CN104127887B - Fe5c2nano-particle application in preparing bio-imaging probe - Google Patents
Fe5c2nano-particle application in preparing bio-imaging probe Download PDFInfo
- Publication number
- CN104127887B CN104127887B CN201410309193.9A CN201410309193A CN104127887B CN 104127887 B CN104127887 B CN 104127887B CN 201410309193 A CN201410309193 A CN 201410309193A CN 104127887 B CN104127887 B CN 104127887B
- Authority
- CN
- China
- Prior art keywords
- nano
- particle
- peg
- tumor
- imaging
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention provides Fe5C2Nano-particle application in preparing bio-imaging probe, uses the Fe used usually used as fischer-tropsch synthetic catalyst5C2Nano-particle is raw material, by the bio-imaging probe that simple method i.e. availability is stable.This bio-imaging probe can be the imaging data that various tumor diagnosis and treatment means provide tumor locus, and then assists and control the diagnosis and treatment process of tumor.Present invention also offers a kind of Fe5C2Nano-particle application in preparing the light thermotherapy probe that bio-imaging guides.At Fe5C2The affinity ligands of coupling tumor cell specific on nano-particle so that probe specific can be targeted to specific tumors cell, it is achieved the selective killing to specific tumors cell, can also understand and control the therapeutic effect of tumor simultaneously by bio-imaging.
Description
Technical field
The present invention relates to a kind of Fe5C2The application of nano-particle, particularly relates to a kind of Fe5C2Nano-particle is at preparation biology
Application in image probe.
Background technology
In the last few years, a kind of important reason causing death in tumor has become as global range.Light heating therapy conduct
A kind of Wicresoft local tumor therapy means cause increasing concern, and its principle is with the help of light absorber, by closely
The electromagnetic radiation of ultrared (NIR) " is burnt " tumor cell, and above-mentioned light absorber is usually nanometer reagent, has such as gold nano
Rod, nanometer star, nanocages, Graphene, CNT etc..
Although above-mentioned nanometer reagent plays an important role in photo-thermal therapy, but understand its metabolic pathway and play work
Mode even more important, also determine that cancer immunotherapies, understand and control the key of oncotherapy effect.Become by biology
As means preferable can must solve this problem.In numerous imaging means, photoacoustic imaging is due to can be further by photo-thermal
Treat the heat energy produced be converted to ultrasound wave by adiabatic expansion and Chang Yuguang thermotherapy with the use of.Additionally, nuclear magnetic resonance due to
There is high spatial resolution and become widely used non-damaging diagnostic imaging means in clinical medicine.This makes photoacoustic imaging and magnetic
Photo-thermal therapy under resonance image-forming guides becomes the problem that numerous researcher is studied, and most important of which is that for for this
The exploitation of the probe of multi-modal bio-imaging or bio-imaging direct light treatment function.
It has been reported that develop can be used for photoacoustic imaging and nuclear magnetic resonance, or the probe that imaging guides is mainly base
Complex in magnetic nanoparticle Yu material with carbon element.But owing to the magnetic performance of composite is different at two kinds with optical property
Embodiment on material, it is generally required to use the method for substep preparation to synthesize, such as Yang K. etc. first synthesizes the magnetic Fe of tool3O4
Nano-particle, resynthesis light absorbs stronger Graphene, and then both are compound to make described probe.Although additionally, Tian
Q. wait by magnetic Fe3O4The method of the copper sulfide of nano grain surface growth strong light absorption so that all functions are received at one
Realizing in rice grain, but this method still needs to multistep processes prepares, process is extremely complex；And Fe3O4The most easily by oxygen
Change, thus change its magnetic performance.
Therefore, how to utilize the material of a kind of high stability, i.e. can be made into bio-imaging probe by simple step, or
The light thermotherapy probe that bio-imaging guides becomes problem to be solved.
Summary of the invention
The invention provides a kind of Fe5C2Nano-particle application in preparing bio-imaging probe, uses usually used as taking
The Fe that Tropsch synthesis catalyst uses5C2Nano-particle is raw material, by the bio-imaging that simple method i.e. availability is stable
Probe.This bio-imaging probe can be the imaging data that various tumor diagnosis and treatment means provide tumor locus, and then assists and control
The diagnosis and treatment process of tumor processed.
Present invention also offers Fe5C2Nano-particle application in preparing the light thermotherapy probe that bio-imaging guides, passes through
By Fe5C2The affinity ligands of nano-particle coupling tumor cell specific so that described probe can be specific with specific targeting
Tumor cell, it is achieved the selective killing to specific tumor cell, can also be understood by bio-imaging and control tumor simultaneously
Therapeutic effect.
Present invention also offers a kind of bio-imaging probe, the bio-imaging to tumor tissues can be realized by this probe.
The bio-imaging probe that the present invention provides can be used for determining and diagnosing tumorigenic position, and can after determining tumor locus,
The processes such as chemotherapy, radiotherapy, excision and the light thermotherapy for tumor provide imaging data, and then assist and control tumor
Treatment.
Present invention also offers the light thermotherapy probe that a kind of bio-imaging guides, described probe achieves in photo-thermal therapy mistake
Cheng Zhong, obtains the situation of tumor tissues by bio-imaging, is conducive to understanding and controlling the therapeutic effect of tumor.
The Fe that the present invention provides5C2Nano-particle application in preparing bio-imaging probe.In this scenario, described
Fe5C2Nano-particle is to be synthesized by the method described in patent 201210580895.1, and has institute's table in this patent documentation
The feature levied.This Fe5C2Nano-particle has nucleocapsid structure, the spacing of lattice (0.205nm) of intercalated nucleus part and Fe5C2's
(510) crystal face matches, and core is Fe5C2, surface is carbon-coating.
Further study show that through the present inventor, this Fe5C2Nano-particle has nuclear magnetic resonance performance or near infrared region
(NIR) the photoacoustic imaging performance of (wavelength is at the electromagnetic wave of 780～1100nm scopes), can be by well known by persons skilled in the art
Various chemical modifications are allowed to have hydrophilic and biocompatibility, carry out bio-imaging, described biological one-tenth hence into organism
Picture is nuclear magnetic resonance and/or photoacoustic imaging.
Further, described probe is by Fe5C2Nano-particle is through DSPE-PEG-NH2Modify and obtain.Through DSPE-PEG-NH2
After modification, the hydrophilic of described probe and biocompatibility strengthen, and the bio-imaging performance of this nano-particle is almost without changing
Become, be conducive to entering organism and carry out bio-imaging.
Further, described probe can be by Fe5C2Nano-particle is through DSPE-PEG-NH2(amidized Polyethylene Glycol
Phospholipid, its No. CAS is 474922-26-4) modify after, the affinity ligands of coupling tumor cell specific obtains.Described affine join
Body is used for making through DSPE-PEG-NH2The Fe obtained after modification5C2-PEG nano-particle can be targeted to specific tumor cell, ability
Field technique personnel can select corresponding affinity ligands and warp according to the type of the tumor tissues of bio-imaging to be carried out
DSPE-PEG-NH2The Fe obtained after modification5C2-PEG nano-particle coupling, thus realize the biological one-tenth to specific tumors tissue
Picture.Further, described tumor includes ovarian cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma or the brain cancer etc..Further, described affinity is joined
Body is part that can be specific binding with the tumor marker on ovarian cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma or brain cancer cell surface.
In a specific embodiment of the present invention, described tumor is ovarian cancer, and described affinity ligands is ZHER2:342。
The Fe that the present invention provides5C2Nano-particle application in preparing the light thermotherapy probe that bio-imaging guides.The party
In case, described Fe5C2Nano-particle is also to be synthesized by the method described in patent 201210580895.1, and it is special to have this
Feature characterized in profit document.Further, described probe can be by Fe5C2Nano-particle is through DSPE-PEG-NH2After modification,
The affinity ligands of coupling tumor cell specific obtains.
Similarly, described affinity ligand is used for making through DSPE-PEG-NH2The Fe obtained after modification5C2-PEG nano-particle target
To specific tumor cell, those skilled in the art can also be according to the tumor of the light thermotherapy of bio-imaging guiding to be carried out
The type of cell, selects corresponding affinity ligands and through DSPE-PEG-NH2The Fe obtained after modification5C2-PEG nano-particle is even
Connection, thus realize specific tumors tissue is carried out the photo-thermal therapy of bio-imaging guiding.Further, described tumor includes ovary
Cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma or the brain cancer etc..Further, described affinity ligands be can with ovarian cancer, breast carcinoma, pulmonary carcinoma,
The part that the tumor marker on hepatocarcinoma or brain cancer cell surface is specific binding.
In a specific embodiment of the present invention, described tumor is ovarian cancer, and described affinity ligands is ZHER2:342。
Present invention also offers a kind of bio-imaging probe, described probe is by Fe5C2Nano-particle is through DSPE-PEG-NH2Repair
Decorations obtain.Further, described probe is by Fe5C2Nano-particle is through DSPE-PEG-NH2After modification, coupling tumor cell specific
Affinity ligands obtain.Further, described tumor includes ovarian cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma or the brain cancer etc..Further
, described affinity ligands is can be with the tumor marker specificity on ovarian cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma or brain cancer cell surface
In conjunction with part.
Present invention also offers the light thermotherapy probe that a kind of bio-imaging guides, described probe is by Fe5C2Nano-particle warp
DSPE-PEG-NH2After modification, the affinity ligands of coupling tumor cell specific obtains.Further, described tumor includes ovary
Cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma or the brain cancer etc..Further, described affinity ligands be can with ovarian cancer, breast carcinoma, pulmonary carcinoma,
The part that the tumor marker on hepatocarcinoma or brain cancer cell surface is specific binding.Further, described tumor is ovarian cancer, institute
Stating affinity ligands is ZHER2:342。
In this article, will be through DSPE-PEG-NH2The Fe modified5C2Nano-particle is referred to as Fe5C2-PEG nano-particle；Will
Coupling affinity ligands ZHER2:342Fe5C2-PEG is referred to as Fe5C2-PEG-ZHER2:342Nano-particle.
The probe that the present invention provides can be dispersed in any normal saline being suitable to clinical practice, and (such as, mass fraction is
The sodium chloride solution of 0.9%) or buffer salt (such as, the PBS of pH=7-9) in, in the way of injection, be applied to machine
Body.
Further, in the light thermotherapy probe that the bio-imaging that the present invention provides guides, the usage amount of affinity ligands can root
According to type or the quantity of tumor cell surface specific marker thing of tumor cell, determined by this area conventional means.Enter one
Step, Fe in the light thermotherapy probe that the bio-imaging that the present invention provides guides5C2Nano-particle is through DSPE-PEG-NH2Degree of modification
As long as can meet and make Fe5C2-PEG-ZHER2:342By the way of injection, enter body swimmingly, and arrive specific tumor portion
Position carries out imaging.
In a specific embodiment of the present invention, at described bio-imaging probe or the light thermotherapy probe that guided by it
In, Fe5C2With DSPE-PEG-NH2Mol ratio be 1:1～5, can be preferably 1:1.3～1.7, more preferably 3:5.Enter
The Fe of one step5C2-PEG-NH2With ZHER2:342Mol ratio can be 100000～1:1, can be preferably 8000～12000:
1, more preferably 10000:1.
In the solution of the present invention, the amount that body is used bio-imaging probe can determine according to imaging requirements；To body
The amount using the light thermotherapy probe that bio-imaging guides can be many according to the type of tumor cell to be treated and tumor cell
Few and to be treated suffer from tumor individual ill stage or age etc. suitably determine.Probe described in the present invention program is (i.e.
Fe5C2-PEG-ZHER2:342Nano-particle or Fe5C2-PEG nano-particle) amount of application to be dispersed in normal saline or buffer salt
The gauge of Fe.
In embodiments of the present invention, the amount that mice is used bio-imaging probe can be 5～15mg/kg Mice Bodies
Weight, preferably 10～15mg/kg Mouse Weight.Use this probe in above-mentioned scope and can obtain good imaging effect.
In yet another embodiment of the present invention, the amount that mice is used the light thermotherapy probe that bio-imaging guides is permissible
It is 17～20mg/kg Mouse Weights, preferably 18～19mg/kg Mouse Weight.Use this probe in above-mentioned scope and carry out light
Thermal therapeutical, can realize the inhibiting tumour cells to mice and killing, and substantially have no side effect.
The bio-imaging probe that the present invention provides, or the light thermotherapy probe guided by it can pass through vein, subcutaneous or flesh
Meat is injected, and is administered body, to carry out bio-imaging, or is suppressed by photo-thermal therapy and killing tumor cell.
In another specific embodiment of the present invention, Fe5C2-PEG nanometer grain preparation method includes: general mole
Than the Fe for 1:1～55C2Nano-particle and DSPE-PEG-NH2It is mixed to get mixed solution in a solvent, by molten for the mixing obtained
Liquid is stirred overnight in protective atmosphere, then removes solvent and obtains this Fe5C2-PEG nano-particle.Further, described solvent can
To be one or more in chloroform, normal hexane, toluene, dichloromethane.Further, can be by DSPE-PEG-NH2Chlorine
Imitative solution is added dropwise to described Fe5C2To realize Fe in the chloroformic solution of-PEG nano-particle5C2Nano-particle and DSPE-
PEG-NH2Mixing in a solvent.Further, stirred overnight temperature controls as room temperature.
In a specific embodiment of the present invention, Fe5C2-PEG nanometer grain preparation method includes 100mg
DSPE-PEG-NH2It is dissolved in the chloroform of 15mL, is added dropwise to containing 25mg Fe5C2Chloroformic solution in.This mixed solution
Being stirred overnight under Ar protects, rotary evaporation removes chloroform.Being disperseed in deionized water by product, dialysis 24h removes unreacted
DSPE-PEG-NH2。
In a specific embodiment of the present invention, Fe5C2-PEG-ZHER2:342The preparation method of nano-particle includes:
Prepare Fe according to the method described above5C2-PEG nano-particle, then by prepared Fe5C2-PEG nano-particle and activated affinity
Part ZHER2:342In the alkaline buffer saline solution of pH7-9 with 100000～1:1 mixed in molar ratio, at room temperature, stir 3-5
Hour, then solid-liquid separation, collect Fe5C2-PEG-ZHER2:342Nano-particle.Further, described affinity ligands ZHER2:342Profit
With 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl) and N-hydroxy thiosuccinimide
(NHS-sulfo) activation.Further, described alkaline buffer saline solution is phosphate solution.
In a specific embodiment of the present invention, Fe5C2-PEG-ZHER2:342The preparation method of nano-particle includes:
By 100 μ L1mM ZHER2:342Solution is dissolved into (PBS, pH=7.4) in 10mL phosphate buffer, adds 30mg1-(3-dimethyl
Aminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl) and 35mg-N-hydroxy thiosuccinimide (NHS-
Sulfo), add 20mg after stir-activating 1h and modify DSPE-PEG-NH2Fe5C2Nano-particle, continues stirring 4h.
20000rpm is centrifuged 15min and collects product Fe5C2-PEG-ZHER2:342Nano-particle, and the 24h unreacted Z of removing that dialysesHER2:342
With EDC HCl, NHS-sulfo.
The present invention program has the advantage that
1) present invention uses Fe5C2Nano-particle carries out bio-imaging probe, or the system of the light thermotherapy probe guided by it
Standby, due to Fe5C2Nano grain surface has one layer of C film protection so that it is not easy oxidized, it is thus possible to make the probe energy of acquisition
Keep stable performance in a long time.
2) Fe that the present invention uses5C2Nano-particle is compared to traditional Fe3O4Nano-particle has higher saturated magnetization strong
Degree so that use its described probe made to have more preferable T2Weighted magnetic resonance performance, simultaneously as carbon-coating is near infrared region
There is stronger light absorpting ability, obtained probe can be made to have than same concentration gold nanorods more preferable light thermotherapy effect and
Photoacoustic imaging effect.
3) it is compared to Precious Metals-Gold, the Fe that the present invention uses5C2The raw material of nano-particle is cheap Fe and C, uses
Fe5C2Nano-particle carries out the preparation of probe, and cost is substantially reduced.
4) the bio-imaging probe of the present invention can obtain and have stable performance by straightforward procedure, passes through further
The affinity ligands of coupling tumor cell specific on probe, can realize the bio-imaging to organism specific part, Jin Erwei
Various tumor diagnosis and treatment means provide the imaging data of tumor locus, assist and control the diagnosis and treatment process of tumor.
5) the light thermotherapy probe that the bio-imaging of the present invention guides, by the parent of coupling tumor cell specific on probe
Close part so that probe specific can be targeted to specific tumors cell, it is achieved the selective killing to specific tumors cell,
The therapeutic effect of tumor can also be understood and control by bio-imaging simultaneously.
6) the light thermotherapy probe that the bio-imaging using the present invention to provide guides carries out photo-thermal therapy, can obtain good swelling
The fragmentation effect of oncocyte, there is not the secondary work such as body weight reduction, Yi Jixin, liver, spleen, lung, renal dysfunction in organism simultaneously
With.
Accompanying drawing explanation
Fig. 1 shows Fe5C2XRD figure (the Fe of nano-particle5C2The line represented), and through DSPE-PEG-NH2Obtain after modification
The Fe obtained5C2XRD figure (the Fe of-PEG nano-particle5C2The line that-PEG represents).
Fig. 2 shows modification DSPE-PEG-NH2Front Fe5C2The magnetization curve (black lines 1) of nano-particle, modification
DSPE-PEG-NH2The Fe of rear acquisition5C2The magnetization curve (red lines 2) of-PEG nano-particle, and modify DSPE-PEG-
NH2The Fe of rear acquisition5C2-PEG nano-particle place 6 months in water after magnetization curve (blue lines 3).
Fig. 3 shows Fe5C2The nuclear magnetic resonance figure of-PEG nano-particle.First behavior Fe in Fig. 35C2-PEG nanometer
The T of grain2Weighted imaging result；The T of the second behavior commercialization ferroso-ferric oxide contrast agent Resovist2Weighted imaging result；3rd, 4
Row the respectively the 1st, the pcolor of 2 row.
Fig. 4 shows Fe5C2-PEG nano-particle and the magnetic resonance transverse relaxation rate of ferroso-ferric oxide contrast agent Resovist
Figure.Red line (lines of red square labelling) and black line (lines of black round dot labelling) are Fe respectively5C2-PEG nano-particle and
The magnetic resonance transverse relaxation rate (r of commercial ferroso-ferric oxide contrast agent Resovist2Value).
Fig. 5 shows Fe5C2-PEG nano-particle heating curve under laser irradiates.
Fig. 6 shows Fe under variable concentrations5C2The photoacoustic imaging figure of-PEG nano-particle.
Fig. 7 shows Fe5C2-PEG-ZHER2:342Nano-particle, Fe5C2-PEG nano-particle is respectively with SK-OV-3 cell altogether
With the T after hatching2Weighted magnetic resonance imaging figure.
Fig. 8 shows after different disposal method processes, the MTT result of the test of SK-OV-3 cell.
Fig. 9 shows after different disposal method processes, the fluoroscopic image of SK-OV-3 cell.Wherein, first it is classified as through PI
Dead cell after dyeing, display redness in white circle, circle is outer does not show redness；Second is classified as after Calcein-AM dyes
Living cells, white circle is outer shows green, does not show green in circle；The 3rd merging figure being classified as first two columns, the outer display of white circle
Green, display redness in circle.The laser intensity of light group is 2W/cm2, wavelength 808nm, laser irradiation time is 3 minutes, irradiates
Scope is within white circle.Length of the scale is 600 μm.
Figure 10 shows the BALB/c mouse tail vein injection Fe of load SK-OV-3 tumor5C2-PEG-ZHER2:342Nanometer
Granule and Fe5C2T before and after-PEG nano-particle2Weighted magnetic resonance imaging figure.Wherein, dotted yellow line is internal is tumor region, color
Color part is the pcolor of corresponding tumor locus.
Figure 11 (a) and Figure 11 (b) shows tail vein injection Fe5C2-PEG-ZHER2:342Optoacoustic before and after nano-particle
Imaging results, Figure 11 (c) and Figure 11 (d) show injection Fe5C2Photoacoustic imaging result before and after-PEG nano-particle, tumor portion
The photoacoustic imaging result of position；Length of the scale is 1mm.
Figure 12 (a)-12 (d) shows the temperature chart with the separate groups of mice tumor locus of temperature thermal imaging systems, wherein
Figure 12 (a) is for only injecting Fe5C2-PEG-ZHER2:342The temperature chart of nano-particle group mice, Figure 12 (b) is intravenous injection Fe5C2-
PEG-ZHER2:342Nano-particle the temperature chart of irradiating laser group mice, Figure 12 (c) is injection Fe5C2-PEG nano-particle also shines
Penetrating the temperature chart of laser group mice, 12 (d) is the temperature chart of only injecting normal saline group mice.
Figure 13 shows the growth curve of mouse tumor after different disposal method processes.
Figure 14 (a)-Figure 14 (e) shows the photo of mice after different disposal method processes 45 days.Figure 14 (a) is that tail is quiet
Arteries and veins injection Fe5C2-PEG-ZHER2:342Nano-particle laser irradiation group mice photo；Figure 14 (b) is tail vein injection Fe5C2-
PEG nano-particle laser irradiation group mice photo；Figure 14 (c) is injecting normal saline laser irradiation group mice photo；Figure
14 (d) is for only injecting Fe5C2-PEG-ZHER2:342Nano-particle group mice photo；Figure 14 (e) is the mice of an injecting normal saline
Photo.The wherein enlarged drawing of part in the second behavior the first row white box.
Figure 15 shows the change of Mouse Weight after different disposal method processes.Error line is the body weight mark of 5 mices
Accurate poor.
Figure 16 shows after different disposal method processes, each H&E coloration result organizing mice main organs.Length of the scale
It is 50 μm.
Figure 17 is Fe5C2The transmission electron microscope picture of nano-particle, shows that it has nucleocapsid structure.
Figure 18 is Fe5C2The high-resolution-ration transmission electric-lens figure of nano-particle.Show the spacing of lattice of its intercalated nucleus part
(0.205nm) and Fe5C2(510) crystal face match, illustrate that its core is Fe5C2。
Figure 19 (a) is Fe5C2The XPS collection of illustrative plates of nano-particle, wherein, Figure 19 (b) figure is blue portion in Figure 19 (a) figure
Enlarged drawing.Figure showing, it has the absworption peak of an obviously C, shows that the surface of granule is one layer of carbon-coating, i.e. described
Nano-particle there is Fe5C2The nucleocapsid structure of@C.
Detailed description of the invention
Various tumor cells, reagent and the laboratory animal used in following embodiment:
The abortion syndrome SK-OV-3 of HER2 high expressed is purchased from Concord Hospital's cell bank.
BALB/c mouse is purchased from Tsing-Hua University's medical experiment animal center, body weight about 18 grams.
18-amine., cetab, Fe (CO)5, ethanol, normal hexane, DSPE-PEG-NH2, chloroform, agarose
Gel, phosphate buffer (PBS, pH=7.4), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC
HCl), N-hydroxy thiosuccinimide (NHS-sulfo), calcein (Calcein-AM), propidium iodide (PI), Lignum Sappan
Essence-according to red, purchased from Sigma, Alfa Aesar company.
Pancreatin, cell culture medium, hyclone, DPBS is purchased from Wei Jie base company.Ferroso-ferric oxide contrast agent, Resovist
Purchased from Beijing 307 hospital.
The probe of the bio-imaging that embodiment 1 present invention provides
1, the preparation process of bio-imaging probe:
1)Fe5C2The synthesis of nano-particle: by the mixture of 18-amine. and cetab at N2Rise under protection
Temperature, to 120 DEG C of dehydrations, is injected 0.5mL and is contained 3.6mmol Fe (CO)5.It is warming up to 180 DEG C, insulation with the speed of 10 DEG C/min
After 10min, it is warming up to 350 DEG C with the speed of 10 DEG C/min, after continuing insulation 10min, is cooled to room temperature.10000rpm is centrifugal to be received
After collection product, the mixed solution of solution with ethanol and normal hexane is washed 3 times, by product Fe5C2Nano-particle is dispersed in normal hexane,
Obtain Fe5C2The hexane solution of nano-particle.Figure 17 shows this Fe5C2The transmission electron microscope picture of nano-particle, shows that it has
Nucleocapsid structure.Figure 18 is Fe5C2The high-resolution-ration transmission electric-lens figure of nano-particle.Show the spacing of lattice of its intercalated nucleus part
(0.205nm) and Fe5C2(510) crystal face match, illustrate that its core is Fe5C2.Figure 19 (a) is Fe5C2The XPS of nano-particle
Collection of illustrative plates, wherein, Figure 19 (b) figure is the enlarged drawing of blue portion in Figure 19 (a) figure.Figure showing, it has one obviously
The absworption peak of C, shows that the surface of granule is one layer of carbon-coating, the most described nano-particle there is Fe5C2The nucleocapsid structure of@C.
2) bio-imaging probe (i.e. Fe5C2-PEG nano-particle) preparation: by amidized for 100mg Polyethylene Glycol phospholipid
(DSPE-PEG-NH2, its No. CAS is 474922-26-4) it is dissolved in the chloroform of 15mL, it is added dropwise to containing 25mg Fe5C2
Chloroformic solution (Fe5C2It is scattered in chloroformic solution after the hexane solution centrifugal segregation normal hexane of nano-particle) in.This mixing is molten
Liquid is stirred overnight under Ar protects, and rotary evaporation removes chloroform.Being disperseed in deionized water by product, dialysis 24h removes the most anti-
The DSPE-PEG-NH answered2, the described probe for photoacoustic imaging can be obtained, described bio-imaging be nuclear magnetic resonance and/or
Photoacoustic imaging.
2, the correlated performance of bio-imaging probe
1)Fe5C2The XRD figure of-PEG nano-particle.
Fig. 1 shows DSPE-PEG-NH2Modify Fe5C2The XRD figure that nano-particle is forward and backward.The Fe obtained after modification5C2-
PEG nano-particle spectrogram can be with the Fe before modifying5C2The characteristic peak of the XRD spectra of nano-particle is corresponding, verifies it further
Crystallization is Fe mutually5C2Nano-particle.
2)Fe5C2The magnetic property of-PEG nano-particle, sees Fig. 2.
The magnetic of material is the strongest (saturation magnetization is the highest), it just can more preferable must be as magnetic resonance contrast agent.Fig. 2 shows
Show DSPE-PEG-NH2Modify Fe5C2The magnetic property that nano-particle is forward and backward, and Fe5C2-PEG nano-particle is stable in water
The figure of property.It can be seen that Fe5C2The saturation magnetization of nano-particle can reach 125emu/g (black lines 1), compares
In conventional Fe3O4(80emu/g), for, there is higher magnetic.Through DSPE-PEG-NH2The Fe obtained is modified on surface5C2-
PEG nano-particle is compared to Fe5C2The saturation magnetization of nano-particle is not changed in (red lines 2) substantially.Owing to having carbon
The protective effect of layer, Fe5C2-PEG nano-particle is not easy oxidized, after housing 6 months in water, and its saturation magnetization
Remain to be maintained at 112emu/g (blue lines 3).Its high stability and high magnetic make it can serve as preferable T2Weighting magnetic
Resonance contrast agent.This result explanation Fe5C2-PEG nano-particle has high stability and high magnetic, is suitable for nuclear magnetic resonance.
3)Fe5C2The nuclear magnetic resonance performance of-PEG nano-particle.
Fig. 3 shows employing 3T clinic nuclear magnetic resonance imaging instrument (Philips) test Fe5C2The magnetic of-PEG nano-particle is altogether
Shake imaging effect: by Fe5C2-PEG nano-particle (Fe concentration is followed successively by 0-0.043mM) is dispersed in containing 1% agarose gel
In water, and it is contained in 1.5mL Ependoff pipe.T2The sequential parameter of weight map picture is: TR=500ms, TE=36.8ms, square
Battle array size (matrix size)=300 × 300, it is seen that scope (FOV)=180 × 180mm2, thickness (slice
Thickness)=3mm, the number of plies (slice)=3.It is compared to the T of commercialization2Magnetic resonance contrast agent Resovist, Fe5C2-PEG
Nano-particle can make signal be even lower (display T2In Fig. 3 of weighted magnetic resonance imaging, image is the most black, illustrates that its radiography is imitated
Fruit is more preferably.In Fig. 3 the 3rd, 4 row be respectively the 1st, the pcolor of 2 row, in pcolor, signal is the lowest, illustrates that contrasting effects is the best).
Fe can be passed through further5C2-PEG nano-particle is horizontal with the magnetic resonance of ferroso-ferric oxide contrast agent Resovist
Relaxation rate comes Fe5C2The nuclear magnetic resonance performance of-PEG nano-particle is evaluated.
T2The efficiency of weighted magnetic resonance contrast agent can pass through its transverse relaxation rate r2Assess, r2Reflect contrast agent shadow
Ring T2Ability.Fig. 4 shows Fe5C2-PEG nano-particle laterally relaxes with the magnetic resonance of ferroso-ferric oxide contrast agent Resovist
Henan rate figure.Fe5C2-PEG nano-particle or the r of ferroso-ferric oxide contrast agent Resovist2Method of testing as follows: by Fe5C2-
PEG nano-particle or Resovist (Fe concentration is followed successively by 0-0.043mM) are dispersed in the water containing 1% agarose gel, and
It is contained in 1.5mL Ependoff pipe.Sequential parameter is: TR=500ms, TE=12,24,36,48,60,72,84,96,108,
120,132,144,156,168,180,192ms, matrix size (matrix size)=300 × 300, it is seen that scope (FOV)=
180×180mm2, thickness (slice thickness)=3mm, the number of plies (slice)=3.Red line in Fig. 4 is Fe5C2-PEG receives
Rice grain magnetic resonance transverse relaxation rate figure, its transverse relaxation rate r2=311.94mM-1s-1, its highly sensitive business in prior art
With ferroso-ferric oxide contrast agent Resovist (r2=173.95mM-1s-1) (black line).
4)Fe5C2The light thermal property of-PEG nano-particle
Fig. 5 shows Fe5C2At laser, (808nm laser, density is 2W/cm to-PEG nano-particle2) irradiate lower intensification song
Line.The test condition of this curve is: by Fe5C2-PEG nano-particle, gold nanorods (Gold nanorods) and commercial four oxidations
Three-iron Resovist is dispersed in water, and wherein, the concentration of Fe or Au is 0.5mM.Irradiating in sample with laser, using thermoelectricity
The even temperature every 5s test solution.As shown in Figure 5.Fe5C2The aqueous dispersions of-PEG nano-particle can make temperature in 6.5min
Rise to 41.6 DEG C, higher than with gold nanorods under concentration (40.4 DEG C) and ferroso-ferric oxide (32.2 DEG C).
5)Fe5C2The photoacoustic imaging performance of-PEG nano-particle
Fe5C2-PEG near infrared region (NIR) photoacoustic imaging mainly by nano-particle near infrared light under energy
Enough producing heat energy, the further adiabatic expansion of this heat energy can produce ultrasound wave and realize.Fig. 6 shows under variable concentrations
Fe5C2The photoacoustic imaging figure of-PEG nano-particle.Will be equipped with variable concentrations Fe5C2The centrifuge tube of-PEG nanoparticles solution floods
In water, and keep it highly consistent.Its differing heights is scanned receiving signal by ultrasonic probe.Obtained signal is being put
Present after big 30 times.
From fig. 6, it can be seen that along with Fe5C2The rising of-PEG concentrations of nanoparticles, the photoacoustic signal of nano-particle gradually increases
By force, even if under the low concentration of 0.3mM, its photoacoustic signal is still it is obvious that illustrate Fe5C2-PEG nano-particle can be used as preferably
Photoacoustic imaging contrast agent.
By above example it can be seen that the bio-imaging probe that the present invention provides can realize the biology to tumor tissues
Imaging, and then be that various tumor diagnosis and treatment means (chemotherapy of such as tumor, radiotherapy, excision and light thermotherapy etc.) provide swollen
The imaging data at tumor position, assists and controls the diagnosis and treatment process of tumor.
The light thermotherapy probe that the photoacoustic imaging that embodiment 2 present invention provides guides
1, the preparation process of probe:
Light thermotherapy probe (the i.e. Fe that photoacoustic imaging guides5C2-PEG-ZHER2:342) preparation: by 100 μ L1mM ZHER2:342
Solution is dissolved into (PBS, pH=7.4) in 10mL phosphate buffer, adds 30mg1-(3-dimethylaminopropyl)-3-ethyl carbon
Change diimmonium salt hydrochlorate (EDC HCl) and 35mg N-hydroxy thiosuccinimide (NHS-sulfo), add after stir-activating 1h
Enter 20mg and modify DSPE-PEG-NH2The Fe obtained5C2-PEG nano-particle, continues stirring 4h.20000rpm is centrifuged 15min and receives
Collection product, dialysis 24h removes unreacted ZHER2:342With EDC HCl, NHS-sulfo, described photoacoustic imaging can be obtained and guide
Light thermotherapy probe Fe5C2-PEG-ZHER2:342, described bio-imaging is nuclear magnetic resonance and/or photoacoustic imaging.
2、Fe5C2-PEG-ZHER2:342The correlated performance of probe
1) Vitro Experimental Results
1.1 be connected to targeting proteins ZHER2:342The Fe of rear acquisition5C2-PEG-ZHER2:342Nano-particle Targeting Performance is verified:
Targeting Performance is the T by 1.5T2Weighted Kernel magnetic resonance checking.By Fe5C2-PEG nano-particle and Fe5C2-
PEG-ZHER2:342After nano-particle SK-OV-3 cell with HER2 high expressed respectively hatches 4h jointly, clear with PBS (pH=7.4)
Wash three times.The cell suspending liquid of 1ml will be made into after SK-OV-3 cell trypsinization.Suspension is carried out T2Weighting nuclear-magnetism is altogether
Shake imaging.Its parameter is TR=3000ms, TE=80ms, FOV=210 × 210mm2, slice thickness=2mm.Such as figure
Shown in 7, it is connected to affinity ligand ZHER2:342Fe5C2-PEG-ZHER2:342Nano-particle can more must be gulped down by SK-OV-3 cell
Bite, image will appear as more black, coupling affinity ligand Z is describedHER2:342After, Fe5C2-PEG-ZHER2:342Nano-particle can be special
It is targeted to specific tumors cell to property.
1.2 cellular level checking light thermotherapy effects
By in SK-OV-3 cell kind to 96 orifice plates, cell density is 5 × 103Individual/hole.By cell at 37 DEG C, CO2Concentration is
In the incubator of 5%, overnight incubation makes cell attachment.Cell is divided into 4 groups: group 1 adds Fe5C2-PEG-ZHER2:342Nano-particle is also
According to laser；Group 2 adds Fe5C2-PEG nano-particle also shines laser；Organize 2 and add Fe5C2-PEG-ZHER2:342Nano-particle；Organize 4 photographs
Laser.Wherein, plus nano granule group is all adding after nano-particle 2h, not granule PBS with cytosis is washed three times clear
Wash clean, the laser intensity according to laser group is 2W/cm2, wavelength is 808nm, and light application time is 3 minutes.Test with MTT below
The suppression situation of card cell.
As shown in Figure 8, targeting group Z it is connected toHER2:342Fe5C2-PEG-ZHER2:342Nano-particle, with cytosis
After 2h, laser can the preferable growth that must suppress cell under irradiating.Even if under low concentration (1 μM of Fe), the survival rate of cell also can
Suppression is about 70%.And do not connect the Fe of targeting proteins5C2-PEG nano-particle only has the most in higher concentrations (100 μMs of Fe),
Laser just can have certain inhibitory action after irradiating.Additionally, only apply Fe5C2-PEG-ZHER2:342Nano-particle or only swash
The survival of light irradiating cell does not has obvious inhibitory action.
Use by cell Calcein-AM, PI are redyed further, can also show that photo-thermal is controlled with fluorescence microscope
Treat the inhibitory action for SK-OV-3 cell.Living cells can be coloured to green by calcein (Calcein-AM), and the thinnest
Born of the same parents can not catch color；Dead cell can be dyed redness by propidium iodide (PI), and living cells can not catch color.
By in SK-OV-3 cell kind to 24 orifice plates.At 37 DEG C, CO2Concentration be 5% incubator in cultivate to cell rich
Degree is to start experiment time 80% (as 100% during to cover with bottom culture bottle).Then cell is divided into 5 groups: group 1 applying
Fe5C2-PEG-ZHER2:342Nano-particle also shines laser；Group 2 applying Fe5C2-PEG nano-particle also shines laser；Organize 3 photograph laser；
Organize 4 and apply Fe5C2-PEG-ZHER2:342Nano-particle；Organize 5 matched groups, only apply normal saline.Apply nano-particle group
(Fe5C2-PEG-ZHER2:342Nano-particle or Fe5C2-PEG nano-particle) all after adding nano-particle 2h, will not make with cell
Granule PBS wash three times and clean up.As it is shown in figure 9, be light area in white circle, laser intensity is 2W/cm2, ripple
A length of 808nm, laser irradiation time is 3min.Fe5C2-PEG-ZHER2:342Nano-particle and SK-OV-3 cytosis laser
After irradiation, the cell of laser-irradiated domain is almost the most dead, and does not has the growth of laser-irradiated domain cell the most not by shadow
Ring；Fe5C2After-PEG nano-particle irradiates with cytosis laser, laser-irradiated domain only has fragmentary cell death；Only use
The cell of laser irradiation group and only use Fe5C2-PEG-ZHER2:342The cell of nano-particle cultivation group does not all have obvious cell death.
This result is consistent with MTT result of the test.
2) experimental result in Mice Body
Nuclear magnetic resonance result in 2.1 Mice Bodies:
Mouse model: the BALB/c Mus in 4-6 week inoculates SK-OV-3 cell in forelimb oxter, and inoculum concentration is 107Individual carefully
Born of the same parents/only, every inoculation 0.2ml cell suspension (being dispersed in serum-free medium).Treat that mouse tumor grows to 100-150mm3After
Test.
Taking two tumor sizes is 100-150mm3BALB/c Mus, with 1% pentobarbital sodium anesthesia.Respectively at 3T magnetic
Prescan is carried out on resonance instrument.Sweep parameter is TR=1200ms, TE=30.2ms, slice thickness=2.5mm.In advance
After scanning, two Mus tail vein injection Fe respectively5C2-PEG-ZHER2:342Nano-particle and Fe5C2-PEG nano-particle.Injection volume
For 10mg Fe kg-1(0.2ml is dispersed in PBS).Within after injection 4h, 24h, 3 day and 7 days, carry out nuclear magnetic resonance respectively.
As shown in Figure 10, Fe has been injected5C2-PEG-ZHER2:342Nano-particle is than injection Fe5C2The image of-PEG nano-particle
Darker, the pcolor of its tumor locus also has higher low signal, and more Fe is described5C2-PEG-ZHER2:342Nano-particle energy
Enough pass through ZHER2:342Effect be targeted to tumor locus, and this targeting can pass through T2Weighted magnetic resonance imaging detects, i.e.
Fe5C2-PEG-ZHER2:342Nano-particle can be used for the T of SK-OV-3 tumor model2Weighted magnetic resonance imaging detects.Meanwhile, injection
Rear 24h, the signal at mouse tumor position is minimum, and when 24h is described, most nano-particle can reach tumor locus.Therefore follow-up
In experiment, can be selected for 24h and carry out photoacoustic imaging and photo-thermal therapy.
It can be seen that under the auxiliary of nuclear magnetic resonance, it may be determined that body is used Fe5C2-PEG-ZHER2:342Nanometer
After granule, carry out the Best Times of photoacoustic imaging and photo-thermal therapy, tumor photo-thermal therapeutic scheme can be optimized further.
2.2 photoacoustic imaging result in Mice Body
Mouse model: the BALB/c Mus in 4-6 week inoculates SK-OV-3 cell on the right side of back, and inoculum concentration is 107Individual carefully
Born of the same parents/only, every inoculation 0.2ml cell suspension (being dispersed in serum-free medium).Treat that mouse tumor grows to 100-150mm3After
Test.
Taking two tumor sizes is 100-150mm3BALB/c Mus, anaesthetize by gas anesthesia system, and to tumor locus
At injection Fe5C2-PEG-ZHER2:342Nano-particle and Fe5C2Photoacoustic imaging is carried out, by obtained signal before-PEG nano-particle
Amplify 40 times respectively, as shown in Figure 11 (a) and Figure 11 (c).Then to two Mus tail vein injection Fe respectively5C2-PEG-
ZHER2:342Nano-particle and Fe5C2-PEG nano-particle.Injection volume is 10mg Fe kg-1(0.2ml is dispersed in PBS), injection
Rear 24h carries out, shown in photoacoustic imaging, result such as Figure 11 (b) and Figure 11 (d), injecting Fe the most again5C2-PEG-ZHER2:342Nanometer
The mice of granule, its tumor locus photoacoustic signal is apparently higher than injecting Fe5C2-PEG nano-particle group, further illustrates Fe5C2-
PEG-ZHER2:342Nano-particle can pass through ZHER2:342With the specific binding tumor locus that is targeted to of tumor, and this spy
The opposite sex can be detected by photoacoustic imaging, i.e. Fe5C2-PEG-ZHER2:342Nano-particle can be used for the optoacoustic of SK-OV-3 tumor model
Image checking.
Checking light thermotherapy effect in 2.3 Mice Bodies
Mouse model: the BALB/c Mus in 4-6 week inoculates SK-OV-3 cell on the right side of back, and inoculum concentration is 107Individual carefully
Born of the same parents/only, every inoculation 0.2ml cell suspension (being dispersed in serum-free medium).Treat that mouse tumor grows to 100-150mm3After
Test.
Taking four tumor sizes is 100-150mm3BALB/c Mus, with 1% pentobarbital sodium anesthesia, and use temperature respectively
The temperature of thermal imaging systems tumor locus.To four Mus tail vein injection Fe respectively5C2-PEG-ZHER2:342Nano-particle also irradiates
Laser；Injection Fe5C2-PEG-ZHER2:342Nano-particle；Injection Fe5C2-PEG nano-particle irradiating laser；And only inject life
Reason saline.Injecting after being dispersed in PBS respectively by each nano-particle, the injection volume of each nano-particle is calculated as with the content of Fe
18mg Fe kg-1(PBS solution of 0.2ml).
Respectively with the laser (2W/cm that wavelength is 808nm after injection 24h2) irradiate after 2 minutes, again use temperature thermal imaging system
The temperature of test tumor locus.Injection Fe5C2-PEG-ZHER2:342Nano-particle irradiating laser group (Figure 12 (b)) are compared to not having
The temperature having the tumor locus of irradiating laser group (Figure 12 (a)) can significantly raise (reaching 46.61 DEG C), and injects Fe5C2-
The rising (reaching 34.27 DEG C) the most slightly of the temperature of the tumor locus of PEG nano-particle irradiating laser group (Figure 12 (c)),
Injecting normal saline group (Figure 12 (d)) can only rise to 31.46 DEG C.Fe is described5C2-PEG-ZHER2:342Nano-particle can target
To tumor locus, heat up under the irradiation of near infrared light, can be used for light thermotherapy.
2.4 smooth full-boiled process make tumor locus temperature rise, and may be used for neoplastic fevers and melt.
Mouse model: the BALB/c mouse in 4-6 week inoculates SK-OV-3 cell on the right side of back, and inoculum concentration is 107Individual carefully
Born of the same parents/only, every inoculation 0.2ml cell suspension (being dispersed in serum-free medium).Treat that mouse tumor grows to 100-150mm3After
Test.
Taking 25 tumor sizes is 100-150mm3BALB/c mouse, be randomly divided into 5 groups, often group 5.Use slide gauge
Measure the long-neck of tumor and short neck.Tumor size equation below calculates: V=ab2/ 2, wherein, a is tumor long-neck, and b is tumor
Short neck.5 groups are respectively as follows: group 1 tail vein injection Fe5C2-PEG-ZHER2:342Nano-particle laser irradiate, and organize 2 tail vein injections
Fe5C2-PEG nano-particle laser irradiate, and organize 3 and carry out laser irradiation, organize 4 and carry out tail vein injection Fe5C2-PEG-
ZHER2:342Nano-particle, organizes 5 and carries out tail vein injection saline, and wherein, the injection volume of group 1,2,4 nano-particle is 18mg
Fe kg-1(0.2ml is dispersed in PBS).After 24h, 1,2,3 group irradiates 3min with the laser that wavelength is 808nm respectively, and laser is strong
Degree is 2W/cm2, all after carrying out injection treatment, 24h carries out laser irradiation.Physiological saline amount is 0.2ml.Hereafter, every
The size of 3 days test tumors.
After the process of different disposal method, the growth curve of mouse tumor as shown in figure 13, injects Fe5C2-PEG-ZHER2:342Receive
Rice grain laser irradiation group mouse tumor were obviously reduced in 3 days, melted completely after 6 days, and not recurrence in 45 days.And
Injection Fe5C2-PEG nano-particle also occurred certain suppression with laser irradiation group mouse tumor at first 6 days, but the slowest
Growth.There is not significantly suppression in the tumor of other three groups of mices, illustrates to be targeted to the Fe of tumor5C2-PEG-ZHER2:342
Nano-particle preferable can must treat SK-OV-3 tumor under the irradiation of laser.
The result of Figure 13 further can be by Figure 14 (a)-Figure 14 (e) mice after different disposal method processes 45 days
Photo confirms.Figure 14 (a) is tail vein injection Fe5C2-PEG-ZHER2:342Nano-particle laser irradiation group mice photo；Figure 14
B () is tail vein injection Fe5C2-PEG nano-particle laser irradiation group mice photo；Figure 14 (c) is injecting normal saline and swashs
Light irradiation group mice photo；Figure 14 (d) is for only injecting Fe5C2-PEG-ZHER2:342Nano-particle group mice photo；Figure 14 (e) is
The mice photo of injecting normal saline.The wherein enlarged drawing of part in the second behavior the first row white box.
2.5Fe5C2-PEG-ZHER2:342The toxic and side effects checking of nano-particle:
The body weight of test mice when measuring tumor size every 3 days.As shown in figure 15, in 2.4 5 groups through Different treatments
After process, the difference of Mouse Weight change is little.Only Fe5C2-PEG-ZHER2:342Nano-particle group laser irradiation group are being opened most
Several days body weight that begin have declined, and the weight declined is close with the quality of tumor.Meanwhile, after the 6th day, body weight has again substantially
Recovery, this time point being completely eliminated with tumor is the most consistent.Illustrate to utilize Fe5C2-PEG-ZHER2:342Mice is carried out photo-thermal
Treatment process toxic and side effects is little.
It addition, also 5 groups of mices in 2.4, after Different treatments processes 45 days, are often organized and take a sacrifice.Take
The heart, liver, spleen, lung, kidney do hematoxylin-dye according to red (H&E).As shown in figure 16, the dyeing of these internal organs in various processing modes
Result does not has too big difference, illustrates this to utilize Fe5C2-PEG-ZHER2:342Tumor is carried out by nano-particle as light thermotherapy probe
Photo-thermal therapy, to these major organs almost without side effect.
Claims (3)
1.Fe5C2Nano-particle application in preparing the light thermotherapy probe that photoacoustic imaging guides.
Application the most according to claim 1, described probe is by Fe5C2Nano-particle is through DSPE-PEG-NH2After modification, coupling
Affinity ligands Z of tumor cell specificHER2:342Obtain.
3. the light thermotherapy probe that photoacoustic imaging guides, described probe is by Fe5C2Nano-particle is through DSPE-PEG-NH2Modify
After, affinity ligands Z of coupling tumor cell specificHER2:342Obtain.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410309193.9A CN104127887B (en) | 2014-03-14 | 2014-07-01 | Fe5c2nano-particle application in preparing bio-imaging probe |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410096506.7 | 2014-03-14 | ||
| CN201410096506 | 2014-03-14 | ||
| CN2014100965067 | 2014-03-14 | ||
| CN201410309193.9A CN104127887B (en) | 2014-03-14 | 2014-07-01 | Fe5c2nano-particle application in preparing bio-imaging probe |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104127887A CN104127887A (en) | 2014-11-05 |
| CN104127887B true CN104127887B (en) | 2016-08-31 |
Family
ID=51800906
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410309193.9A Active CN104127887B (en) | 2014-03-14 | 2014-07-01 | Fe5c2nano-particle application in preparing bio-imaging probe |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104127887B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107596387B (en) * | 2017-08-24 | 2020-04-03 | 北京大学 | Gold/iron carbide heterogeneous nano-particles and preparation and application thereof |
| CN109781871B (en) * | 2018-12-05 | 2021-11-19 | 北京农业质量标准与检测技术研究中心 | Aflatoxin B1And B2Magnetic solid phase extraction material, preparation method and application |
| CN111134894B (en) * | 2020-01-17 | 2022-02-22 | 上海长海医院 | Sampling method for in vivo determination of continuous dynamic free drug concentration of canine prostate tissue |
-
2014
- 2014-07-01 CN CN201410309193.9A patent/CN104127887B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Fe5C2 Nanoparticles with High MRI Contrast Enhancement for Tumor Imaging;Wei Tang et al.;《small》;20131218;第10卷(第7期);第1245–1249页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104127887A (en) | 2014-11-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Bao et al. | Multifunctional Hf/Mn-TCPP metal-organic framework nanoparticles for triple-modality imaging-guided PTT/RT synergistic cancer therapy | |
| CN106267241B (en) | The multi-functional multi-modal fluorescent dye with tumour-specific targeting inversion of phases nanosphere photoacoustic contrast agent of one kind and its application | |
| CN103623437B (en) | A kind of imaging nano-probe material and its preparation method and application | |
| CN109776380A (en) | It is applied in the bis- targeting near infrared fluorescent probe preparations of IR780 and tumour diagnosis and treatment | |
| CN108704134A (en) | A kind of targeting multifunctional nano grain containing IR780, using and preparation method thereof | |
| Chen et al. | Tumor reoxygenation for enhanced combination of radiation therapy and microwave thermal therapy using oxygen generation in situ by CuO nanosuperparticles under microwave irradiation | |
| CN104548095B (en) | A kind of PLGA/MoS2Composite medicament stent material and its preparation method and application | |
| CN108219782A (en) | Near-infrared fluorescent probe, multi-modal nano contrast agent based on probe, preparation and application thereof | |
| CN107551279A (en) | Extra small albumen composite nano-granule near infrared light fuel factor and multi-modality imaging function and its preparation method and application | |
| CN105106958B (en) | Copper-based human serum albumin nano-complex near infrared light fuel factor and its preparation method and application | |
| CN104127887B (en) | Fe5c2nano-particle application in preparing bio-imaging probe | |
| CN105906822A (en) | Preparation method and application of polylactic acid-glycolic acid copolymer coated by manganese dioxide layer | |
| CN104288786B (en) | Tumor targeted diagnosing and treating system based on near-infrared quantum dot and preparation method thereof | |
| CN104258391B (en) | A kind of multi-functional stimulation sensitive polymer-nanometer gold cage carrier and preparation method thereof | |
| CN106139160A (en) | The maytansine prodrug of hyaluronic acid derivatization, its preparation method and the application in preparing neoplasm targeted therapy medicine | |
| CN110893237A (en) | Application of copper-palladium alloy nanoparticles and autophagy inhibitor in preparation of medicine or kit for killing tumors based on photothermal effect | |
| CN106668859B (en) | A kind of photosensitive drug and preparation method thereof to faint photaesthesia | |
| CN106581683B (en) | A kind of polyethyleneglycol modified metal organic nano material and preparation method thereof, application | |
| CN103539799B (en) | A kind of water soluble amino poly carboxylic acid modifies preparation method and the purposes of phthalocyanine compound | |
| CN108264514A (en) | A kind of organic matter and its preparation method and application | |
| CN108434121B (en) | A kind of bilayer core-shell structure molecular vehicle | |
| Li et al. | Ultrasound and laser-promoted dual-gas nano-generator for combined photothermal and immune tumor therapy | |
| CN105999262A (en) | Nanometer drug carrier (bevacizumab medicated-SiO2@LDH (sodium dioxide @ double hydroxide)) with active tumor targeting function, preparation method and application | |
| CN110559453B (en) | Magnetic nano-particles for imaging guidance and preparation method thereof | |
| CN108653732A (en) | PH response type ferriferrous oxide nano grains and the preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |