CN104013978B - Polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent and its preparation method and application - Google Patents
Polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent and its preparation method and application Download PDFInfo
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- CN104013978B CN104013978B CN201410274326.3A CN201410274326A CN104013978B CN 104013978 B CN104013978 B CN 104013978B CN 201410274326 A CN201410274326 A CN 201410274326A CN 104013978 B CN104013978 B CN 104013978B
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Abstract
The invention discloses a kind of polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent and its preparation method and application, wherein, polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent has layer structure, it includes the most successively: FeS layer, trioctylphosphine oxide layer, octylame polypropylene acid layer, PAH layer, polypropylene acid layer, and polypropylene acid layer surface is modified with six amino branched chair polymacrogols.The diagnosis and treatment agent of the present invention can have the highest enriching quantity at tumor locus by delay and the osmosis of tumor, carries out photo-thermal therapy the most again, and effect is notable, other position will not be caused damage, non-relapse after healing, and compared with prior art effect is notable.Additionally, it can carry out early diagnosis by nuclear magnetic resonance to cancer, can monitor in real time in the magnetic resonance radiography after healing simultaneously, rational treatment plan can be provided in conjunction with real-time monitoring result, can be widely used in clinical conditions technology.
Description
Technical field
The present invention relates to field of medicaments, particularly relate to a kind of polyethyleneglycol modified Iron sulfuret. magnetic Nano and examine
Treat agent and preparation method thereof, and its tumor photo-thermal treatment under preparing medical imaging reagent and imaging guidance
Application in medicine.
Background technology
Cancer has become as 21st century affects that human body is healthy and the maximum killer of life.The tool U.S. is
New investigation report shows, the cases of cancer being newly diagnosed to be for 2011 is about 1,529,960 examples, about
569,490 Americans die from cancer, death toll average every day 1, people more than 500.Malignant tumor has become threat
Human health and No.1 " killer " of life.
Now, the treatment means of cancer mainly include operation, chemotherapy and radiation, but each therapeutic modality
There is its limitation: operation is often difficult to, by fully erased for internal all of cancerous cell, especially send out at cancerous cell
More difficult in the case of raw transfer；Chemotherapy and radiation is all to cancerous cell and normal cell indistinction or difference
Kill the biglyyest, there is the biggest toxic and side effects, and the Drug resistance of cancerous cell may be induced.
Meanwhile, in traditional clinical is applied, the diagnosis of cancer and treatment are two relatively independent processes,
In this case, the best period of cancer diagnosis and treatment can be delayed in the time waiting diagnostic result.Moreover diagnosis is used
Medicine and medicine for treatment are also that two kinds of independent medicines all have certain side effect to patient.In recent years, control
Treatment diagnostics (Theranostics), as a kind of new theory, gradually grows up.
Diagnosis and two processes for the treatment of are united two into one, while obtaining diagnostic result, by treatment diagnostics
Cancer is treated through starting, so can be played good therapeutic effect for some cancers in early days.
This reagent for treating diagnostics is commonly called treatment diagnostic preparation (Theranostic Agent).In recent years,
The exploitation for treatment diagnostic agent that develops rapidly of nanotechnology provides brand-new condition.Utilize nano material
Controlledly synthesis and surface are modified, and can obtain having diagnosis and the nano material for the treatment of dual-use function.
At present, in imaging pattern used clinically, nuclear magnetic resonance is as a kind of AT imaging mould
Formula is applied to clinical diagnosis widely, and its advantage includes the whole body shadow that can provide fine definition and sensitivity
Ringing, on the other hand, nuclear magnetic resonance is the safest a kind of imaging mould relative to CT and radio nuclide imaging
Formula, will cause any ionizing radiation to affect on patient.In recent years, a lot of seminar are by various light
Absorb nano material and magnetic nanoparticle compound structure multifunctional composite, it is achieved nuclear magnetic resonance is instructed
Under oncotherapy.
Such as, by preparation Fe3O4@Cu2-xS nano-complex, uses it for tumor nuclear magnetic resonance and instructs
Under photo-thermal therapy；By preparation Fe5C2@C nano complex, thus achieve nuclear magnetic resonance equally and refer to
Oncotherapy under leading.But, the synthesis of these function and service things includes that multiple step and needs carefully control
The synthesis of nano material, on the other hand, different component metabolism in vivo and degradation pathway are also different.
Therefore, existing exploitation has imaging and treatment several functions still suffers from the technology of the nanometer diagnosis and treatment agent of one
Many not enough.
At present, ferroferric oxide nano granules is modified through suitable surface and is had become as the safest clinic
T2 magnetic resonance contrast agent, it can be used for the diagnosis of disease.But the contrast agent of these clinical approvals is only to make
For magnetic resonance contrast agent for medical diagnosis on disease, not disease therapeuticing effect.Thus cause medical diagnosis on disease and
Treatment is two relatively independent processes, and patient all can be caused certain poison secondary by diagnostic agent and medicine for treatment
Effect.
Summary of the invention
In view of this, the present invention is based on treatment diagnostics, it is provided that a kind of polyethyleneglycol modified Iron sulfuret. magnetic
Property nanometer diagnosis and treatment agent, this diagnosis and treatment agent simultaneously have diagnosis and treatment dual function, the present invention also provides for one
The preparation method of above-mentioned polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent, and it is in preparation medical science
The application in tumor photo-thermal medicine under imaging agents and imaging guidance.
For achieving the above object, a kind of polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent of the present invention,
It has layer structure, and it includes the most successively: FeS layer, trioctylphosphine oxide layer, octylame-
Polypropylene acid layer, PAH layer, polypropylene acid layer, described polypropylene acid layer surface is modified with
Six amino branched chair polymacrogols.
Preferably, the thickness range of described FeS layer is: 30-50nm.
Preferably, described FeS layer has class three-legged structure.
Preferably, the thickness of described polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent is
110-130nm。
For achieving the above object, the offer the most polyethyleneglycol modified a kind of Iron sulfuret. magnetic of the present invention
The preparation method of property nanometer diagnosis and treatment agent, the method comprises the steps:
S1. with Iron sulfuret. nanometer sheet as basal layer, it is coated with trioctylphosphine oxide layer at substrate surface, obtains
Surface is formed with the Iron sulfuret. nanometer sheet of trioctylphosphine oxide layer；
S2. on described trioctylphosphine oxide layer, modify octylame-polypropylene acid layer, obtain electronegative function material
Material A；
S3. in described octylame-polypropylene acid layer, connect PAH, form PAH hydrochloric acid
Salt deposit, obtains positively charged functional material B；
S4. on the PAH layer of described formation, connect polyacrylic acid, form polypropylene acid layer,
Obtain electronegative functional material C；
S5. six amino branched chair polymacrogols are modified on the surface at described functional material C, obtain target product.
Preferably, described step S1 specifically includes:
S11. provide acetylacetone,2,4-pentanedione ferrous, ferrous for acetylacetone,2,4-pentanedione and trioctylphosphine oxide are added in solvent, lazy
Property atmosphere in, in 140 DEG C react 1h remove impurity；
S12. reaction temperature is improved to 220 DEG C of reaction 1h, add the oleyl amine solution dissolved with sulfur powder, react 1h；
S13. cool down after reaction terminates, add precipitant ethanol, be precipitated and wash, obtain surface and be formed
The Iron sulfuret. nanometer sheet solution of trioctylphosphine oxide layer, is dissolved in cyclohexane solution standby.
Preferably, described step S2 specifically includes:
Iron sulfuret. nanometer sheet solution is dried up, and the Iron sulfuret. nanometer sheet after drying up transfers to tetrahydrochysene furan
Mutter in solution, add octylame-polyacrylic acid in described tetrahydrofuran solution, ultrasonic 30min, be stirred overnight,
Utilize nitrogen to dry up, re-use weak caustic solution and dissolve and centrifuge washing, obtain electronegative functional material A.
Preferably, in described step S3, described PAH is by Electrostatic Absorption and is cross-linked with each other
Effect is connected in described octylame-polypropylene acid layer.
Preferably, in described step S4, described polyacrylic acid is connected by Electrostatic Absorption and the effect of being cross-linked with each other
On described PAH layer.
For achieving the above object, the present invention also provides for the sulfuration that a kind of basis is the most polyethyleneglycol modified
Ferrimagnetism nanometer diagnosis and treatment agent application in preparation tumor nuclear magnetic resonance reagent.
For achieving the above object, the present invention also provides for the sulfuration that a kind of basis is the most polyethyleneglycol modified
Application in the photo-thermal therapy medicine of ferrimagnetism nanometer diagnosis and treatment agent cancerous cell under imaging is instructed.
Compared with prior art, the invention has the beneficial effects as follows:
The preparation method of the Iron sulfuret. magnetic Nano diagnosis and treatment agent that synthesizing polyethylene glycol the most of the present invention is modified is simple,
Can be completed by the layer-by-layer between electric charge, the polyethyleneglycol modified Iron sulfuret. magnetic of synthesis
Property nanometer diagnosis and treatment agent tumor photo-thermal therapeutic effect in nuclear magnetic resonance notable, and water solublity is good.
2. the application polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent synthesized by the present invention, by swollen
The delay of tumor and osmosis can have the highest enriching quantity at tumor locus, carry out photo-thermal therapy the most again,
Effect is notable, and other position will not be caused damage, non-relapse after healing, compared with prior art effect
Significantly.
3. the application polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent synthesized by the present invention, passes through magnetic
Resonance image-forming can carry out early diagnosis to cancer, can carry out in real time in the magnetic resonance radiography after healing simultaneously
Monitoring, can provide rational treatment plan in conjunction with real-time monitoring result, can be widely used in clinical diagnosis and control
In treatment technology.
Accompanying drawing explanation
Fig. 1 is the stream of the preparation method of the polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent of the present invention
Journey schematic diagram；
Fig. 2 is the transmission electron microscope picture of the Iron sulfuret. being coated with trioctylphosphine oxide in embodiment；
Fig. 3 is the powder diffraction data of the Iron sulfuret. being coated with trioctylphosphine oxide in embodiment；
Fig. 4 is the Magnetic Characterization data of the Iron sulfuret. being coated with trioctylphosphine oxide in embodiment；
Fig. 5 is that the target product of the synthesis in embodiment is scattered in the stability photo in different physiological solution；
Fig. 6 is the ultraviolet of the ferroso-ferric oxide of the aqueous solution of target product of synthesis in embodiment and same concentration
Abosrption spectrogram；
Fig. 7 (a) be in embodiment synthesis target product magnetic resonance radiography imaging performance test in each concentration
The magnetic resonance radiography imaging of lower target product；
Fig. 7 (b) be the target product of synthesis in embodiment the test of magnetic resonance radiography imaging performance in different dense
The lower T of degree2The curve chart of value；
Fig. 8 be the target product of synthesis in embodiment optical absorption properties test in the target of variable concentrations
Reaction mixture heating curve under laser irradiates；
Fig. 9 be the target product of synthesis in embodiment optical absorption properties test in the target of variable concentrations
Reaction mixture intensification photo under laser irradiates；
Figure 10 is that in embodiment, the near infrared imaging of the target product of synthesis carries out light to mice in testing
Near infrared imaging photo during thermal therapeutical；
Figure 11 be the target product of synthesis in embodiment near infrared imaging test in the tumor of matched group
The micrograph of tissue slice；
Figure 12 be in embodiment synthesis target product near infrared imaging test in inject target product
The micrograph of the tumor tissue section of group；
Figure 13 be in embodiment synthesis target product magnetic resonance radiography imaging test in matched group and
Nuclear magnetic resonance photo in the Mice Body of injection target product solution, wherein, photo is arranged above mouse tumor
Radiography, lower section is Mouse Liver radiography.
Figure 14 (a) be in embodiment synthesis target product magnetic resonance radiography imaging test in matched group
The tumor biopsy of mice micrograph after Prussian blue dyes；
Figure 14 (b) is the magnetic resonance radiography imaging test injection target of the target product of synthesis in embodiment
The tumor biopsy of product group mice micrograph after Prussian blue dyes；
Figure 15 be the target product of synthesis in embodiment the test of live body photo-thermal therapy in process group and each right
Gross tumor volume according to group mice changes over curve chart；
Figure 16 be in embodiment synthesis target product live body photo-thermal therapy test in process group and each matched group
The survival curve of mice；
Figure 17 be the target product of synthesis in embodiment the test of live body photo-thermal therapy in process group and each right
Take group small mouse dorsal tumors form picture, Figure 17 is respectively as follows: matched group (1), comparison from left to right
Group (3), matched group (2), process group；
Figure 18 is that in embodiment, the bio distribution at vivo long-term of the target product of synthesis is different in testing
The block diagram of iron content in mice major organs under time；
Figure 19 is that in embodiment, the bio distribution at vivo long-term of the target product of synthesis compares in testing
The liver of the mice of group and injection target product group and spleen carry out the microcosmic of prussian blue staining after making tissue slice
Photo；
Figure 20 (a) be in embodiment synthesis target product toxotest in matched group and injection target product
Glutamate pyruvate transaminase content in group Mice Body, content of alkaline phosphatase, glutamic oxaloacetic transaminase, GOT content are time dependent
Block diagram；
Figure 20 (b) be in embodiment synthesis target product toxotest in matched group and injection target product
The time dependent block diagram of urea nitrogen content in group Mice Body；
Figure 20 (c) be in embodiment synthesis target product toxotest in matched group and injection target product
Albumin and the time dependent block diagram of globulin in group Mice Body；
Figure 20 (d) be in embodiment synthesis target product toxotest in matched group and injection target product
The time dependent block diagram of albumin content in group Mice Body；
Figure 20 (e) be in embodiment synthesis target product toxotest in matched group and injection target product
The time dependent block diagram of leucocyte content in group Mice Body；
Figure 20 (f) be in embodiment synthesis target product toxotest in matched group and injection target product
The time dependent block diagram of content of hemoglobin in group Mice Body；
Figure 20 (g) be in embodiment synthesis target product toxotest in matched group and injection target product
The time dependent block diagram of hematocrit value in group Mice Body；
Figure 20 (h) be in embodiment synthesis target product toxotest in matched group and injection target product
The time dependent block diagram of platelet content in group Mice Body；
Figure 20 (i) be in embodiment synthesis target product toxotest in matched group and injection target product
The time dependent block diagram of red blood cell content in group Mice Body；
Figure 20 (j) be in embodiment synthesis target product toxotest in matched group and injection target product
The time dependent block diagram of hemoglobin average content in erythrocyte in group Mice Body；
Figure 20 (k) be in embodiment synthesis target product toxotest in matched group and injection target product
The time dependent block diagram of mean corpuscular volume in group Mice Body；
Figure 20 (l) be in embodiment synthesis target product toxotest in matched group and injection target product
The time dependent block diagram of erythrocyte mean concentration in group Mice Body；
Figure 21 is to utilize matched group and injection target product in embodiment in the toxotest of the target product of synthesis
The time dependent micrograph of tissue slice that in the Mice Body of group, major organs makes.
Detailed description of the invention
Technical scheme in the embodiment of the present invention will be described in detail below, it is clear that described reality
Executing example is only a part of embodiment of the present invention rather than whole embodiments.Based on the enforcement in the present invention
Example, the every other reality that those of ordinary skill in the art are obtained on the premise of not making creative work
Execute example, broadly fall into the scope of protection of the invention.
The polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent (hereinafter referred to as " diagnosis and treatment agent ") of the present invention
Having layer structure, it includes the most successively: FeS layer, trioctylphosphine oxide layer, octylame-poly-
Acrylate layer, PAH layer, polypropylene acid layer, described polypropylene acid layer surface is modified with six
Amino branched chair polymacrogol.Formed by the active force LBL self-assembly of electric charge between above layers.
Specifically, diagnosis and treatment agent, with FeS layer as substrate, this substrate is coated with trioctylphosphine oxide layer,
Octylame-polypropylene acid layer is modified on trioctylphosphine oxide layer by hydrophobic forces.Further, polyene third
Base amine hydrochlorate layer is connected in described octylame-polypropylene acid layer by Electrostatic Absorption and the effect of being cross-linked with each other, poly-
Acrylate layer is connected on described PAH layer with Electrostatic Absorption and the effect of being cross-linked with each other equally.
Described diagnosis and treatment agent has superpower magnetic resonance radiography effect and the strong absorption near infrared region, Ke Yiyong
Photo-thermal therapy in tumor.Thus, the tumor photo-thermal that available same nano-particle completes under imaging is instructed is controlled
Treat, it is to avoid the dual toxic and side effects that two kinds of medicines of imaging and two processes for the treatment of bring to patient.
The size range of described FeS layer is: 30-50nm, and this FeS layer has class three-legged structure.
The size of described polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent is 110-130nm, and this size is preferred
For 120mm.The particle diameter of the diagnosis and treatment agent of the present invention is 100～120nm.
Described polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent simultaneously have diagnosis and treatment dual
Effect, the character of polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent based on the present invention.The present invention
Also propose a kind of preparing medical imaging according to described polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent
Application in reagent.Specifically, this medical imaging reagent is the contrast agent in tumor mr imaging technique.
Meanwhile, the present invention also proposes a kind of according to described polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment
Application in the photo-thermal therapy medicine of agent cancerous cell under imaging is instructed.
As it is shown in figure 1, the preparation side of the polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent of the present invention
Method comprises the steps:
S1. with Iron sulfuret. nanometer sheet as basal layer, it is coated with trioctylphosphine oxide layer at substrate surface, obtains
Surface is formed with the Iron sulfuret. nanometer sheet of trioctylphosphine oxide layer；
S2. on described trioctylphosphine oxide layer, modify octylame-polypropylene acid layer, obtain electronegative function material
Material A；
S3. in described octylame-polypropylene acid layer, connect PAH, form polyallyl amine salt
Silicate layer, obtains positively charged functional material B；
S4. on the PAH layer of described formation, connect polyacrylic acid, form polypropylene acid layer,
Obtain electronegative functional material C；
S5. six amino branched chair polymacrogols are modified on the surface at described functional material C, obtain target product.
Wherein, described step S1 specifically includes:
S11. provide acetylacetone,2,4-pentanedione ferrous, ferrous for acetylacetone,2,4-pentanedione and trioctylphosphine oxide are added in solvent, lazy
Property atmosphere in, in 140 DEG C react 1h remove impurity；
S12. reaction temperature is improved to 220 DEG C of reaction 1h, add the oleyl amine solution dissolved with sulfur powder, react 1h；
S13. cool down after reaction terminates, add precipitant ethanol, be precipitated and wash, obtain surface and be formed
The Iron sulfuret. nanometer sheet solution of trioctylphosphine oxide layer, is dissolved in cyclohexane solution standby.
Described step S2 specifically includes:
Iron sulfuret. nanometer sheet solution is dried up, and the Iron sulfuret. nanometer sheet after drying up transfers to tetrahydrochysene furan
Mutter in solution, add octylame-polyacrylic acid in described tetrahydrofuran solution, ultrasonic 30min, be stirred overnight,
Utilize nitrogen to dry up, re-use weak caustic solution and dissolve and centrifuge washing, obtain electronegative functional material A.
In described step S3, described PAH is connected by Electrostatic Absorption and the effect of being cross-linked with each other
In described octylame-polypropylene acid layer.
In described step S4, described polyacrylic acid is connected to described poly-by Electrostatic Absorption and the effect of being cross-linked with each other
On allylamine hydrochloride layer.
Below in conjunction with specific embodiment, diagnosis and treatment agent of the present invention and preparation method thereof is illustrated.
Embodiment
In 50ml three-neck flask, the acetylacetone,2,4-pentanedione adding 0.39mmol is ferrous pungent with the three of 0.78mmol
Base phosphorous oxide, adds 10ml oleyl amine.Under the protective effect of nitrogen, it is first to heat to 140 DEG C and maintains 30min,
The most slowly it is warmed up to 220 DEG C of reaction 1h.
Then quickly will inject in reactant liquor dissolved with the 5ml oleyl amine of 3.125mmol sulfur powder, then at 220 DEG C
Reaction 1h.After reaction terminates, wash four times with hexamethylene and alcohol mixed solution, be finally dispersed in 5ml ring
In hexane, obtain the cyclohexane solution of Iron sulfuret. nanometer sheet.
Below the Iron sulfuret. of synthesis is characterized.
As in figure 2 it is shown, the transmission electron microscope picture of the Iron sulfuret. that it is synthesis, can be seen that from this picture
Iron sulfuret. Surface coating has a substantial amounts of trioctylphosphine oxide layer, and formed be coated with trioctylphosphine oxide layer
A diameter of 30-50nm of Iron sulfuret..
As shown in Figure 3,4, Fig. 3 is the powder diffraction data of the Iron sulfuret. of synthesis, and Fig. 4 is the sulfur of synthesis
Change ferrous Magnetic Characterization data.From the figure 3, it may be seen that the material carrying out characterizing is Iron sulfuret..
Iron sulfuret. nanometer sheet is dispersed in oxolane, is subsequently adding the octylame-polypropylene from synthesis
The ultrasonic 30min of acid, is then stirred overnight.Dry up with nitrogen, be dissolved in water, centrifugal segregation many
Remaining octylame-polyacrylic acid.
Then the PAH of positive charge is added, pungent with Iron sulfuret. nanometer sheet surface
Amine-polyacrylic acid carries out Electrostatic Absorption and crosslinking, makes Iron sulfuret. nanometer sheet surface with the strongest just
Electric charge.Add polyacrylic acid to cross-link with PAH, make Iron sulfuret. nanometer sheet surface
With negative charge, now six amino branched chair polymacrogols will be covalently attached to Iron sulfuret. nanometer sheet table
Face so that it is there is good biocompatibility, thus obtain target product.
As it is shown in figure 5, the target product for the synthesis in embodiment is scattered in stablizing in different physiological solution
Property photo.In Fig. 5, from left to right, the physiological solution used is followed successively by water, normal saline, cell training
Nutrient solution, serum.As shown in Figure 5, target product has good water solublity in aqueous, is giving birth to
In reason saline or in serum, the most also there is good water solublity and stability.
As shown in Figure 6, three are aoxidized for the aqueous solution of the target product of synthesis in embodiment and the four of same concentration
The uv absorption spectra of ferrum.It will be appreciated from fig. 6 that target product has the strongest optical absorption properties, can
To be applied in photo-thermal therapy.
Below the magnetic resonance radiography imaging performance of the target product in embodiment is tested.
Target product is diluted to different Concentraton gradient the most successively, and this Concentraton gradient is successively
For: 0.008mM, 0.016mM, 0.032mM, 0.065mM and 0.13mM.At magnetic
On resonance imaging system, (Bruker) tests its magnetic resonance radiography imaging performance.
As described in Fig. 7 (a), 7 (b), Fig. 7 (a) is the magnetic resonance of target product under above-mentioned gradient concentration
Contrast imaging, 7 (b) is T under variable concentrations in magnetic resonance radiography imaging2The curve chart of value.
From Fig. 7 (a), 7 (b), by measuring its T2Value, this T2It is worth linear change, from
And can serve as magnetic resonance radiography reagent.With existing magnetic resonance contrast agent (such as: ferumoxsil, ferrixan
With ferumoxide) to compare, target product has the strongest magnetic resonance radiography effect and is significantly higher than existing magnetic
Resonance contrast agent, significantly improves sensitivity and the resolution of the Clinics and Practices of cancer.
Below the optical absorption properties of the target product in embodiment is tested.
As shown in Figure 8,9, Fig. 8 is the target product solution of variable concentrations heating curve under laser irradiates,
Fig. 9 is the target product solution of variable concentrations intensification photo under laser irradiates.
Specifically, the target product solution of variable concentrations is placed in 1.5ml centrifuge tube, utilizes 808nm's
(power is 1W/cm to laser2) each centrifuge tube is irradiated, and utilize near infrared imaging camera to supervise
Survey the variations in temperature of solution.The concentration value of above-mentioned variable concentrations is respectively as follows: 0.125mg/ml, 0.25mg/ml,
0.5mg/ml.Meanwhile, when the optical absorption properties carrying out target product is tested, utilize water for comparison
Group contrasts.
From Fig. 8,9, within 5 minutes, the target product of 0.5mg/ml under the irradiation of laser temperature
Degree quickly rises to 70 degree from room temperature 22 degree, and matched group coolant-temperature gage there is no and changes.So
Show that the optical absorption properties that target product is stronger can be as the material of photo-thermal therapy.
Below the target product in embodiment is carried out near infrared imaging test.
Specifically, by target product by tail vein injection to Mice Body, injection dosage is 20mg/kg, note
After penetrating 24h, the same near infrared laser using 808 nanometers irradiates mouse tumor position, and laser power is
1W/cm2, irradiation time is 5 minutes.Meanwhile, when the near infrared imaging carrying out target product is tested,
It is matched group that the mice of target product is not injected in setting.
As shown in Figure 10, Figure 10 be target product near infrared imaging test in mice carried out photo-thermal control
Near infrared imaging photo during treatment, wherein, is arranged above matched group, and lower section is injection target product solution group.
As shown in Figure 10, injection has the mice of target product solution, after laser irradiates, tumor surface
Temperature is significantly increased to 60 degree, and the highest temperature be enough to kill tumor.And the tumor surface of control group mice
Temperature only has faint intensification.
After irradiation, the tumor tissues of matched group and the mice of injection target product is made section.
As shown in Figure 11,12, matched group and injection target product group during respectively near infrared imaging is tested
The micrograph of tumor tissue section.As seen from the figure, the tumor tissues of injection target product group irradiates at laser
After demonstrate significantly damage.
Below the target product in embodiment is carried out magnetic resonance radiography imaging test.
First by the long mouse anesthesia having 4T1 tumor, use and carry out nuclear magnetic resonance on magnetic resonance imaging system
(MRI) as blank, then by target product solution by tail vein injection in Mice Body, time different
Between put the tumor regulating liver-QI position to mice and carry out nuclear magnetic resonance.Meanwhile, target product solution is not injected in setting
Mice be matched group, and make matched group and the tumor biopsy of target product group, and the tumor made cut
Sheet carries out Prussian blue dyeing.
As shown in figure 13, in magnetic resonance radiography imaging test matched group and injection target product solution
Nuclear magnetic resonance photo in Mice Body, wherein, photo is arranged above mouse tumor radiography, and lower section is Mouse Liver
Dirty radiography.As shown in Figure 13, in target product solution injection Mice Body after 48h, tumor locus is significant
Blackening, shows that target product passes through the infiltration of tumor and retention effect (EPR) is significantly gathered in tumor locus.
As shown in Figure 14 (a), (b), the respectively tumor of matched group and injection target product group mice is cut
Sheet micrograph after Prussian blue dyes, is understood be injected in Mice Body by Figure 14 (a), (b)
Target product be mainly gathered in tumor locus.
Below the target product in embodiment is carried out live body photo-thermal therapy test.
Choose 7～10 long mices having 4T1 tumor model, from tail vein injection target product solution, injection
Dosage is 20mg/kg, after injection 24h, is exposed to tumor locus under 808 nanometer lasers irradiate 5min,
Laser power is 1W/cm2.Injection has target product solution and to carry out the mice of laser irradiation be process group.
The other three groups long equally mices (often group 7) having 4T1 tumor model are tested, three as a control group
Group matched group is respectively as follows: (1) and did not enter any process；(2) laser treatment with irradiation is only carried out；(3)
Inject same dose of target product solution, but do not carry out laser treatment with irradiation.Mice is often organized when having processed
Afterwards, the gross tumor volume of mouse back uses slide gauge to measure once every two days.
As seen in figs. 15-17, Figure 15 is that the gross tumor volume of process group and each control group mice changes over song
Line chart；Figure 16 is process group and the survival curve of each control group mice in the test of live body photo-thermal therapy, wherein,
The longitudinal axis represents the percentage ratio of mouse survival, the most often group survival mice quantity/experiment mice sum；Figure 17 is
Process group and each matched group small mouse dorsal tumors form photo.In Figure 17, it is respectively as follows: comparison from left to right
Group (1), matched group (3), matched group (2), process group.
As shown in Figure 15, over time, the gross tumor volume of process group small mouse is not further added by, and each right
Change over according to the gross tumor volume organizing mice and be gradually increased.Thus, the target product of injection has well
Photo-thermal therapy effect.
As shown in Figure 16, process group mice can cross survival 60 days and the most dead, and other control group mice
Died off at about 18 days, thus again show that the target product obtained by above-described embodiment has for tumor
There is good photo-thermal therapy effect, the most do not cause toxicity or the death of mice simultaneously.
As shown in Figure 17, in process group, all of tumor after target product and laser photo-irradiation treatment, two days
Rear all eliminations, stay the cicatricle of next black, and after the week, black cicatricle is all decorporated, and tumor is complete
Disappear.Additionally, other matched group tumor is in constantly growth.When the volume of tumor is more than 1cm3Time, recognize
For death, when 18 days, control group mice was the most dead, and treatment group is the most all survived,
And tumor locus regenerates the most again.
Below target product is tested in bio distribution and the toxicity thereof of vivo long-term.
By target product solution by tail vein injection to Mice Body (dosage of every mice is 100mg/kg,
It is 5 times of therapeutic dose), often group 5.At different time points by sacrifice, take out main dirty
Device, weighs, and with chloroazotic acid and perchloric acid high-temperature digestion, constant volume also measures wherein iron ion by plasma emission
Content, and calculate the iron content in per gram of tissue.
The blood of the mice collecting different time points carries out the blood biochemistry of mice and the mensuration of routine blood indexes.Separately
External different time point takes out main internal organs (liver, spleen, kidney, the heart and lung) and fixes with 4% formaldehyde, cuts
Sheet, and dye by hematoxylin and eosin.Under coming card optical microscope, object observing product is to main internal organs
There is not damaged.
Meanwhile, target product mice is not injected in setting is matched group.
As shown in figure 18, it is the block diagram of iron content in mice major organs under different time, setting time
Between put and respectively inject latter 1 day, inject latter 7 days, inject latter 50 days.As shown in Figure 18, target product
Mainly it is enriched with in liver and spleen.Prolongation over time, target product gradually decreases in each internal organs,
After 50 days, ferrum is down to the value close with matched group in the amount of the enrichment of each organ.Thus, show target
Product can be gone out by slowly metabolism in vivo.
Matched group and the liver of mice of injection target product group and spleen are made tissue slice, carries out Prussian blue
Dyeing display.
As shown in figure 19, it is matched group and the liver of mice of injection target product group and spleen makes tissue slice
After carry out the micrograph of prussian blue staining.It appears from figure 19 that target product is mainly gathered in the liver of mice
With in spleen, prolongation over time, the content of ferrum is gradually dropped to background value.
As shown in Figure 20 (a)-(l), measure change matched group over time and injection target product respectively
In the Mice Body of group, glutamate pyruvate transaminase content, content of alkaline phosphatase, glutamic oxaloacetic transaminase, GOT content, blood urea nitrogen contain
Amount, albumin and globulin, albumin content, leucocyte content, content of hemoglobin, erythrocyte
Hemoglobin average content, erythrocyte average body in specific volume, platelet content, red blood cell content, erythrocyte
Long-pending, erythrocyte mean concentration.
From Figure 20 (a)-(l), injection has the mice of target product solution, in the time of 50 days,
Its indices maintains essentially in normal level, thus target product does not has the liver function to mice and kidney merit
Energy and routine blood test cause obvious toxicity.
Additionally, for the impact on mice major organs of the goal in research product, the solution that target product is formed
It is injected into the internal of multiple healthy mice, and in different time points, the major organs of mice is fabricated to tissue
Section, and dye by hematoxylin and eosin.Above-mentioned different time points be respectively as follows: injection latter 1 day,
Inject latter 7 days, inject latter 50 days.Meanwhile, the mice arranging unimplanted target product solution makees
For matched group.
As shown in figure 21, major organs in it is the Mice Body utilizing matched group and injection target product group
The time dependent micrograph of tissue slice made.Wherein, major organs includes: liver, spleen,
Kidney, heart, lung.
As shown in Figure 21, in the time of 50 days, target product is the brightest to the major organs of mice
Aobvious damage influence.
In sum, the useful effect of the polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent of the present invention
Fruit is:
The preparation method of the Iron sulfuret. magnetic Nano diagnosis and treatment agent that synthesizing polyethylene glycol the most of the present invention is modified is simple,
Can be completed by the layer-by-layer between electric charge, the polyethyleneglycol modified Iron sulfuret. magnetic of synthesis
Property nanometer diagnosis and treatment agent tumor photo-thermal therapeutic effect in nuclear magnetic resonance notable, and water solublity is good.
2. the application polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent synthesized by the present invention, by swollen
The delay of tumor and osmosis can have the highest enriching quantity at tumor locus, carry out photo-thermal therapy the most again,
Effect is notable, and other position will not be caused damage, non-relapse after healing, compared with prior art effect
Significantly.
3. the application polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent synthesized by the present invention, passes through magnetic
Resonance image-forming can carry out early diagnosis to cancer, can carry out in real time in the magnetic resonance radiography after healing simultaneously
Monitoring, can provide rational treatment plan in conjunction with real-time monitoring result, can be widely used in clinical diagnosis and control
In treatment technology.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment,
And without departing from the spirit or essential characteristics of the present invention, it is possible to realize in other specific forms
The present invention.Therefore, no matter from the point of view of which point, embodiment all should be regarded as exemplary, and right and wrong
Restrictive, the scope of the present invention is limited by claims rather than described above, it is intended that will fall
All changes in the implication of equivalency and scope of claim are included in the present invention.
Moreover, it will be appreciated that although this specification is been described by according to embodiment, but the most each enforcement
Mode only comprises an independent technical scheme, and this narrating mode of description is only for clarity sake,
Those skilled in the art should be using description as an entirety, and the technical scheme in each embodiment can also be through
Appropriately combined, form other embodiments that it will be appreciated by those skilled in the art that.
Claims (10)
1. a polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent, it is characterised in that described poly-second
The Iron sulfuret. magnetic Nano diagnosis and treatment agent that glycol is modified has layer structure, and it includes the most successively: sulfur
Change ferrous layer, trioctylphosphine oxide layer, octylame-polypropylene acid layer, PAH layer, polypropylene
Acid layer, described polypropylene acid layer surface is modified with six amino branched chair polymacrogols.
Polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent the most according to claim 1, it is special
Levying and be, described FeS layer has class three-legged structure.
Polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent the most according to claim 1, it is special
Levying and be, the size of described polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent is 110-130nm.
4. the polyethyleneglycol modified Iron sulfuret. magnetic Nano as described in any one of claims 1 to 3 is examined
Treat the preparation method of agent, it is characterised in that described preparation method comprises the steps:
S1. with Iron sulfuret. nanometer sheet as basal layer, it is coated with trioctylphosphine oxide layer at substrate surface, obtains
Surface is formed with the Iron sulfuret. nanometer sheet of trioctylphosphine oxide layer；
S2. on described trioctylphosphine oxide layer, modify octylame-polypropylene acid layer, obtain electronegative function material
Material A；
S3. in described octylame-polypropylene acid layer, connect PAH, form PAH hydrochloric acid
Salt deposit, obtains positively charged functional material B；
S4. on the PAH layer of described formation, connect polyacrylic acid, form polypropylene acid layer,
Obtain electronegative functional material C；
S5. six amino branched chair polymacrogols are modified on the surface at described functional material C, obtain target product.
The preparation of polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent the most according to claim 4
Method, it is characterised in that described step S1 specifically includes:
S11. provide acetylacetone,2,4-pentanedione ferrous, ferrous for acetylacetone,2,4-pentanedione and trioctylphosphine oxide are added in solvent, lazy
Property atmosphere in, in 140 DEG C react 1h, remove impurity；
S12. reaction temperature is improved to 220 DEG C of reaction 1h, add the oleyl amine solution dissolved with sulfur powder, react 1h；
S13. cool down after reaction terminates, add precipitant ethanol, be precipitated and wash, obtain surface and be formed
The Iron sulfuret. nanometer sheet solution of trioctylphosphine oxide layer, is dissolved in cyclohexane solution standby.
The preparation of polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent the most according to claim 5
Method, it is characterised in that described step S2 specifically includes:
Iron sulfuret. nanometer sheet solution is dried up, and the Iron sulfuret. nanometer sheet after drying up transfers to tetrahydrochysene furan
Mutter in solution, add octylame-polyacrylic acid in described tetrahydrofuran solution, ultrasonic 30min, be stirred overnight,
Utilize nitrogen to dry up, re-use weak caustic solution and dissolve and centrifuge washing, obtain electronegative functional material A.
The preparation of polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent the most according to claim 4
Method, it is characterised in that in described step S3, described PAH passes through Electrostatic Absorption and phase
Crosslinked action is connected in described octylame-polypropylene acid layer mutually.
The preparation of polyethyleneglycol modified Iron sulfuret. magnetic Nano diagnosis and treatment agent the most according to claim 4
Method, it is characterised in that in described step S4, described polyacrylic acid is by Electrostatic Absorption and the work that is cross-linked with each other
With being connected on described PAH layer.
9. one kind according to the polyethyleneglycol modified Iron sulfuret. magnetic Nano described in any one of claims 1 to 3
Diagnosis and treatment agent application in preparation tumor nuclear magnetic resonance reagent.
10. receive according to the polyethyleneglycol modified Iron sulfuret. magnetic described in any one of claims 1 to 3 for one kind
Rice diagnosis and treatment agent is being prepared as the application in the photo-thermal therapy medicine of the cancerous cell under guidance.
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