CN109453395A - Overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe and its preparation method and application - Google Patents
Overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe and its preparation method and application Download PDFInfo
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- CN109453395A CN109453395A CN201811504382.6A CN201811504382A CN109453395A CN 109453395 A CN109453395 A CN 109453395A CN 201811504382 A CN201811504382 A CN 201811504382A CN 109453395 A CN109453395 A CN 109453395A
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Abstract
The present invention relates to a kind of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probes and its preparation method and application, which includes: the magnetic nano-particle for being enclosed with polyethylene glycol PEG and the CaCO mixed with photosensitizer3Clad；Wherein, magnetic nano-particle and CaCO3The mass ratio of clad is 10:1~3, and the capacity value of photosensitizer is 8.9~10.3wt%；Ascorbic acid is placed in iron salt solutions, adjusts pH value of solution most 9 ~ 12, hydro-thermal reaction obtains magnetic nano-particle dispersion liquid；By CaCl2It is added thereto, is stirred to react with ICG, add Na2CO3It is reacted 24 hours with ICG, obtains purpose product.The advantages that this nano-probe has blood circulation time long for bimodal in animal body at, the present invention, and the tumor locus residence time is long, and drug targeting delivery efficiency is high, and preparation process is simple.
Description
Technical field
The present invention relates to nanometer field of medicaments, in particular to a kind of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe
And its preparation method and application.
Background technique
Gastric cancer is one of most common malignant tumor of digestive tract in global range at present, is the malignant tumour derived from epithelium,
Wherein the patient in the whole world 40% is distributed in China.In recent years, there is very big progress in China to the treatment of gastric cancer, at gastric cancer
In early carcinoma of stomach, advanced gastric carcinoma and late gastric cancer different times, using different treatment methods, such as surgical operation is changed
It learns treatment, radiotherapy and put/chemotherapy combined treatment etc., but these medical intervention means are controlled there is no ideal expection is obtained
Therapeutic effect.
With the development of modern medicine, nanotechnology and nano material are increasingly used in early diagnosis of tumor and tumour
The research for the treatment of.The side such as early diagnosis and therapy of medical domain, especially cancer is given in the development of nanotechnology and nano material
Face brings the change at field depth quarter.
Currently, there is researcher that Magnetic Resonance Imaging is designed fluorescence magnetic nanometer in conjunction with the advantage that photosensitizer fluorescence images
Probe, but it is still difficult in normal tissue (such as: liver, spleen etc.) damage, the residence time of tumor locus and aggregate amount etc.
Accomplish fully up to expectations.In order to reduce the damage of fluorescence magnetic nano-probe normal tissue (such as: liver, spleen etc.), increase in drug
It in the aggregate amount of tumor locus, needs to improve nano-probe to the capacity value of drug, and tumor locus specificity is discharged, thus
It is given full play in the application potential of field of biomedicine.
Summary of the invention
Goal of the invention: aiming at the problems existing in the prior art, the present invention provides a kind of overstable monodispersed fluorescent magnetic
Property diagnosis and treatment nano-probe and its preparation method and application, this nano-probe is for bimodal in animal body at present invention tool
There is the advantages that blood circulation time is long, and the tumor locus residence time is long, and drug targeting delivery efficiency is high, and preparation process is simple.
Technical solution: the present invention provides a kind of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe, feature exists
In including being enclosed with the magnetic nano-particle of polyethylene glycol PEG and doped with the CaCO of photosensitizer3Clad；In the nanometer
In probe, the magnetic nano-particle and the CaCO3The mass ratio of clad is 10:1~3；The capacity value of the photosensitizer
For 8.9~10.3wt%.
Preferably, the molecular weight of the PEG is 5000, and one end is sulfydryl, and the other end is carboxyl.
Preferably, the photosensitizer is chlorin e 6 (Ce6) or indocyanine green ICG.
Preferably, the average-size of the nano-probe is 5~6 nm.
The present invention also provides a kind of preparation method of above-mentioned overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe, packets
It includes following steps: (1) ascorbic acid being placed in iron salt solutions, adjusting pH value to 9 ~ 12, after being stirred, hydro-thermal reaction, instead
Should be dialysed to obtain magnetic nano-particle dispersion liquid after the completion；(2) after taking the magnetic nano-particle dispersion liquid to be centrifuged, supernatant is removed
Liquid, by CaCl2It is added in freshly prepared magnetic nano-particle with ICG, stirs 24 h, obtain MNPs@CaCl2/ ICG hangs molten
Liquid；(3) the MNPs@CaCl is taken2After/ICG hangs solution centrifugation, supernatant is removed, Na is added2CO3And ICG, sustained response 24
H, centrifugation remove unsupported drug to get fluorescence magnetic diagnosis and treatment nano-probe.
Preferably, in the step (1), the iron salt solutions by molar ratio are organic molysite of 1 ~ 3:1 ~ 7 and inorganic
Molysite, which adds water and stirs, to be dissolved, wherein Fe2+And Fe3+Molar ratio be 1:1 ~ 3.
Preferably, organic molysite be it is following any one or combinations thereof: ironic citrate, ferric acetyl acetonade, dextrose
Acid anhydride iron, ferrous gluconate；The inorganic molysite be it is following any one or combinations thereof: ferrous sulfate, ferric sulfate, protochloride
Iron, iron chloride.
Preferably, in the step (1), the CaCl of addition2And Na2CO3Molar ratio be 1:1~3.
Preferably, in the step (1), the process conditions of the hydro-thermal reaction are as follows: kept the temperature at 150 ~ 230 DEG C anti-
Answer 4 ~ 15 h.
Preferably, in the step (2): the CaCl2Molar ratio with ICG is 1:1~3.
Preferably, in the step (2): by CaCl2After being added in the magnetic nano-particle with ICG,
At 25 DEG C, in thermostat water bath, 24 h are stirred persistently with the mixing speed of 300 rpm.
Preferably, in the step (3), the Na of addition2CO3Molar ratio with ICG is 1:1~3.
Preferably, in the step (3), centrifugal rotational speed when centrifugation removes unsupported drug is 9000rpm, when centrifugation
Between be 10min.
Preferably, in the step (3), in the MNPs@CaCl of purifying2/ ICG, which hangs in solution, is added Na2CO3And ICG
Afterwards, at 25 DEG C, 24 h are stirred persistently with the mixing speed of 300 rpm.
The present invention also provides a kind of above-mentioned overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe in vivo fluorescence at
Application in picture, NMR imaging or bimodal imaging.
It is used as and examines in preparation the present invention also provides a kind of above-mentioned overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe
The application in antitumor delivery system drug that disconnected and treatment is integrated.
It is aoxidized the utility model has the advantages that the present invention prepares the excellent carboxylated four of small size, good water solubility, magnetic property by hydro-thermal method
Three ferromagnetism nanometer particles (carboxylated of the PEG for magnetic nano-particle is modified), using it as probe nuclei, are then wrapped on its surface
It wraps one layer and loads the CaCO for having photosensitizer3, i.e. the high-efficient, normal tissue (such as liver, spleen) of composition tumor locus targeting is not easy
Enrichment, tumor locus specificity discharge the fluorescence magnetic nano-probe of drug.
Compared with prior art, the invention has the following advantages that
(1) preparation step is simple, quick, only a small amount of several reagents need to be used to can be prepared by；
(2) it is based on magnetic nano-particle, coats one layer of CaCO on surface3, while CaCO3Photo-dynamical medicine is photosensitive in middle cladding
The fluorescence magnetic diagnosis and treatment nano-probe of the excellent tumour response of overstable monodisperse biocompatibility is made in agent；
(3) it is 5-6 nm that tumour made from, which responds fluorescence magnetic diagnosis and treatment nano-probe average-size, and particle diameter distribution is uniform；
(4) tumour made from responds fluorescence magnetic diagnosis and treatment nano-probe and targets high-efficient, tumor locus response medicine release.
Detailed description of the invention
Fig. 1 is the transmission electron microscope picture after fluorescence magnetic nano-probe produced by the present invention is placed 1 year；
Fig. 2 is the high-resolution-ration transmission electric-lens picture of fluorescence magnetic nano-probe of the invention；
Fig. 3 is that the NMR imaging photo of fluorescence magnetic nano-probe of the invention in bearing mouse model (is in red circle
Tumor region).
Fig. 4 is the fluorescent images (red circle of fluorescence magnetic nano-probe of the invention in bearing mouse model
Interior is tumor region).
Specific embodiment
The present invention is described in detail with reference to the accompanying drawing.
Embodiment 1:
(1) preparation of magnetic particle (carboxylated): the ferrous sulfate and ironic citrate that molar ratio is 1:1 are weighed, deionization is dissolved in
In water, mix well it with the speed stirring of 600 rpm；Then a certain amount of ascorbic acid is added, makes itself and Fe3+Ion
Molar ratio is 1:3, and adjusting reacting liquid pH value using the sodium hydroxide solution of 0.5 M is 9, after stirring 120 min, by mixed solution
It is transferred in hydrothermal reaction kettle, with 150 DEG C of 4 h of temperature；Dialysis 2 days obtains MNPs-COOH and hangs solution, then places
In 4 DEG C of refrigerator long-term preservations；
(2) magnetic nano-particle is PEGylated: taking the outstanding solution of the MNPs-COOH of 1 mL, shifting is centrifuged in the super filter tube of 10K, is freezed
The parameter of centrifuge is set as: 4 DEG C, 12000 rpm, 5 min；Then the borate buffer solution constant volume for being 7.2 with pH to original volume,
Carboxyl on MNPs-COOH is activated by the way that a certain amount of EDC/NHS is added, and makes its molar ratio 1:1 with carboxyl amount, then
After rotating 30min on XH-1T type multitube adjustable rotary mixer, revolving speed is 30 revs/min, a certain amount of PEG is added, with carboxylic
The molar ratio of base unit weight is 1:1, is placed in 37 DEG C of incubator and shakes 60min, obtains MNPs-PEG and hangs solution, is then placed into 4 DEG C
Refrigerator long-term preservation；
(3) MNPs@CaCl2/ ICG preparation: taking the outstanding solution of the MNPs-PEG of 10 mL, and weighing molar ratio respectively is 1；1
CaCl2And ICG, it is added in the outstanding solution of MNPs-PEG.At 25 DEG C, in thermostat water bath, speed is stirred with 300 rpm
Degree, persistently stirs 24 h, obtains MNPs@CaCl2/ ICG hangs solution, is then placed into 4 DEG C of refrigerator long-term preservations；
(4) MNPs@CaCO3/ ICG preparation: the MNPs@CaCl of 10 mL is taken2The outstanding solution of/ICG, weighing molar ratio respectively is 1:1
Na2CO3And ICG, it is added to MNPs@CaCl2In the outstanding solution of/ICG.At 25 DEG C, in thermostat water bath, with 300 rpm
Mixing speed persistently stirs 24 h, obtains MNPs@CaCO3/ ICG hangs solution, and shifting is centrifuged in 15mL centrifuge tube, refrigerated centrifuge
The parameter of machine is set as: 4 DEG C, 6000 rpm, 10 min；The Multifunction fluorescent magnetism diagnosis and treatment nano-probe purified.
To MNPs@CaCO obtained above3/ ICG is detected, and Fig. 1 is that fluorescence magnetic diagnosis and treatment made from the present embodiment are received
The transmission electron microscope photo of rice probe, it is known that, after fluorescence magnetic diagnosis and treatment nano-probe stands 1 year, still it is uniformly dispersed, does not send out
Raw dissociation phenomenon, it was demonstrated that the excellent stability of the nano-probe；Fig. 2 is that fluorescence magnetic diagnosis and treatment nanometer made from the present embodiment is visited
The high-resolution-ration transmission electric-lens picture of needle, it is known that, the nano-probe is in package CaCO3Afterwards, still have good dispersed and equal
One property, and CaCO3Wrapping layer with a thickness of 1.5 nm；Fig. 3 shows tumor-bearing mice before and after injecting multifunctional nano probe
NMR imaging photo, it is known that, fluorescence magnetic diagnosis and treatment nano-probe has good T2 contrasting effects, and identification is high, is somebody's turn to do in injection
Position and the size of tumour can be clearly identified after nano-probe 24 hours；Fig. 4 shows that tumor-bearing mice is examined in injection fluorescence magnetic
Treat nano-probe after living body fluorescent images, it is known that, fluorescence magnetic diagnosis and treatment nano-probe have good tumour fluorescence at
As effect, identification is high, and position and the size of tumour can be clearly identified after injection the nano-probe 24 hours.
Embodiment 2:
(1) preparation of magnetic particle (carboxylated): the ferrous sulfate and ironic citrate that molar ratio is 1:2 are weighed, deionization is dissolved in
In water, mix well it with the speed stirring of 600 rpm；Then a certain amount of ascorbic acid is added, makes itself and Fe3+Ion
Molar ratio is 1:2, and adjusting reacting liquid pH value using the sodium hydroxide solution of 0.5 M is 10, after stirring 120 min, will be mixed molten
Liquid is transferred in hydrothermal reaction kettle, with 150 DEG C of 4 h of temperature；Dialysis 2 days obtains MNPs-COOH and hangs solution, then puts
It is placed in 4 DEG C of refrigerator long-term preservations；
(2) magnetic nano-particle is PEGylated: taking the outstanding solution of the MNPs-COOH of 1 mL, shifting is centrifuged in the super filter tube of 10K, is freezed
The parameter of centrifuge is set as: 4 DEG C, 12000 rpm, 5 min；Then the borate buffer solution constant volume for being 7.2 with pH to original volume,
Carboxyl on MNPs-COOH is activated by the way that a certain amount of EDC/NHS is added, and makes its molar ratio 1:1 with carboxyl amount, then
After rotating 30min on XH-1T type multitube adjustable rotary mixer, revolving speed is 30 revs/min, a certain amount of PEG is added, with carboxylic
The molar ratio of base unit weight is 1:1, is placed in 37 DEG C of incubator and shakes 60min, obtains MNPs-PEG and hangs solution, is then placed into 4 DEG C
Refrigerator long-term preservation；
(3) MNPs@CaCl2/ ICG preparation: taking the outstanding solution of the MNPs-PEG of 10 mL, and weighing molar ratio respectively is 1:2's
CaCl2And ICG, it is added in the outstanding solution of MNPs-PEG.At 25 DEG C, in thermostat water bath, speed is stirred with 300 rpm
Degree, persistently stirs 24 h, obtains MNPs@CaCl2/ ICG hangs solution, is then placed into 4 DEG C of refrigerator long-term preservations；
(4) MNPs@CaCO3/ ICG preparation: the MNPs@CaCl of 10 mL is taken2The outstanding solution of/ICG, weighing molar ratio respectively is 1:2
Na2CO3And ICG, it is added to MNPs@CaCl2In the outstanding solution of/ICG.At 25 DEG C, in thermostat water bath, with 300 rpm
Mixing speed persistently stirs 24 h, obtains MNPs@CaCO3/ ICG hangs solution, and shifting is centrifuged in 15mL centrifuge tube, refrigerated centrifuge
The parameter of machine is set as: 4 DEG C, 6000 rpm, 10 min；The Multifunction fluorescent magnetism diagnosis and treatment nano-probe purified.
Embodiment 3:
(1) preparation of magnetic particle (carboxylated): the ferrous sulfate and ironic citrate that molar ratio is 1:1 are weighed, deionization is dissolved in
In water, mix well it with the speed stirring of 600 rpm；Then a certain amount of ascorbic acid is added, makes itself and Fe3+Ion
Molar ratio is 1:3, and adjusting reacting liquid pH value using the sodium hydroxide solution of 0.5 M is 12, after stirring 120 min, will be mixed molten
Liquid is transferred in hydrothermal reaction kettle, with 150 DEG C of 4 h of temperature；Dialysis 2 days obtains MNPs-COOH and hangs solution, then puts
It is placed in 4 DEG C of refrigerator long-term preservations；
(2) magnetic nano-particle is PEGylated: taking the outstanding solution of the MNPs-COOH of 1 mL, shifting is centrifuged in the super filter tube of 10K, is freezed
The parameter of centrifuge is set as: 4 DEG C, 12000 rpm, 5 min；Then the borate buffer solution constant volume for being 7.2 with pH to original volume,
Carboxyl on MNPs-COOH is activated by the way that a certain amount of EDC/NHS is added, and makes its molar ratio 1:1 with carboxyl amount, then
After rotating 30min on XH-1T type multitube adjustable rotary mixer, revolving speed is 30 revs/min, a certain amount of PEG is added, with carboxylic
The molar ratio of base unit weight is 1:1, is placed in 37 DEG C of incubator and shakes 60min, obtains MNPs-PEG and hangs solution, is then placed into 4 DEG C
Refrigerator long-term preservation；
(3) MNPs@CaCl2/ ICG preparation: taking the outstanding solution of the MNPs-PEG of 10 mL, and weighing molar ratio respectively is 1:3's
CaCl2And ICG, it is added in the outstanding solution of MNPs-PEG.At 25 DEG C, in thermostat water bath, speed is stirred with 300 rpm
Degree, persistently stirs 24 h, obtains MNPs@CaCl2/ ICG hangs solution, is then placed into 4 DEG C of refrigerator long-term preservations；
(4) MNPs@CaCO3/ ICG preparation: the MNPs@CaCl of 10 mL is taken2The outstanding solution of/ICG, weighing molar ratio respectively is 1:3
Na2CO3And ICG, it is added to MNPs@CaCl2In the outstanding solution of/ICG.At 25 DEG C, in thermostat water bath, with 300 rpm
Mixing speed persistently stirs 24 h, obtains MNPs@CaCO3/ ICG hangs solution, and shifting is centrifuged in 15mL centrifuge tube, refrigerated centrifuge
The parameter of machine is set as: 4 DEG C, 6000 rpm, 10 min；The Multifunction fluorescent magnetism diagnosis and treatment nano-probe purified.
The technical concepts and features of above embodiment only to illustrate the invention, its object is to allow be familiar with technique
People cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent transformation or modification that Spirit Essence is done, should be covered by the protection scope of the present invention.
Claims (17)
1. a kind of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe characterized by comprising be enclosed with polyethylene glycol
The magnetic nano-particle of PEG and CaCO doped with photosensitizer3Clad；In the nano-probe, the magnetic nano particle
The sub and CaCO3The mass ratio of clad is 10:1~3, and the capacity value of the photosensitizer is 8.9~10.3wt%.
2. overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to claim 1, which is characterized in that described
The molecular weight of PEG is 5000, and one end is sulfydryl, and the other end is carboxyl.
3. overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to claim 1, which is characterized in that described
Photosensitizer is chlorin e 6 or indocyanine green ICG.
4. overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to claim 1, which is characterized in that described to receive
The average-size of rice probe is 5~6 nm.
5. a kind of system of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to any one of claims 1 to 4
Preparation Method, which comprises the following steps:
(1) ascorbic acid is placed in iron salt solutions, adjusting pH value to 9 ~ 12, after being stirred, hydro-thermal reaction, after the reaction was completed
It dialyses to obtain magnetic nano-particle dispersion liquid；
(2) after taking the magnetic nano-particle dispersion liquid to be centrifuged, supernatant is removed, by CaCl2It is added to ICG freshly prepared
In magnetic nano-particle, 24 h are stirred, MNPs@CaCl is obtained2/ ICG hangs solution；
(3) the MNPs@CaCl is taken2After/ICG hangs solution centrifugation, supernatant is removed, Na is added2CO3And ICG, sustained response 24
H, centrifugation remove unsupported drug to get fluorescence magnetic diagnosis and treatment nano-probe.
6. the preparation method of overstable monodispersed fluorescence magnetic nano-probe according to claim 5, which is characterized in that
Fe in the step (1), in the ascorbic acid and the iron salt solutions3+Molar ratio be 1:1~3.
7. the preparation method of overstable monodispersed fluorescence magnetic nano-probe according to claim 5, which is characterized in that
In the step (1), the iron salt solutions add water and stir dissolution by organic molysite that molar ratio is 1 ~ 3:1 ~ 7 and inorganic molysite
It forms, wherein Fe2+And Fe3+Molar ratio be 1:1 ~ 5.
8. the preparation method of overstable monodispersed fluorescence magnetic nano-probe according to claim 5, which is characterized in that
Organic molysite be it is following any one or combinations thereof:
Ironic citrate, ferric acetyl acetonade, iron-dextrin, ferrous gluconate；
The inorganic molysite be it is following any one or combinations thereof:
Ferrous sulfate, ferric sulfate, frerrous chloride, iron chloride.
9. the preparation method of overstable monodispersed fluorescence magnetic nano-probe according to any one of claim 5 to 8,
It is characterized in that, in the step (1), the CaCl of addition2And Na2CO3Molar ratio be 1:1~3.
10. the preparation side of overstable monodispersed fluorescence magnetic nano-probe according to any one of claim 5 to 8
Method, which is characterized in that in the step (1), the process conditions of the hydro-thermal reaction are as follows: the insulation reaction at 150 ~ 230 DEG C
4~15 h。
11. the preparation method of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to claim 5, feature
It is, in the step (2): the CaCl2Molar ratio with ICG is 1:1~3.
12. the preparation method of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to claim 5, feature
It is, in the step (2): by CaCl2After being added in the magnetic nano-particle with ICG, at 25 DEG C, in perseverance
In warm water bath, 24 h are stirred persistently with the mixing speed of 300 rpm.
13. the preparation method of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to claim 5, feature
It is, in the step (3), the Na of addition2CO3Molar ratio with ICG is 1:1~3.
14. the preparation method of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to claim 5, feature
It is, in the step (3), centrifugal rotational speed when centrifugation removes unsupported drug is 9000rpm, centrifugation time 10min.
15. the preparation method of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to claim 5, feature
It is, in the step (3), in the MNPs@CaCl of purifying2/ ICG, which hangs in solution, is added Na2CO3After ICG, at 25 DEG C,
24 h are persistently stirred with the mixing speed of 300 rpm.
16. a kind of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to any one of claims 1 to 4 is in body
Application in interior fluorescence imaging, NMR imaging or bimodal imaging.
17. a kind of overstable monodispersed fluorescence magnetic diagnosis and treatment nano-probe according to any one of claims 1 to 4 is being made
Application in the standby antitumor delivery system drug being integrated as diagnosing and treating.
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