below by specific embodiment.
Embodiment 1
IR1061 (100mg, 0.13mmol) and 3- butene-1-amine (15mg, 0.21mmol) is miscible in anhydrous N, N- bis-
In methylformamide (DMF) (8mL), 3h is stirred at 40 DEG C.After being cooled to room temperature, vacuum decompression removes solvent.Pass through dioxy
SiClx purified by flash chromatography crude product uses petrol ether/ethyl acetate (5:1) as eluant, eluent, obtains brown solid IR-pH
(acid response organic molecule), yield 20.4% (22.3mg).
1mg IR-pH and 5mg DSPE-PEG2000 are dissolved in 1mL methylene chloride, 4mL deionized water is added, is surpassed
After sonication 2min, methylene chloride is removed under nitrogen flowing, obtains clear solution.The solution is driven by 0.22 μm of PVDF syringe
Dynamic filter filtering, and be centrifuged 5min in 5000rpm using 30K super filter tube and wash three times.Finally it is concentrated to get LET-4
Solution (sour response nano probe).
Embodiment 2
The structure of obtained LET-4 is characterized, carries out mass spectrogram, hydrogen nuclear magnetic resonance spectrogram, nuclear magnetic resonance respectively
Carbon spectrogram is characterized.
As shown in Fig. 2, the molecular weight of the IR-pH is 696.27505.
As shown in figures 3 and 4, nuclear magnetic resonance spectroscopy and carbon-13 nmr spectra confirm the molecular structure of IR-pH.
Embodiment 3
Transmission electron microscope and water particle diameter dynamic scattering test are done to obtained LET-4
As shown in Fig. 5, by transmission electron microscope observing, its partial size is about 65nm to obtained LET-4.
As shown in Fig. 6, the water particle diameter of LET-4 is 91.2 ± 15.1nm.
Embodiment 4
LET-4 solution is dispersed in buffer solution, changing pH value of solution respectively is 3,4,5,6 and 7, observes LET-4 (10 μ
M UV absorption) is with the variation of pH value of solution, and as shown in attached drawing 7 (1), the UV absorption of LET-4 solution is with pH at 808nm
Decline significantly increase.When pH value of solution is 0-10, the OD value variation diagram of LET-4 (10 μM) solution, such as figure attached drawing 7 (2) institute
Show.
LET-4 solution is dispersed in buffer solution, changing pH value of solution respectively is 3,4,5,6 and 7, observes LET-4 (20 μ
M optoacoustic intensity) is with the variation of pH value of solution, and as shown in attached drawing 7 (3), the optoacoustic intensity of LET-4 solution is with pH at 808nm
Decline significantly increase.As shown in attached drawing 7 (4), when pH value of solution changes, the optoacoustic amplitude of LET-4 (20 μM).
Fig. 7 (1) is the UV-vis-NIR absorption spectrum of the LET-4 solution (10 μM) of different pH value；Fig. 7 (2) is different pH
When value, optical density (OD) figure of LET-4 solution (10 μM) at 808nm；Fig. 7 (3) is the LET- of different pH value at 808nm
The PA image of 4 solution；Fig. 7 (4) is Fig. 7 (3) corresponding PA808Amplitude.
Embodiment 5
NaHCO is used in advance3In solution and the gastric acid of mouse, by LET-4 solution (60 μM, 100 μ L) gastric infusion,
By 3D photoacoustic imaging modular view as gastric acid secretion and probe are metabolized, the imaging contexts of mouse stomach.Such as attached drawing 8 (1) institute
Show, after gastric acid is neutralized, mouse web portion does not have apparent optoacoustic.With gastric acid secretion, mouse stomach photoacoustic signal is gradually increased.
Reach maximum value in 90min.With the metabolism of probe, completely disappeared in 240min mouse stomach photoacoustic signal.
Fig. 8 (1) be by administration by gavage (60 μM, 100 μ L) processing nude mice stomach of LET-4 solution after, in different time points
The 3D PA of nude mice stomach808Image；Fig. 8 (2) is control group and the corresponding PA of experimental group nude mice stomach different time points808Intensity
As shown in attached drawing 8 (2), grey histogram is represented with time change, mouse stomach photoacoustic signal situation of change；It is white
Color represents the situation of change of background.
Embodiment 6
It observed by 3D photo-acoustic module, compare the stomach optoacoustic that the mouse under gastric emptying state and gastric acid secretor state separates
Intensity.As a result it is consistent with above-mentioned theory situation.
Such as the 3D PA image that Fig. 9 (1) is different disposal group nude mice stomach；It (2) is the stomach of different disposal group nude mice separation
Photo；(3) PA of the stomach of different disposal group nude mice separation808Intensity.Wherein, a is background group, and b is acid response probe processing
Stomach group, c are that sodium bicarbonate acid adding responds probe processing stomach group.
Embodiment 7
As shown in attached drawing 10 (1) and attached drawing 10 (2), the absorption of LET-4 solution (60 μM) and photoacoustic signal are in simulation hydrochloric acid
It in environment, changes over time (0-24h) to be held essentially constant, this demonstrate that LET-4 solution is with good stability.
As shown in attached drawing 10 (3) and attached drawing 10 (4), Figure 10 (3) column is to three kinds of cells respectively (from a left side in adjacent column
Cell A375, cell MCF-10a, cell U87MG are respectively represented to the right side) toxicity.By the way that 0.5mL blood sample and 1mL will be contained
The mixture of PBS solution obtains red blood cell (RBC) with 4500rpm centrifugation 3.5min from serum.RBC tri- to five is washed with PBS
It is secondary, until supernatant is not marked with red, and the cell of purifying is diluted to 5mL.Then the diluted RBC of 0.3mL is suspended
Liquid is added in the 1.2mL PBS solution containing various concentration LET-4 (1.25 to 20 μM).Mixture is vortexed and in room temperature ring
Border stands 3h.Then after sample being centrifuged, absorbance of the UV-vis spectroscopy measurements supernatant at 541nm is used.It will spend
Ionized water and the RBC of PBS processing are set as positive and negative control.The cytotoxicity of the results show LET-4 is low.
Attached drawing 10 (1) and attached drawing 10 (2) are stability test result figure, and attached drawing 10 (3) is cytotoxicity test results figure,
Attached drawing 10 (4) is biological compatibility test result figure, in which: attached drawing 10 (1) is the Abs of LET-4 (10 μM)808In simulation hydrochloric acid
The intensity map of different time points in solution；Attached drawing 10 (2) is the PA of LET-4 (10 μM)808The different time in simulation hydrochloric acid solution
The intensity map of point；Attached drawing 10 (3) is LET-4 (0~10 μM) to A375, the toxicity test figure of MCF-10a and U87MG cell；It is attached
Figure 10 (4) is the hemolytic experiment of the LET-4 of various concentration.
Embodiment 8
Female nude mice deionized water 100 μ L (as a control group) and LET-4 (60 μM, 100 μ L) are given respectively.After administration
It puts to death nude mice afterwards for 24 hours and collects main organs: stomach, intestines, heart, kidney, liver, lung and spleen, and fixed with 4% paraformaldehyde solution.
Finally by hematoxylin eosin stain, the histotomy of mouse is obtained, disease does not occur for mice organs tissue after as a result proving administration
Become, it was demonstrated that the tissue toxicity of LET-4 is low.
Figure 11 (1) is after Mouse oral is administered for 24 hours, to pass through the stomach figure of h and E (H&E) dyeing；Figure 11 (2)
For Mouse oral administration for 24 hours after, by h and E (H&E) dyeing intestines, heart, liver, kidney, spleen and lung figure
Picture.
Embodiment 9
LET-4 is prepared according to the method for embodiment 1, wherein unlike the first embodiment, IR-pH and DSPE-PEG2000
Mass ratio be respectively 1:1,1:2,1:10 and 1:15.
The nano particle size and degree of polymerization PDI of prepared LET-4 is as shown in table 1
Table 1, influence of the mass ratio of DSPE-PEG2000 to LET-4
As seen from Table 1, nano particle size and degree of polymerization PDI show that 1:5 is preferable synthesis ratio.
In acid condition, electric charge transfer, structure changes IR-pH of the present invention, and solution colour changes, in absorption
It rises, photoacoustic signal significantly increases.When nano-probe LET-4 monitors gastric acid secretion, the animal model used is nude mice.Stomach-filling injection
After LET-4, which has good responsiveness to mouse stomach gastric acid secretion, can successfully monitor mouse by photoacoustic imaging
The state of stomach gastric acid secretion.Molecular probe LET-4 can monitor mouse stomach gastric emptying-gastric acid secretion-by photoacoustic imaging
Metabolism state.And passes through the building of 3D photo-acoustic module, reduce interference of the signal from its hetero-organization to imaging.Molecular probe
LET-4 is scattered in simulation hydrochloric acid solution (pH 3), and reaction temperature is 37 DEG C, and the absorption of probe and photoacoustic signal can be for a long time
It remains unchanged, this demonstrate that stability of the LET-4 in stomach, meets organism Physiology and biochemistry environment.
The present invention has synthesized a kind of near-infrared (NIR) the PA nano-probe (LET-4) of pH response, the reality for internal gastric acid
When monitor.In acid condition, Protonation effect occurs for nano-probe LET-4, its absorption at 808nm is caused significantly to increase
Add, to generate strong PA signal output under the excitation of 808nm laser.And in neutral and alkaline conditions, the suction at 808nm
Accept drop, PA blackout.Using PAI technology, the secretion that nano-probe LET-4 can be effectively used for living body gastric acid is commented.It is opposite and
Speech, small organic molecule dyestuff have reproducible, and convenient for modification, preparation method is simple, metabolism in vivo is fast and good biocompatibility
Etc. advantages, therefore be more suitable the design of PA probe, meet the requirement for detecting and being imaged to internal gastric acid.
It should be understood that the application of the present invention is not limited to the above for those of ordinary skills can
With improvement or transformation based on the above description, all these modifications and variations all should belong to the guarantor of appended claims of the present invention
Protect range.
Claims (10)
1. a kind of acid response nano probe characterized by comprising acid response organic molecule and to be coated on the acid response organic
Distearoylphosphatidylethanolamine-polyethylene glycol on molecule；
Wherein, the structural formula of the acid response organic molecule is as follows:
2. a kind of preparation method of sour response nano probe as described in claim 1 characterized by comprising
Substitution reaction is occurred into for infrared cyanine dye and 3- butene-1-amine, acid response organic molecule is prepared；
The acid response organic molecule is co-precipitated with the distearoylphosphatidylethanolamine-polyethylene glycol, is prepared
Obtain sour response nano probe；
Wherein, the infrared cyanine dye has the following structure formula:
3. the preparation method of acid response nano probe according to claim 2, which is characterized in that described by infrared cyanine dye
Substitution reaction is carried out with 3- butene-1-amine, acid response organic molecule is prepared and specifically includes:
Infrared cyanine dye and 3- butene-1-amine is miscible in the first solvent, it is stirred, prepares under the conditions of 25 DEG C-45 DEG C
Obtain acid response organic molecule.
4. the preparation method of acid response nano probe according to claim 2, which is characterized in that described to respond the acid
Organic molecule is co-precipitated with distearoylphosphatidylethanolamine-polyethylene glycol, and sour response nano probe tool is prepared
Body includes:
The acid response organic molecule and distearoylphosphatidylethanolamine-polyethylene glycol is miscible in the second solvent, then
It is ultrasonically treated after deionized water is added, then removes the second solvent, sour response nano probe is prepared.
5. the preparation method of acid response nano probe according to claim 3, which is characterized in that first solvent is amine
Class solvent.
6. the preparation method of acid response nano probe according to claim 5, which is characterized in that first solvent is N,
One of dinethylformamide, 2 hydroxy ethylamine, isopropanolamine.
7. the preparation method of acid response nano probe according to claim 2, which is characterized in that described organic point of acid response
Son and the mass ratio of distearoylphosphatidylethanolamine-polyethylene glycol are 1:5.
8. the preparation method of acid response nano probe according to claim 4, which is characterized in that second solvent is two
One of chloromethanes, petroleum ether, ether.
9. the preparation method of acid response nano probe according to claim 4, which is characterized in that the second solvent of the removing
To remove the second solvent by nitrogen stream.
10. a kind of sour response nano probe as described in claim 1 is in the nano-probe pharmaceutical preparation of preparation detection gastric acid
Application.
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