CN105412948B - It is multi-functional to contain hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium and its preparation method and application - Google Patents
It is multi-functional to contain hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to multi-functional containing hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium and its preparation method and application, the nanometer diagnosis and treatment agent is with mesoporous and boring the particle of prussian blue nano containing gadolinium, and wherein the molar ratio of ferro element and gadolinium element is (0.8~200): 1.Hollow meso-porous nano diagnosis and treatment agent good biocompatibility of the invention, T1Weighted magnetic resonance imaging is had excellent performance, and has strong absorption in the near infrared region, and have excellent photothermal conversion performance, has promotion in terms of being imaged and treating tumour compared to other Prussian blue nanoparticles.
Description
Technical field
The present invention relates to technical field of nano material and field of biomedical materials, and in particular to a kind of with excellent core
Hollow mesoporous Prussian blue (HGPB) nanoparticle containing gadolinium of magnetic resonance imaging (MRI), photoacoustic imaging and photothermal conversion performance,
To tumor thermotherapy, the multifunctional nano diagnosis and treatment agent of the treatments such as chemotherapy and its preparation side under being guided as a kind of realization multi-modal imaging
Method.
Background technique
In recent years, significant growth trend is presented in China in the disease incidence of malignant tumour.Malignant tumour has been more than angiocarpy
Disease becomes city dweller's primarily lethal cause of disease, seriously threatens the life and health of the mankind, brings to society, family and individual
Greatly burden and pain.It is to the treatment gold criterion of malignant tumour in the world, it is early to find early treatment, strive in tumour cell
Realize that tumour is efficiently treated before not spreading, to save more life.Therefore, research and development high-performance, low cost, user
Just Imaging for Monitoring and efficient oncotherapy technology are us in tumour early detection and treatment, especially infantile tumour generaI investigation and art
The special needs of society of state and science and technology development strategy have huge scientific meaning.
The problem and research hotspot of the early diagnosis of tumour and treatment always medical field, especially with diagnosis and prison
The crucial scientific and technical research that the functions such as control, treatment are integrated is even more the hot spot of scientific circles' concern.Magnetic resonance imaging (Magnetic
Resonace imaging, MRI) generated under the influence of external magnetic field using organism different tissues different resonance signals come at
Picture, relaxation time of the power of signal depending on proton in the content and hydrone of water in tissue.This imaging technique has non-invade
It the advantages that diagnosis of entering property, the imaging of high-resolution anatomy and qualitative assessment pathogenesis, is clinically widely used.T1
Weighted magnetic resonance imaging technology enhances signal strength, has higher detection accuracy, therefore become the hot spot of MRI research.
The complex of Gd played an important role in the diagnosis of clinical MRI disease.Photoacoustic imaging is developed in recent years one
The lossless medical imaging procedure of kind, principle is when pulsed laser irradiation is into biological tissue, and the light absorption of tissue will generate light
Acoustical signal, the photoacoustic signal of biological tissue carry the light absorption characteristics information of tissue, can be reconstructed by measuring photoacoustic signal
Light absorption distributed image in tissue.It combines the high contrast features of pure optical imagery and the high-penetration depth of pure ultrasonic imaging
Characteristic is spent, the imaging of tissue of high-resolution and high contrast can be provided, becomes and carries out cancer early detection and treatment prison at present
One of the important means of control.
Serious toxic side effect can occur for nearly all patient according to statistics, and different degrees of drug resistance occurs in 90% patient,
There are metastases etc. in first visit patients more than half.The appearance of nanometer biotechnology is that the efficient treatment of tumour and reduction poison pair are made
With providing new approach.The novel photo-thermal therapy technology based on nano-carrier a kind of in recent years causes extensive concern.
It is by the nano carrier material with near-infrared photo-thermal converting function, and tumor locus is arrived in selectivity accumulation, then only to tumor area
Near infrared light photograph is locally implemented in domain, makes between tumour cell and intracellular nano material absorbs near infrared light, and efficiently convert
For thermal energy, tumour is set to generate local ultra-high temperature, to easily kill tumour cell.The heat that this near infrared light mediates is swollen
Tumor targeted delivery, ensure that treatment in will not normal tissue cause to damage, significantly improve the safety and validity of thermotherapy.
This treatment mode is tumour " photo-thermal therapy ", its biggest characteristic is that theoretically realizing to nearly all entity tumor
Effectively treatment, including the efficient treatment to chemicotherapy failure and generation resistant tumors, while it is adjoint to generate chemicotherapy
Life in patients declines caused by toxic side effect.
Therefore, if can provide it is a kind of can be used as effective Magnetic resonance imaging and photoacoustic imaging contrast agent simultaneously, and can be with
The nanometer diagnosis and treatment agent that photo-thermal therapy and chemotherapy are realized to tumour, will have good potential applicability in clinical practice.
Chinese patent CN102397562A discloses one kind by Prussian blue load Gd3+Contrast agent, Chinese patent
CN103449477A discloses a kind of prussian blue nano material contrast agent containing gadolinium element, but in these contrast agent, gadolinium is only
It is adsorbed in Prussian blue, and Prussian blue particle does not have cavity and mesoporous, can not load anti-tumor drug etc..Furthermore this
A little contrast agent cannot effectively be adjusted its near infrared absorption, not only can not achieve more efficient photoacoustic imaging and photo-thermal
Treatment, can't be used as the regulatable chemical probe of sensitivity.
Summary of the invention
For the above problem present in the prior art and demand, the present invention is intended to provide a kind of multi-functional hollow Jie containing gadolinium
Prussian blue nanometer diagnosis and treatment agent in hole and preparation method thereof and Accurate Diagnosis and efficient treatment side for major diseases such as tumours
The biomedical applications in face.
On the one hand, the present invention provides a kind of multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium, and the nanometer is examined
Treating agent is with mesoporous and boring the particle of prussian blue nano containing gadolinium, and wherein the molar ratio of ferro element and gadolinium element is
(0.8~200): 1.
Hollow meso-porous nano diagnosis and treatment agent good biocompatibility of the invention, T1Weighted magnetic resonance imaging is had excellent performance, close
Infrared region have it is strong absorb, and there is excellent photothermal conversion performance, compared to other Prussian blue nanoparticles at
There is promotion in terms of picture and treatment tumour.In nanometer diagnosis and therapy system based on HGPB, by adjusting the ratio of iron gadolinium, realize to it
Magnetic resonance imaging performance is adjusted, and the ratio of iron gadolinium is smaller, and longitudinal relaxation rate is bigger, T1Weight nuclear magnetic resonance at
As performance is better；Due to gadolinium ion different position in the structure, influence cyanogen bridge and ion-electron density in combination and
Orbital energy, pass through adjust iron gadolinium ratio, so that it may realize the absorption of HGPB in the near infrared region, thus realize to optoacoustic at
The regulation of picture and photo-thermal therapy efficiency.Further, since its hollow meso-hole structure, good biocompatibility and biological safety,
Its huge applications potentiality as pharmaceutical carrier is imparted, supporting to chemotherapeutics etc. may be implemented.This nanometer of diagnosis and therapy system
The diagnosing and treating efficiency to tumour is substantially increased, reaches the integrated purpose of diagnosing and treating, solves traditional tumour light
Heat is unevenly distributed incomplete to tumour ablation in inside tumor in heat cure, causes tumour to be easy to recur, chemical therapy toxic side effect
It is big to wait clinical applications problem, there is good potential applicability in clinical practice.
Preferably, the dynamics light scattering partial size of the nano particle is 100~600nm, the size range of cavity is 80
~200nm.
Preferably, the nano particle has micropore and mesoporous, wherein the size of micropore is 0.5~2nm, mesoporous size
For 2.5~15nm.
Preferably, being mounted with anti-tumor drug and/or gene in the cavity of the nano particle and/or duct.
On the other hand, the present invention provides the preparation side of the above-mentioned multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium
Method, comprising the following steps:
(1) there are gadolinium source, source of iron, the organic polymer protective agent with good biocompatibility and reproducibility for evenly dispersed
Mixed solution with acid isolates solid after 60~120 DEG C of heat preservation a period of times to get the prussian blue nano grain containing gadolinium
Son；
(2) the prussian blue nano particle by resulting containing gadolinium with it is organic high with good biocompatibility and reproducibility
Molecule protective agent and acid were uniformly mixed and after 100~160 DEG C of heat preservation a period of times, isolated solid and examined to get the nanometer
Treat agent.
Preparation method low in raw material price of the invention is easy to get, preparation method is simple, is easy to produce in batches.
Preferably, in step (1), the gadolinium source is the water soluble salt of gadolinium, the source of iron be the potassium ferricyanide, the sodium ferricyanide and
At least one of potassium ferrocyanide, the organic polymer protective agent with good biocompatibility and reproducibility are poly- second
Alkene pyrrolidone and/or chitosan, the acid are hydrochloric acid and/or sulfuric acid.
Preferably, in the mixed solution, gadolinium source, has good biocompatibility and reduction at source of iron in step (1)
Property the protectant mass ratio of organic polymer be 1:(0.2~100): (100~2000), the concentration in the gadolinium source is 0.01~
0.5mol/L, the concentration of the acid are 0.0001~2mol/L, and soaking time is 4~72 hours.
Preferably, in step (1), the preparation of the mixed solution the following steps are included:
A) gadolinium source, polyvinylpyrrolidone and acid are thoroughly mixed to form gadolinium source, and by source of iron, polyvinylpyrrolidone
Source of iron solution is thoroughly mixed to form with acid；
B) gadolinium source solution is added drop-wise in source of iron solution under stiring, continues stirring after being added dropwise 1~6 hour.
Preferably, the organic polymer protective agent with good biocompatibility and reproducibility is poly- in step (2)
Vinylpyrrolidone and/or chitosan, the acid are hydrochloric acid and/or sulfuric acid, and the concentration of the acid is 1~4mol/L.
Preferably, in step (2), prussian blue nano particle containing gadolinium, with good biocompatibility and reproducibility
Organic polymer protective agent, sour mass ratio are 1:(0.5~10): (0.5~5), soaking time are 1~5 hour.
In another aspect, the present invention also provides it is above-mentioned it is multi-functional containing the hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium prepare it is simultaneous
Have the application in the nanometer diagnosis and treatment agent of Magnetic resonance imaging, photoacoustic imaging and photo-thermal therapy effect, or is reflected in preparation media
Application in rate sensor.
Detailed description of the invention
Fig. 1 is transmission electron microscope (TEM) photo and preparation stream of 1 gained HGPB nanoparticle of the embodiment of the present invention
Journey；
Fig. 2 is that the element mapping of 1 gained HGPB nanoparticle of the present embodiment schemes (Gd, Fe, C, N and K)；
Fig. 3 is the corresponding UV~vis absorption curve of 1 gained HGPB nanoparticle of the embodiment of the present invention；
The HGPB nanoparticle of 1 gained various concentration of Fig. 4 embodiment is under the irradiation of laser, the change of solution temperature at any time
Change curve graph；
Fig. 5 is the photoacoustic signal value curve of 1 gained various concentration HGPB nanoparticle of the embodiment of the present invention and corresponding
Optoacoustic picture；
Fig. 6 is the external 1/T of 1 gained HGPB nanoparticle of the embodiment of the present invention1~concentration curve；
Fig. 7 is the external 1/T of 1 gained HGPB nanoparticle of the embodiment of the present invention2~concentration curve；
Fig. 8 is that UV~vis of the HGPB nano-particle solution containing different gadolinium amounts prepared in the embodiment of the present invention 1 absorbs
Curve；Fig. 9 is the refractive index of 1 gained HGPB nanoparticle of the embodiment of the present invention and the relation curve of maximum absorption band.
Specific embodiment
The present invention is further illustrated below in conjunction with attached drawing and following embodiments, it should be appreciated that attached drawing and following embodiments
It is merely to illustrate the present invention, is not intended to limit the present invention.
The present invention is directed to bottleneck of the existing NMR contrast agent in clinical application, by Prussian blue structure
Middle introducing gadolinium element has Modulatory character in the near infrared region, forms multifunctional nano diagnosis and treatment agent.This nanometer of diagnosis and treatment agent can be made
For effective Magnetic resonance imaging and photoacoustic imaging contrast agent, diagnosis and monitoring therapeutic process and treatment effect for tumour
Rate.In addition, the nanoparticle can realize photo-thermal therapy to tumour, tumour is effectively eliminated.
The present invention provides a kind of multi-functional hollow mesoporous Prussian blue (HGPB) nanoparticle containing gadolinium, the HGPB is received
Rice corpuscles includes the prussian blue nano particle with mesoporous, boring structure, and in Prussian blue middle introducing gadolinium, wherein
The molar ratio of iron gadolinium is in (0.8~200): it is controllable in 1 range, preferably in (1~30): it is controllable in 1 range, more preferably
Ground, iron gadolinium molar ratio are 3.5:1, and r1 value can achieve 34.1mM at this time-1S-1, r2 value can achieve 243mM-1S-1.Pass through tune
The ratio of iron gadolinium is saved, its Magnetic resonance imaging performance is adjusted in realization, and realizes the absorption of HGPB in the near infrared region, from
And realize the regulation to photoacoustic imaging and photo-thermal therapy efficiency.HGPB particle of the invention can be used as excellent nuclear magnetic resonance at
As contrast agent, it is particularly suitable for T1The magnetic resonance imaging of weighting.
Maximum absorption band is controllable within the scope of 680~950nm in the near infrared region for the HGPB particle.HGPB shell exists
Near infrared light region (λ=700~1100nm) has strong absorption, high photothermal conversion efficiency.Under the irradiation of near infrared light,
Temperature at pathological tissues is set to reach 42.5 DEG C or more.Therefore, which can realize photo-thermal therapy to tumour, effectively disappear
Except tumour.
The HGPB nanoparticle can be used as excellent photoacoustic imaging contrast agent, realize the early diagnosis to tumour, swell
Tumor treatment ground real time monitoring etc..
The HGPB nanoparticle is controllable in 0~-600nm/RIU range to the sensitivity of medium refraction index, can be with
As a kind of excellent medium refraction index chemical probe etc..
The surface of the HGPB nanoparticle is negatively charged, and electro kinetic potential is about -60~0mV.The HGPB nanoparticle
Nano-particle kinetics light scattering partial size be about 100~600nm (preferably 200~600nm) controllably, cavity size range is
80~200nm is controllable.The HGPB nanoparticle has micropore and mesoporous, wherein the size of micropore be 0.5~2nm (preferably
0.5~1.5nm) controllably, macropore range are as follows: 2.5~15nm is controllable.The HGPB nanoparticle specific surface area is 70~300m2/
0.1~1cm of g, Kong Rongwei3/ g, aperture are 2~15nm.
HGPB nanometer diagnosis and treatment agent of the invention has huge cavity (hollow cube) and meso-hole structure, can be used as
Pharmaceutical carrier, realization support guest molecule, including anti-tumor drug, large biological molecule (such as gene) etc., such as can be with
Realize the cladding and transmission to anti-tumor drug and gene, as good drug delivery system, the anti-tumor drug and base
Cause including but not limited to doxorubicin hydrochloride, taxol, Irinotecan, Aclarubicin, oxaliplatin, mitoxantrone, vincristine
One of equal Nano medications or two kinds and two or more mixtures.Anti-tumor drug is discharged in tumor locus, realizationization
Treat the synergistic treatment tumour with above-mentioned photo-thermal therapy.Meanwhile Magnetic resonance imaging and photoacoustic imaging diagnosis are realized in tumor locus
And the real-time monitoring therapeutic effect for tumour, realize Magnetic resonance imaging and thermotherapy and chemotherapy association under photoacoustic imaging guidance
With the diagnosis and therapy system for the treatment of tumour.
HGPB nanometer diagnosis and treatment agent of the invention has excellent biocompatibility and biological safety, is improving it in nuclear-magnetism
On the basis of resonance image-forming, photoacoustic imaging and photo-thermal therapy performance, realize to the Magnetic resonance imaging of tumour and optoacoustic at
As the photo-thermal therapy etc. under guidance, the Precise Diagnosis to tumour and the efficiency for the treatment of are substantially increased.
HGPB nanoparticle of the invention can be prepared via a method which: prepare first monodisperse, size uniformity containing gadolinium
It is equal that monodisperse, size is prepared then using the method for " surface protection, inside etching " in mesoporous prussian blue nano particle
One HGPB nanoparticle.Specifically, gadolinium source, source of iron and protective agent with good biocompatibility and reproducibility is abundant
Mixing, forms the prussian blue nano particle containing gadolinium using it under conditions of hydro-thermal, protects surface, acid followed by protective agent
As etching agent, HGPB nanoparticle is prepared in hydrothermal method, and obtained nanoparticle is in imaging (photoacoustic imaging and nuclear-magnetism
Resonance image-forming) and treatment (photo-thermal therapy) can play a role, realize tumour diagnosis and treatment integration.
In one embodiment, the preparation method of HGPB nanoparticle of the invention includes the following steps:
A) respectively by gadolinium source, organic polymer protective agent and acid and iron with good biocompatibility and reproducibility
Source, the organic polymer protective agent with good biocompatibility and reproducibility and acid are sufficiently mixed at room temperature；
B) the gadolinium source solution mixed is added drop-wise in source of iron solution, continues magnetic stirring；
C) solution is transferred under certain temperature environment and is handled；
D) the prussian blue nano particle that can be obtained containing gadolinium is collected by centrifugation for 10 minutes in 13000rpm/min；
E) the above-mentioned nanoparticle of certain mass and it is certain density acid and have good biocompatibility and reproducibility
Organic polymer protective agent be sufficiently mixed, place in the baking oven of certain temperature, etch certain time, 13000rpm/min, 10
HGPB nanoparticle can be obtained in minute centrifugation.
Gadolinium source described in step a) can be the water soluble salt, such as gadolinium nitrate, gadolinium chloride etc. of gadolinium, preferably gadolinium nitrate.
The concentration in gadolinium source can be 0.01~0.5mol/L, preferably 0.05~0.2mol/L in the solution of gadolinium source.
Source of iron described in step a) can be the potassium ferricyanide, the sodium ferricyanide or potassium ferrocyanide, preferably iron cyaniding
Potassium.The concentration of source of iron can be 0.01~0.5mol/L, preferably 0.05~0.2mol/L in source of iron solution.
Organic polymer protective agent with good biocompatibility and reproducibility described in step a) can be poly- second
Alkene pyrrolidone, chitosan etc..
In one example, in the solution of gadolinium source, overall solution volume is 10~1000ml, preferably 50~200ml, protective agent
The amount of (such as polyvinylpyrrolidone) is 500mg~10g, preferably 1~5g.In another example, molten in source of iron solution
Liquid total volume is 10~1000ml, preferably 50~200ml, the amount of protective agent (such as polyvinylpyrrolidone) be 500mg~
10g, preferably 1~5g.It should be understood that each dosage shown here is only an example for showing usage ratio, Ke Yigen
It is scaled up or reduces in each dosage according to actual needs.
Acid described in step a) is recommended as hydrochloric acid, sulfuric acid etc., preferably hydrochloric acid.The concentration of acid is recommended as 0.0001~
2mol/L, preferably 0.01~0.1mol/L.
Hybrid mode described in step a) is recommended as magnetic stirring, ultrasonic mixing etc., and preferably magnetic is stirred mode.
Drop rate described in step b) is recommended as 10~100ml/h, preferably 30~60ml/h.
Magnetic stirring condition described in step b) is recommended as that 1~6h is stirred at room temperature, and is recommended as room temperature magnetic and stirs 2~4h.
Present embodiment a) is prepared with step b) for synthesizing the prussian blue nano particle containing gadolinium through the above steps
Reaction solution, it should be appreciated that it is without being limited thereto, as long as can be made it is evenly dispersed have gadolinium source, source of iron, have good biocompatibility
With the organic polymer protective agent of reproducibility and the mixed solution of acid.In the mixed solution, gadolinium source, source of iron, have it is good
Good biocompatibility and the protectant mass ratio of organic polymer of reproducibility can be 1:(0.2~100): (100~2000).Gadolinium
The concentration in source can be 0.01~0.5mol/L, preferably 0.025~0.1mol/L.The concentration of acid can be 0.0001~2mol/L,
Preferably 0.01~0.1mol/L.
Environment described in step c) is recommended as 60~120 DEG C of baking oven, oil bath etc., preferably 80~100 DEG C of baking oven.Processing
Time can be 4~72 hours, preferably 12~24 hours.
In present embodiment, the revolving speed of centrifugation and time are not limited to above-mentioned in step d), in addition, separate mode is also not necessarily limited to
Centrifugation, such as can also be using filtering etc., as long as the prussian blue nano particle containing gadolinium can be obtained.
In step e), the organic polymer protective agent with good biocompatibility and reproducibility can be polyvinyl pyrrole
Alkanone, chitosan etc..
In step e), acid is recommended as hydrochloric acid, sulfuric acid etc., preferably hydrochloric acid.The concentration of acid is recommended as 1~4mol/L, preferably 1
~2mol/L.
In one example, in step e), the quality of nanoparticle is 10~200mg, preferably 20~100mg, protection
The quality of agent (such as polyvinylpyrrolidone) be 5~2000mg, preferably 100~1000mg, sour volume be 10~
200mL, preferably 30~80mL.It should be understood that each dosage shown here is only an example for showing usage ratio, it can
To be scaled up or reduce in each dosage according to actual needs.
Certain temperature described in step e) is recommended as 100~160 DEG C, preferably 120~140 DEG C.
Certain time described in step e) is recommended as 1~5h, preferably 3~4h.In addition, it will similarly be understood that step e)
The revolving speed of middle centrifugation and time are not limited to above-mentioned, and separate mode is also not necessarily limited to be centrifuged, such as can also be using filtering etc., as long as energy
Obtain HGPB nanoparticle.
The method preparation that the present invention provides a kind of low in raw material price to be easy to get, preparation method is simple, is easy to produce in batches
It has provided good dispersion and stability, good biocompatibility, partial size and aperture is controllable, excellent photothermal conversion performance, obvious
Magnetic resonance imaging radiography and photoacoustic imaging performance and the multi-functional of photo-thermal therapy and chemotherapy synergistic treatment is carried out to tumour
Nanometer diagnosis and treatment agent.
Enumerate embodiment further below with the present invention will be described in detail.It will similarly be understood that following embodiment is served only for this
Invention is further described, and should not be understood as limiting the scope of the invention, those skilled in the art is according to this hair
Some nonessential modifications and adaptations that bright above content is made all belong to the scope of protection of the present invention.Following examples are specific
Technological parameter etc. is also only an example in OK range, i.e. those skilled in the art can be done properly by the explanation of this paper
In the range of select, and do not really want to be defined in hereafter exemplary specific value.
Embodiment 1
Prepare the mesoporous prussian blue nano particle of monodisperse, uniform particle diameter:
A) respectively by 45mg gadolinium nitrate, 1g polyvinylpyrrolidone and concentration be 0.01mol/L hydrochloric acid solution and
The hydrochloric acid solution of the 33mg potassium ferricyanide, 1g polyvinylpyrrolidone and 0.01mol/L is sufficiently mixed at room temperature；
B) the gadolinium source solution mixed is added drop-wise in source of iron solution with the rate of 40ml/h, continues magnetic and stirs 3h；
C) solution is transferred in 80 DEG C of baking ovens and is aged for 24 hours；
D) the prussian blue nano particle that can be obtained containing gadolinium is collected by centrifugation for 10 minutes in 13000rpm/min；
E) the above-mentioned nanoparticle of certain mass and certain density acid are sufficiently mixed, and are placed in the baking oven of certain temperature,
Certain time is etched, 13000rpm/min, HGPB nanoparticle can be obtained in centrifugation in 10 minutes, specific as follows:
It prepares HGPB nanoparticle: weighing the poly- of the above-mentioned mesoporous prussian blue nano particle prepared of 40mg and 100mg
Vinylpyrrolidone is sufficiently mixed in the hydrochloric acid solution that 40ml concentration is 1mol/L, and magnetic stirs 3h, goes to water heating kettle in 140 DEG C
3h is placed in baking oven, the HGPB nanoparticle that iron gadolinium ratio is 3.5:1 can be obtained in centrifugation washing.
Fig. 1 is the transmission electron microscopy of the present embodiment 1 resulting mesoporous prussian blue nano particle and HGPB nanoparticle
Mirror (TEM) photo and preparation flow schematic diagram.Leftmost one is the mesoporous prussian blue nano particle containing gadolinium, rightmost
For HGPB nanoparticle, the mesoporous prussian blue nano particle containing gadolinium can be formed under protectant protection through acid etch
HGPB nanoparticle.
Fig. 2 is that the element mapping of 1 gained HGPB nanoparticle of the present embodiment schemes (Gd, Fe, C, N and K)；It can be seen that
Gadolinium element is uniformly distributed in nano particle structure.In the resulting HGPB nanoparticle of the present embodiment, the molar ratio of iron gadolinium
For 3.5:1.
Embodiment 2
Prepare the hollow mesoporous prussian blue nano particle containing gadolinium that iron gadolinium ratio is 200:1:
A) respectively by 45mg gadolinium nitrate, 1g polyvinylpyrrolidone and concentration be 0.01mol/L hydrochloric acid solution and
The hydrochloric acid solution of the 33mg potassium ferricyanide, 1g polyvinylpyrrolidone and 2mol/L is sufficiently mixed at room temperature；
B) the gadolinium source solution mixed is added drop-wise in source of iron solution with the rate of 40ml/h, continues magnetic and stirs 3h；
C) solution is transferred in 80 DEG C of baking ovens and is aged for 24 hours；
D) the prussian blue nano particle that can be obtained containing gadolinium is collected by centrifugation for 10 minutes in 13000rpm/min；
E) the above-mentioned nanoparticle of certain mass and certain density acid are sufficiently mixed, and are placed in the baking oven of certain temperature,
Certain time is etched, 13000rpm/min, HGPB nanoparticle can be obtained in centrifugation in 10 minutes, specific as follows:
It prepares HGPB nanoparticle: weighing the poly- of the above-mentioned mesoporous prussian blue nano particle prepared of 40mg and 100mg
Vinylpyrrolidone is sufficiently mixed in the hydrochloric acid solution that 40ml concentration is 2mol/L, and magnetic stirs 3h, goes to water heating kettle in 140 DEG C
3h is placed in baking oven, the HGPB nanoparticle that iron gadolinium ratio is 200:1 can be obtained in centrifugation washing.
Embodiment 3
Prepare the hollow mesoporous prussian blue nano particle containing gadolinium that iron gadolinium ratio is 0.8:1:
A) respectively by 180mg gadolinium nitrate, 1g polyvinylpyrrolidone and concentration be 0.01mol/L hydrochloric acid solution and
The hydrochloric acid solution of the 33mg potassium ferricyanide, 1g polyvinylpyrrolidone and 0.0001mol/L is sufficiently mixed at room temperature；
B) the gadolinium source solution mixed is added drop-wise in source of iron solution with the rate of 40ml/h, continues magnetic and stirs 3h；
C) solution is transferred in 80 DEG C of baking ovens and is aged 72h；
D) the prussian blue nano particle that can be obtained containing gadolinium is collected by centrifugation for 10 minutes in 13000rpm/min；
E) the above-mentioned nanoparticle of certain mass and certain density acid are sufficiently mixed, and are placed in the baking oven of certain temperature,
Certain time is etched, 13000rpm/min, HGPB nanoparticle can be obtained in centrifugation in 10 minutes, specific as follows:
It prepares HGPB nanoparticle: weighing the poly- of the above-mentioned mesoporous prussian blue nano particle prepared of 40mg and 100mg
Vinylpyrrolidone is sufficiently mixed in the hydrochloric acid solution that 40ml concentration is 1mol/L, and magnetic stirs 3h, goes to water heating kettle in 140 DEG C
2.5h is placed in baking oven, the HGPB nanoparticle that iron gadolinium ratio is 0.8:1 can be obtained in centrifugation washing.
Embodiment 4
HGPB obtained in embodiment 1 is scattered in PBS, surveys it near infrared light with ultraviolet-uisible spectrophotometer
Absorption peak, as shown in Figure 3.As can be seen that prepared material has relatively strong wider absorption peak near infrared light region,
808nm or so is most strong.
Embodiment 5
More parts of HGPB obtained in Example 1 dissipate in PBS respectively, and 12.5ppm, 25ppm, 50ppm, 100ppm's is molten
Each 1mL of liquid is in quartz colorimetric utensil, power density 1W/cm2, wavelength is 808nm laser irradiation 10min, and recording solution is not
With time point temperature as shown in figure 4, with irradiation time increase, solution temperature gradually rises, and concentration is higher, heating speed
Rate is faster, and when 100ppm, irradiation can be raised to 23 DEG C in ten minutes, illustrates that HGPB nanoparticle has excellent photothermal conversion
Energy.
Embodiment 6
The HGPB nano-particle solution of the HGPB nanoparticle that will be prepared in embodiment 1, various concentration carries out photoacoustic imaging
Experiment obtains photoacoustic imaging figure and photoacoustic signal value, such as Fig. 5, shows that HGPB nanoparticle is a kind of excellent photoacoustic imaging
Contrast agent.
Embodiment 7
By the HGPB nano-particle solution prepared in embodiment 1 at 37 DEG C, its T1~MRI and T2~MRI imaging is tested
Performance.Such as Fig. 6 and Fig. 7, the r1 value of HGPB nanoparticle are up to 34.1mM as the result is shown~1s~1, r2 value reaches 243mM~1s~1,
Show it with excellent Magnetic resonance imaging radiography performance.
Embodiment 8
The HGPB nano-particle solution containing different gadolinium amounts that will will be prepared in embodiment 1, with UV, visible light spectrophotometric
Its absorption peak near infrared light is measured, as shown in figure 8, wherein GPB-1, GPB-2, GPB-3, GPB-4 respectively indicate iron gadolinium
Ratio is 100:1,30:1,3.5:1,0.9:1.As can be seen that prepared material have near infrared light region it is relatively strong wider
Absorption peak, it is controllable within the scope of 735~920nm.
Embodiment 9
The HGPB nano-particle solution that will will be prepared in embodiment 1, in the medium of different refractivity, with UV, visible light point
Light luminosity measures its maximum absorption band near infrared light, the relation curve of refractive index and maximum absorption band is obtained, such as Fig. 9 institute
Show.Its sensitivity can reach -450nm/RIU.
Finally it is necessary to explanations, above that specific embodiments of the present invention are described in detail, but it is only made
For example, the present invention is not restricted to particular embodiments described above.To those skilled in the art, any pair of this hair
The equivalent modifications and substitution of bright progress are also all among scope of the invention.Therefore, the spirit and scope of the present invention are not being departed from
Equal transformation made by lower and modification, all should be contained within the scope of the invention.
Claims (10)
1. a kind of multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium, which is characterized in that the nanometer diagnosis and treatment agent is tool
There is mesoporous and boring the particle of prussian blue nano containing gadolinium, wherein the molar ratio of ferro element and gadolinium element is 3.5:1, institute
A nanometer diagnosis and treatment agent is stated to be prepared via a method which:
(1) there are gadolinium source, source of iron, organic polymer protective agent and acid with good biocompatibility and reproducibility for evenly dispersed
Mixed solution after 60~120 DEG C of heat preservation a period of times, isolate solid to get the prussian blue nano particle containing gadolinium；
(2) the prussian blue nano particle by resulting containing gadolinium and the organic polymer with good biocompatibility and reproducibility
Protective agent and acid were uniformly mixed and after 100~160 DEG C of heat preservation a period of times, isolated solid to get the nanometer diagnosis and treatment
Agent.
2. the multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium according to claim 1, which is characterized in that described
The dynamics light scattering partial size of nano particle is 100~600 nm, and the size range of cavity is 80~200 nm.
3. the multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium according to claim 1 or 2, which is characterized in that
The nano particle has micropore and mesoporous, and wherein the size of micropore is 0.5~2 nm, and mesoporous size is 2.5~15 nm.
4. the multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium according to claim 1 or 2, which is characterized in that
Anti-tumor drug and/or gene are mounted in the cavity of the nano particle and/or duct.
5. the multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium according to claim 1, which is characterized in that step
(1) in, the gadolinium source be gadolinium water soluble salt, the source of iron be the potassium ferricyanide, the sodium ferricyanide and potassium ferrocyanide at least
One kind, the organic polymer protective agent with reproducibility are polyvinylpyrrolidone and/or chitosan, and the acid is hydrochloric acid
And/or sulfuric acid.
6. the multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium according to claim 1, which is characterized in that step
(1) in, in the mixed solution, gadolinium source, source of iron, the protectant mass ratio of the organic polymer with reproducibility are 1:(0.2
~100): (100~2000), the concentration in the gadolinium source are 0.01~0.5mol/L, and the concentration of the acid is 0.0001~2
Mol/L, soaking time are 4~72 hours.
7. the multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium according to claim 1, which is characterized in that step
(1) in, the preparation of the mixed solution the following steps are included:
A) gadolinium source, polyvinylpyrrolidone and acid are thoroughly mixed to form gadolinium source solution, and by source of iron, polyvinylpyrrolidine
Ketone and acid are thoroughly mixed to form source of iron solution；
B) gadolinium source solution is added drop-wise in source of iron solution under stiring, continues stirring after being added dropwise 1~6 hour.
8. the multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium according to claim 1, which is characterized in that step
(2) in, the organic polymer protective agent with reproducibility is polyvinylpyrrolidone and/or chitosan, and the acid is salt
Acid and/or sulfuric acid, the concentration of the acid are 1~4 mol/L.
9. the multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium according to claim 1, which is characterized in that step
(2) in, the prussian blue nano particle containing gadolinium, the organic polymer protective agent with reproducibility, sour mass ratio are 1:(0.5
~10): (0.5~5), soaking time are 1~5 hour.
10. the multi-functional hollow mesoporous prussian blue nano diagnosis and treatment agent containing gadolinium described in a kind of any one of claims 1 to 9 is being made
Application in the standby nanometer diagnosis and treatment agent for having both Magnetic resonance imaging, photoacoustic imaging and photo-thermal therapy effect, or in preparation media
Application in index sensor.
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| CN107496377B (en) * | 2017-10-16 | 2020-08-18 | 郑州大学 | Preparation method and application of hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug loading system |
| CN107890566A (en) * | 2017-11-13 | 2018-04-10 | 北京大学 | A kind of diagnosing tumor treatment preparation and its preparation method and application |
| CN107837404B (en) * | 2017-11-13 | 2018-12-28 | 中国科学院生物物理研究所 | A kind of nanoparticle diagnosing tumor treatment combination preparation and its preparation method and application |
| CN108840351B (en) * | 2018-05-23 | 2021-08-27 | 上海市第六人民医院 | Hollow mesoporous Prussian blue nanoparticles and preparation method thereof |
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| CN111821281A (en) * | 2020-07-31 | 2020-10-27 | 湖北大学 | Gd/Tm-PB nano-particles, preparation method thereof, multifunctional composite material, and preparation method and application thereof |
| CN116510040B (en) * | 2023-03-15 | 2023-09-22 | 徐州医科大学科技园发展有限公司 | Nanometer osteoarthritis diagnosis and treatment agent responded by metalloprotease and preparation method thereof |
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