CN105412948A - Multifunctional gadolinium-contained hollow mesoporous Prussian-blue nanometer treatment agent and preparation method and application thereof - Google Patents
Multifunctional gadolinium-contained hollow mesoporous Prussian-blue nanometer treatment agent and preparation method and application thereof Download PDFInfo
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
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- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
Abstract
The invention relates to multifunctional gadolinium-contained hollow mesoporous Prussian-blue nanometer treatment agent and a preparation method and application thereof. The nanometer treatment agent is gadolinium-contained Prussian-blue nanometer particles which have mesopores and are hollow inside, wherein the molar ratio of iron to gadolinium is (0.8-200) to 1. The hollow mesoporous nanometer treatment agent is good in biocompatibility, T1 weighted magnetic resonance imaging performance is outstanding, and the nanometer treatment agent has high absorption and outstanding photothermal conversion performance in a near-infrared area and is improved in imaging and tumor treatment compared with other Prussian-blue nanometer particles.
Description
Technical field
The present invention relates to technical field of nano material and field of biomedical materials, be specifically related to a kind of NMR (Nuclear Magnetic Resonance)-imaging (MRI) with excellence, photoacoustic imaging and photothermal deformation performance containing gadolinium hollow mesoporous Prussian blue (HGPB) nanoparticle, as one realize multi-modal imaging guide under to tumor thermotherapy, multifunctional nano diagnosis and treatment agent and preparation method thereof of the treatment such as chemotherapy.
Background technology
In recent years, the sickness rate of malignant tumor presents significant growth trend in China.Malignant tumor exceedes cardiovascular disease, becomes the primary lethal cause of disease of urbanite, life and the health of the serious threat mankind, brings burden and misery greatly to society, family and individual.Early find early treatment, strive for that before tumor cell does not spread, realize tumor efficiently treats, to save more life in the world to the treatment gold criterion of malignant tumor.Therefore, research and development high-performance, low cost, tumor earlier detection easy to use and treatment, the special needs that particularly infantile tumour is generally investigated and in art, Imaging for Monitoring and efficient oncotherapy technology are Chinese society and science and technology development strategy, have huge scientific meaning.
The early diagnosis of tumor and treatment are a difficult problem and the study hotspots of medical circle always, the focus of the crucial scientific and technical research be particularly integrated with functions such as diagnosis and monitoring, treatments scientific circles' concern especially.Nuclear magnetic resonance (Magneticresonaceimaging, MRI) utilize organism different tissues outside magnetic field to affect lower produce different resonance signals and carry out imaging, the power of signal depends on the relaxation time of proton in the content of the interior water of tissue and hydrone.This imaging technique has the advantages such as non-invasive diagnostic, the imaging of high-resolution anatomy and qualitative assessment pathogeny, is widely used clinically.T
1weighted magnetic resonance imaging technology makes signal intensity strengthen, and has higher detection accuracy, therefore becomes the focus of MRI research.The coordination compound of Gd has played important effect in the diagnosis of clinical MRI disease.Photoacoustic imaging is that the one that development in recent years is got up can't harm medical imaging procedure, its principle is when in pulsed laser irradiation to biological tissue, the light absorption of tissue will produce photoacoustic signal, the photoacoustic signal of biological tissue carries the light absorption characteristics information of tissue, can be reconstructed the light absorption distributed image in tissue by measurement photoacoustic signal.It combines the high contrast features of pure optical imagery and the high-penetration depth characteristic of pure ultra sonic imaging, the imaging of tissue of high-resolution and high-contrast can be provided, become one of important means of carrying out cancer earlier detection and treatment monitoring at present.
Can be there is serious toxic and side effects in nearly all patient according to statistics, and drug resistance in various degree appears in 90% patient, and neoplasm metastasis etc. appears in first visit patient more than half.The efficient treatment appearing as tumor and the minimizing toxic and side effects of nanometer biotechnology provide new approach.A kind of photo-thermal therapy technology of the novelty based on nano-carrier causes and pays close attention to widely in recent years.It will have the nano carrier material of near-infrared photo-thermal converting function, selectivity is accumulated to tumor locus, then only implement near infrared light to tumor region local to shine, make between tumor cell and intracellular nano material absorption near infrared light, and be converted into heat energy efficiently, make tumor produce local ultra-high temperature, thus easily tumor cell is killed.The heat cancer target of this near infrared light mediation transmits, and ensure that in treatment and can not cause damage by normal tissue, significantly improve safety and the effectiveness of thermotherapy.This Therapeutic mode is tumor " photo-thermal therapy ", its maximum feature achieves the effective treatment to nearly all entity tumor theoretically, comprise chemicotherapy failure and produce the efficient treatment of resistant tumors, the adjoint toxic and side effects of chemicotherapy can not be produced and the life in patients that causes declines simultaneously.
Therefore, if can provide a kind of simultaneously as effective NMR (Nuclear Magnetic Resonance)-imaging and photoacoustic imaging contrast agent, and can realize the nanometer diagnosis and treatment agent of photo-thermal therapy and chemotherapy to tumor, good potential applicability in clinical practice will be had.
Chinese patent CN102397562A is open a kind of by Prussian blue load Gd
3+contrast agent, Chinese patent CN103449477A discloses a kind of prussian blue nano material contrast agent containing gadolinium element, but in these contrast agent, gadolinium be only adsorbed in Prussian blue in, and Prussian blue particle does not have cavity and mesoporous, cannot load antitumor drug etc.In addition these contrast agent can not regulate effectively to its near infrared absorption, not only can not realize photoacoustic imaging and photo-thermal therapy more efficiently, can't as the regulatable chemical probe of sensitivity.
Summary of the invention
For the problems referred to above existing for prior art and demand, the present invention aims to provide a kind of multi-functional containing hollow mesoporous Prussian blue nanometer diagnosis and treatment agent of gadolinium and preparation method thereof with for the Accurate Diagnosis of the major diseases such as tumor and the biomedical applications of efficient treatment aspect.
On the one hand, the invention provides a kind of multi-functional containing the hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium, described nanometer diagnosis and treatment agent be have mesoporous and boring containing gadolinium prussian blue nano granule, wherein the mol ratio of ferrum element and gadolinium element is (0.8 ~ 200): 1.
Hollow meso-porous nano diagnosis and treatment agent good biocompatibility of the present invention, T
1weighted magnetic resonance imaging excellent performance, has strong absorption near infrared region, and has excellent photothermal deformation performance, and the nanoparticle Prussian blue compared to other has lifting in imaging and treatment tumor.Based in the nanometer diagnosis and therapy system of HGPB, by regulating the ratio of ferrum gadolinium, realize regulating its NMR (Nuclear Magnetic Resonance)-imaging performance, the ratio of ferrum gadolinium is less, and its longitudinal relaxation rate is larger, T
1-Weighted Kernel nuclear magnetic resonance performance is better; Due to the position that gadolinium ion is different in the structure, affect cyanogen bridge and the ion-electron density combined with it and orbital energy, by regulating the ratio of ferrum gadolinium, just can realize the absorption of HGPB near infrared region, thus realize the regulation and control to photoacoustic imaging and photo-thermal therapy efficiency.In addition, due to its hollow meso-hole structure, good biocompatibility and biological safety, impart its huge applications potentiality as pharmaceutical carrier, can supporting chemotherapeutics etc. be realized.This nanometer diagnosis and therapy system substantially increases the Diagnosis and Treat efficiency to tumor, reach the object of Diagnosis and Treat integration, solve heat in traditional tumour photo-thermal therapy incomplete to tumour ablation at inside tumor skewness, cause tumor to be easy to clinical practice difficult problems such as recurring, chemical therapy toxic side effect is large, there is good potential applicability in clinical practice.
Preferably, the kinetics light scattering particle diameter of described nano-particle is 100 ~ 600nm, and the size range of cavity is 80 ~ 200nm.
Preferably, described nano-particle has micropore and mesoporous, and wherein the size of micropore is 0.5 ~ 2nm, and mesoporous size is 2.5 ~ 15nm.
Preferably, in the cavity and/or duct of described nano-particle, antitumor drug and/or gene is mounted with.
On the other hand, the invention provides the above-mentioned multi-functional preparation method containing the hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium, comprise the following steps:
(1) by dispersedly having gadolinium source, source of iron, there is the organic polymer protective agent of good biocompatibility and reproducibility and the mixed solution of acid after 60 ~ 120 DEG C of insulation a period of times, isolate solid, obtain the prussian blue nano particle containing gadolinium;
(2) by gained containing gadolinium prussian blue nano particle with there is the organic polymer protective agent of good biocompatibility and reproducibility and sourly mix homogeneously and after being incubated a period of time in 100 ~ 160 DEG C, isolating solid, obtain described nanometer diagnosis and treatment agent.
Preparation method low in raw material price of the present invention is easy to get, preparation method simple, be easy to batch production.
Preferably; in step (1); described gadolinium source is the water soluble salt of gadolinium; described source of iron is at least one in the potassium ferricyanide, sodium ferricyanide and potassium ferrocyanide; the described organic polymer protective agent with good biocompatibility and reproducibility is polyvinylpyrrolidone and/or chitosan, and described acid is hydrochloric acid and/or sulphuric acid.
Preferably; in step (1); in described mixed solution; gadolinium source, source of iron, the protectant mass ratio of organic polymer with good biocompatibility and reproducibility are 1:(0.2 ~ 100): (100 ~ 2000); the concentration in described gadolinium source is 0.01 ~ 0.5mol/L; the concentration of described acid is 0.0001 ~ 2mol/L, and temperature retention time is 4 ~ 72 hours.
Preferably, in step (1), the preparation of described mixed solution comprises the following steps:
A) gadolinium source, polyvinylpyrrolidone and acid are thoroughly mixed to form gadolinium source, and source of iron, polyvinylpyrrolidone and acid are thoroughly mixed to form source of iron solution;
B) under agitation gadolinium source solution is added drop-wise in source of iron solution, dropwises rear continuation stirring 1 ~ 6 hour.
Preferably, in step (2), described in there is good biocompatibility and reproducibility organic polymer protective agent be polyvinylpyrrolidone and/or chitosan, described acid is hydrochloric acid and/or sulphuric acid, and the concentration of described acid is 1 ~ 4mol/L.
Preferably; in step (2); containing gadolinium prussian blue nano particle, have good biocompatibility and reproducibility organic polymer protective agent, acid mass ratio be 1:(0.5 ~ 10): (0.5 ~ 5), temperature retention time is 1 ~ 5 hour.
Again on the one hand, the present invention also provides the above-mentioned multi-functional application had concurrently in preparation containing the hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium in the nanometer diagnosis and treatment agent of NMR (Nuclear Magnetic Resonance)-imaging, photoacoustic imaging and photo-thermal therapy effect, or is preparing the application in medium refraction index sensor.
Accompanying drawing explanation
Fig. 1 is transmission electron microscope (TEM) photo and the preparation flow of the embodiment of the present invention 1 gained HGPB nanoparticle;
Fig. 2 is that the element mapping of the present embodiment 1 gained HGPB nanoparticle schemes (Gd, Fe, C, N and K);
Fig. 3 is UV ~ vis absorption curve that the embodiment of the present invention 1 gained HGPB nanoparticle is corresponding;
The HGPB nanoparticle of Fig. 4 embodiment 1 gained variable concentrations is under the irradiation of laser, and solution temperature is curve chart over time;
Fig. 5 is the photoacoustic signal value curve of the embodiment of the present invention 1 gained variable concentrations HGPB nanoparticle and the optoacoustic picture of correspondence;
Fig. 6 is the external 1/T of the embodiment of the present invention 1 gained HGPB nanoparticle
1~ concentration curve;
Fig. 7 is the external 1/T of the embodiment of the present invention 1 gained HGPB nanoparticle
2~ concentration curve;
Fig. 8 is UV ~ vis absorption curve of the HGPB nano-particle solution containing different gadolinium amount of preparation in the embodiment of the present invention 1; Fig. 9 is the refractive index of the embodiment of the present invention 1 gained HGPB nanoparticle and the relation curve of maximum absorption band.
Detailed description of the invention
Further illustrate the present invention below in conjunction with accompanying drawing and following embodiment, should be understood that accompanying drawing and following embodiment are only for illustration of the present invention, and unrestricted the present invention.
The present invention is directed to the bottleneck of existing NMR contrast agent in clinical practice, by introducing gadolinium element in Prussian blue structure, near infrared region, there is Modulatory character, form multifunctional nano diagnosis and treatment agent.This nanometer diagnosis and treatment agent can as effective NMR (Nuclear Magnetic Resonance)-imaging and photoacoustic imaging contrast agent, for the diagnosis of tumor and monitor treatment process and therapeutic efficiency.In addition, this nanoparticle can realize photo-thermal therapy to tumor, effectively eliminates tumor.
The invention provides a kind of multi-functional containing gadolinium hollow mesoporous Prussian blue (HGPB) nanoparticle, described HGPB nanoparticle comprises the prussian blue nano granule of the structure with mesoporous, boring, and at Prussian blue middle introducing gadolinium, wherein the mol ratio of ferrum gadolinium is in (0.8 ~ 200): controllable in 1 scope, be preferably in (1 ~ 30): controllable in 1 scope, more preferably, ferrum gadolinium molar ratio is 3.5:1, and now r1 value can reach 34.1mM
-1s
-1, r2 value can reach 243mM
-1s
- 1.By regulating the ratio of ferrum gadolinium, realizing regulating its NMR (Nuclear Magnetic Resonance)-imaging performance, and realizing the absorption of HGPB near infrared region, thus realize the regulation and control to photoacoustic imaging and photo-thermal therapy efficiency.HGPB particle of the present invention as the NMR contrast agent of excellence, can be particularly useful for T
1the nuclear magnetic resonance of weighting.
Described HGPB particle is near infrared region maximum absorption band controllable within the scope of 680 ~ 950nm.HGPB shell has strong absorption, high photo-thermal conversion efficiency near infrared light region (λ=700 ~ 1100nm).Under the irradiation of near infrared light, pathological tissues place temperature is made to reach more than 42.5 DEG C.Therefore, this HGPB particle can realize photo-thermal therapy to tumor, effectively eliminates tumor.
Described HGPB nanoparticle as the photoacoustic imaging contrast agent of excellence, can realize the early diagnosis to tumor, oncotherapy ground monitoring in real time etc.
Described HGPB nanoparticle, can as a kind of medium refraction index chemical probe etc. of excellence to the sensitivity of medium refraction index controllable in 0 ~-600nm/RIU scope.
The surface band negative charge of described HGPB nanoparticle, electrokinetic potential is about-60 ~ 0mV.It is controlled that the nano-particle kinetics light scattering particle diameter of described HGPB nanoparticle is about 100 ~ 600nm (being preferably 200 ~ 600nm), and cavity size scope is that 80 ~ 200nm is controlled.Described HGPB nanoparticle has micropore and mesoporous, and wherein the size of micropore is that 0.5 ~ 2nm (being preferably 0.5 ~ 1.5nm) is controlled, and macropore range is: 2.5 ~ 15nm is controlled.Described HGPB nanoparticle specific surface area is 70 ~ 300m
2/ g, pore volume is 0.1 ~ 1cm
3/ g, aperture is 2 ~ 15nm.
HGPB nanometer diagnosis and treatment agent of the present invention has huge cavity (hollow cubic body) and meso-hole structure, can as pharmaceutical carrier, realize supporting guest molecule, comprise antitumor drug, biomacromolecule (such as gene) etc., such as can realize the coated and transmission to antitumor drug and gene, as good drug delivery system, described antitumor drug and gene include but not limited to doxorubicin hydrochloride, paclitaxel, irinotecan, aclarubicin, oxaliplatin, mitoxantrone, a kind of or two kinds and two or more mixture in the Nano medications such as vincristine.Antitumor drug discharges at tumor locus, realizes the Synergistic treatment tumor of chemotherapy and above-mentioned photo-thermal therapy.Meanwhile, realize NMR (Nuclear Magnetic Resonance)-imaging and photoacoustic imaging diagnosis and for the Real-Time Monitoring therapeutic effect of tumor at tumor locus, realize NMR (Nuclear Magnetic Resonance)-imaging and photoacoustic imaging guide under thermotherapy and the diagnosis and therapy system of chemotherapy Synergistic treatment tumor.
HGPB nanometer diagnosis and treatment agent of the present invention has excellent biocompatibility and biological safety, improving it on the basis of NMR (Nuclear Magnetic Resonance)-imaging, photoacoustic imaging and photo-thermal therapy performance, achieve the photo-thermal therapy etc. under the NMR (Nuclear Magnetic Resonance)-imaging of tumor and photoacoustic imaging are guided, substantially increase the efficiency of Precise Diagnosis to tumor and treatment.
HGPB nanoparticle of the present invention is prepared by following method: first prepare single dispersing, size uniformity containing the mesoporous prussian blue nano particle of gadolinium; then adopt the method for " surface protection; inner etching ", prepare the HGPB nanoparticle of single dispersing, size uniformity.Specifically; gadolinium source, source of iron and the protective agent with good biocompatibility and reproducibility are fully mixed; utilize it under the condition of hydro-thermal, form the prussian blue nano particle containing gadolinium; then protective agent is utilized to protect surface; acid is as etching agent; hydrothermal method prepares HGPB nanoparticle, and the nanoparticle obtained can play a role in imaging (photoacoustic imaging and NMR (Nuclear Magnetic Resonance)-imaging) and treatment (photo-thermal therapy), realizes the diagnosis and treatment integration of tumor.
In one embodiment, the preparation method of HGPB nanoparticle of the present invention comprises the steps:
A) fully mix under gadolinium source, the organic polymer protective agent with good biocompatibility and reproducibility and acid and source of iron, the organic polymer protective agent with good biocompatibility and reproducibility and sour room temperature respectively;
B) the gadolinium source solution mixed is added drop-wise in source of iron solution, continues magnetic and stir;
C) process under solution being transferred to uniform temperature environment;
D) 13000rpm/min, within 10 minutes, collected by centrifugation can obtain the prussian blue nano particle containing gadolinium;
E) the above-mentioned nanoparticle of certain mass and certain density acid and the organic polymer protective agent with good biocompatibility and reproducibility fully mix; place in the baking oven of uniform temperature; etching certain hour, 13000rpm/min, 10 minutes centrifugal can obtain HGPB nanoparticle.
Step a) described in gadolinium source can be the water soluble salt of gadolinium, such as Gadolinium trinitrate, Gadolinium trichloride etc., be preferably Gadolinium trinitrate.In the solution of gadolinium source, the concentration in gadolinium source can be 0.01 ~ 0.5mol/L, is preferably 0.05 ~ 0.2mol/L.
Step a) described in source of iron can be the potassium ferricyanide, sodium ferricyanide or potassium ferrocyanide, be preferably the potassium ferricyanide.In source of iron solution, the concentration of source of iron can be 0.01 ~ 0.5mol/L, is preferably 0.05 ~ 0.2mol/L.
Step a) described in the organic polymer protective agent with good biocompatibility and reproducibility can for polyvinylpyrrolidone, chitosan etc.
In one example, in the solution of gadolinium source, overall solution volume is 10 ~ 1000ml, and be preferably 50 ~ 200ml, the amount of protective agent (such as polyvinylpyrrolidone) is 500mg ~ 10g, is preferably 1 ~ 5g.In another example, in source of iron solution, overall solution volume is 10 ~ 1000ml, and be preferably 50 ~ 200ml, the amount of protective agent (such as polyvinylpyrrolidone) is 500mg ~ 10g, is preferably 1 ~ 5g.Should be understood that each consumption of shown here is only an example for illustrating usage ratio, can expand in proportion on each consumption according to actual needs or reduce.
Step a) described in acid be recommended as hydrochloric acid, sulphuric acid etc., preferred hydrochloric acid.The concentration of acid is recommended as 0.0001 ~ 2mol/L, is preferably 0.01 ~ 0.1mol/L.
Step a) described in hybrid mode be recommended as magnetic stirring, ultrasonic mixing etc., be preferably magnetic be uniformly mixed mode.
Step b) described in drop rate be recommended as 10 ~ 100ml/h, be preferably 30 ~ 60ml/h.
Step b) described in magnetic stirring condition be recommended as stirring at room temperature 1 ~ 6h, be recommended as room temperature magnetic stir 2 ~ 4h.
Present embodiment by above-mentioned steps a) and step b) come for the preparation of the reaction solution of prussian blue nano particle of synthesis containing gadolinium; but should understand; be not limited thereto, dispersedly have gadolinium source, source of iron as long as can obtain, there is the organic polymer protective agent of good biocompatibility and reproducibility and the mixed solution of acid.In this mixed solution, gadolinium source, source of iron, the protectant mass ratio of organic polymer with good biocompatibility and reproducibility can be 1:(0.2 ~ 100): (100 ~ 2000).The concentration in gadolinium source can be 0.01 ~ 0.5mol/L, is preferably 0.025 ~ 0.1mol/L.The concentration of acid can be 0.0001 ~ 2mol/L, is preferably 0.01 ~ 0.1mol/L.
Step c) described in environment be recommended as baking oven, oil bath etc. 60 ~ 120 DEG C, be preferably 80 ~ 100 DEG C, baking oven.Processing time can be 4 ~ 72 hours, is preferably 12 ~ 24 hours.
In present embodiment, steps d) in centrifugal rotating speed and time be not limited to above-mentioned, in addition, separate mode is also not limited to centrifugal, such as, also can adopt filtration etc., as long as can obtain the prussian blue nano particle containing gadolinium.
Step e) in, the organic polymer protective agent with good biocompatibility and reproducibility can be polyvinylpyrrolidone, chitosan etc.
Step e) in, acid is recommended as hydrochloric acid, sulphuric acid etc., preferred hydrochloric acid.The concentration of acid is recommended as 1 ~ 4mol/L, is preferably 1 ~ 2mol/L.
In one example, step e) in, the quality of nanoparticle is 10 ~ 200mg; be preferably 20 ~ 100mg, the quality of protective agent (such as polyvinylpyrrolidone) is 5 ~ 2000mg, is preferably 100 ~ 1000mg; the volume of acid is 10 ~ 200mL, is preferably 30 ~ 80mL.Should be understood that each consumption of shown here is only an example for illustrating usage ratio, can expand in proportion on each consumption according to actual needs or reduce.
Step e) described in uniform temperature be recommended as 100 ~ 160 DEG C, be preferably 120 ~ 140 DEG C.
Step e) described in certain hour be recommended as 1 ~ 5h, be preferably 3 ~ 4h.In addition, should be understood that step e equally) in centrifugal rotating speed and time be not limited to above-mentioned, separate mode is also not limited to centrifugal, such as, also can adopt filtration etc., as long as can obtain HGPB nanoparticle.
The invention provides a kind of method that low in raw material price is easy to get, preparation method simple, be easy to produce in batches and prepare the multifunctional nano diagnosis and treatment agent that there is controlled, the excellent photothermal deformation performance of good dispersion and stability, good biocompatibility, particle diameter and aperture, significantly NMR (Nuclear Magnetic Resonance)-imaging radiography and photoacoustic imaging performance and tumor is carried out to photo-thermal therapy and chemotherapy Synergistic treatment.
Exemplify embodiment below further to describe the present invention in detail.Should understand equally; following examples are only used to further illustrate the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.The technological parameter etc. that following example is concrete is also only an example in OK range, and namely those skilled in the art can be done in suitable scope by explanation herein and select, and do not really want the concrete numerical value being defined in Examples below.
Embodiment 1
Prepare the mesoporous prussian blue nano particle of single dispersing, uniform particle diameter:
A) be fully mix under the hydrochloric acid solution of 0.01mol/L and the hydrochloric acid solution room temperature of the 33mg potassium ferricyanide, 1g polyvinylpyrrolidone and 0.01mol/L respectively by 45mg Gadolinium trinitrate, 1g polyvinylpyrrolidone and concentration;
B) the gadolinium source solution mixed is added drop-wise in source of iron solution with the speed of 40ml/h, continues magnetic and stir 3h;
C) solution is transferred to ageing 24h in 80 DEG C of baking ovens;
D) 13000rpm/min, within 10 minutes, collected by centrifugation can obtain the prussian blue nano particle containing gadolinium;
E) the above-mentioned nanoparticle of certain mass and certain density acid fully mix, and place in the baking oven of uniform temperature, etching certain hour, 13000rpm/min, and 10 minutes centrifugal can obtain HGPB nanoparticle, specific as follows:
Preparation HGPB nanoparticle: it is in the hydrochloric acid solution of 1mol/L that the polyvinylpyrrolidone weighing the above-mentioned mesoporous prussian blue nano particle for preparing of 40mg and 100mg is fully mixed in 40ml concentration, magnetic stirs 3h, go to water heating kettle and place 3h in 140 DEG C of baking ovens, centrifugal washing can obtain the HGPB nanoparticle that ferrum gadolinium ratio is 3.5:1.
Fig. 1 is the mesoporous prussian blue nano particle of the present embodiment 1 gained and transmission electron microscope (TEM) photo of HGPB nanoparticle and preparation flow schematic diagram.Wherein leftmost for containing the mesoporous prussian blue nano particle of gadolinium, rightmost is HGPB nanoparticle, containing the mesoporous prussian blue nano particle of gadolinium under protectant protection, can form HGPB nanoparticle through acid etch.
Fig. 2 is that the element mapping of the present embodiment 1 gained HGPB nanoparticle schemes (Gd, Fe, C, N and K); Can find out that gadolinium element is uniformly distributed in the middle of nano particle structure.In the HGPB nanoparticle of the present embodiment gained, the mol ratio of ferrum gadolinium is 3.5:1.
Embodiment 2
Prepare ferrum gadolinium ratio be 200:1 containing the hollow mesoporous prussian blue nano particle of gadolinium:
A) be fully mix under the hydrochloric acid solution of 0.01mol/L and the hydrochloric acid solution room temperature of the 33mg potassium ferricyanide, 1g polyvinylpyrrolidone and 2mol/L respectively by 45mg Gadolinium trinitrate, 1g polyvinylpyrrolidone and concentration;
B) the gadolinium source solution mixed is added drop-wise in source of iron solution with the speed of 40ml/h, continues magnetic and stir 3h;
C) solution is transferred to ageing 24h in 80 DEG C of baking ovens;
D) 13000rpm/min, within 10 minutes, collected by centrifugation can obtain the prussian blue nano particle containing gadolinium;
E) the above-mentioned nanoparticle of certain mass and certain density acid fully mix, and place in the baking oven of uniform temperature, etching certain hour, 13000rpm/min, and 10 minutes centrifugal can obtain HGPB nanoparticle, specific as follows:
Preparation HGPB nanoparticle: it is in the hydrochloric acid solution of 2mol/L that the polyvinylpyrrolidone weighing the above-mentioned mesoporous prussian blue nano particle for preparing of 40mg and 100mg is fully mixed in 40ml concentration, magnetic stirs 3h, go to water heating kettle and place 3h in 140 DEG C of baking ovens, centrifugal washing can obtain the HGPB nanoparticle that ferrum gadolinium ratio is 200:1.
Embodiment 3
Prepare ferrum gadolinium ratio be 0.8:1 containing the hollow mesoporous prussian blue nano particle of gadolinium:
A) be fully mix under the hydrochloric acid solution of 0.01mol/L and the hydrochloric acid solution room temperature of the 33mg potassium ferricyanide, 1g polyvinylpyrrolidone and 0.0001mol/L respectively by 180mg Gadolinium trinitrate, 1g polyvinylpyrrolidone and concentration;
B) the gadolinium source solution mixed is added drop-wise in source of iron solution with the speed of 40ml/h, continues magnetic and stir 3h;
C) solution is transferred to ageing 72h in 80 DEG C of baking ovens;
D) 13000rpm/min, within 10 minutes, collected by centrifugation can obtain the prussian blue nano particle containing gadolinium;
E) the above-mentioned nanoparticle of certain mass and certain density acid fully mix, and place in the baking oven of uniform temperature, etching certain hour, 13000rpm/min, and 10 minutes centrifugal can obtain HGPB nanoparticle, specific as follows:
Preparation HGPB nanoparticle: it is in the hydrochloric acid solution of 1mol/L that the polyvinylpyrrolidone weighing the above-mentioned mesoporous prussian blue nano particle for preparing of 40mg and 100mg is fully mixed in 40ml concentration, magnetic stirs 3h, go to water heating kettle and place 2.5h in 140 DEG C of baking ovens, centrifugal washing can obtain the HGPB nanoparticle that ferrum gadolinium ratio is 0.8:1.
Embodiment 4
The HGPB obtained in embodiment 1 is scattered in PBS, surveys its absworption peak near infrared light place with ultraviolet-uisible spectrophotometer, as shown in Figure 3.Can find out, prepared material has comparatively strong wider absworption peak near infrared light region, the strongest at about 808nm.
Embodiment 5
The many parts of HGPB obtained in Example 1 fall apart respectively in PBS, and each 1mL of solution of 12.5ppm, 25ppm, 50ppm, 100ppm is in quartz colorimetric utensil, and power density is 1W/cm
2wavelength is 808nm laser irradiation 10min, recording solution different time points temperature as shown in Figure 4, with the increase of exposure time, solution temperature raises gradually, and concentration is higher, heating rate is faster, during 100ppm, irradiation can be raised to 23 DEG C in ten minutes, illustrates that HGPB nanoparticle has excellent photothermal deformation performance.
Embodiment 6
By the HGPB nanoparticle of preparation in embodiment 1, the HGPB nano-particle solution of variable concentrations carries out photoacoustic imaging experiment, obtains photoacoustic imaging figure and photoacoustic signal value, as Fig. 5, shows that HGPB nanoparticle is a kind of photoacoustic imaging contrast agent of excellence.
Embodiment 7
By the HGPB nano-particle solution of preparation in embodiment 1 at 37 DEG C, test its T1 ~ MRI and T2 ~ MRI imaging performance.Result display is if the r1 value of Fig. 6 and Fig. 7, HGPB nanoparticle is up to 34.1mM
~ 1s
~ 1, r2 value reaches 243mM
~ 1s
~ 1, show that it has excellent NMR (Nuclear Magnetic Resonance)-imaging radiography performance.
Embodiment 8
The just HGPB nano-particle solution containing different gadolinium amount of preparation in embodiment 1, its absworption peak near infrared light place is surveyed with ultraviolet-uisible spectrophotometer, as shown in Figure 8, wherein GPB-1, GPB-2, GPB-3, GPB-4 represent that ferrum gadolinium ratio is 100:1,30:1,3.5:1,0.9:1 respectively.Can find out, prepared material has comparatively strong wider absworption peak near infrared light region, controllable within the scope of 735 ~ 920nm.
Embodiment 9
The just HGPB nano-particle solution of preparation in embodiment 1, in the medium of different refractivity, surveys its maximum absorption band near infrared light place with ultraviolet-uisible spectrophotometer, obtains the relation curve of refractive index and maximum absorption band, as shown in Figure 9.Its sensitivity can reach-450nm/RIU.
Finally be necessary to illustrate, be described in detail specific embodiments of the invention above, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, equalization conversion done without departing from the spirit and scope of the invention and amendment, all should contain within the scope of the invention.
Claims (11)
1. multi-functional containing the hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium, it is characterized in that, described nanometer diagnosis and treatment agent be have mesoporous and boring containing gadolinium prussian blue nano granule, wherein the mol ratio of ferrum element and gadolinium element is (0.8 ~ 200): 1.
2. according to claim 1 multi-functional containing the hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium, it is characterized in that, the kinetics light scattering particle diameter of described nano-particle is 100 ~ 600nm, and the size range of cavity is 80 ~ 200nm.
3. according to claim 1 and 2 multi-functional containing the hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium, it is characterized in that, described nano-particle has micropore and mesoporous, and wherein the size of micropore is 0.5 ~ 2nm, and mesoporous size is 2.5 ~ 15nm.
4. according to any one of claim 1 to 3 multi-functional containing the hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium, it is characterized in that, in the cavity and/or duct of described nano-particle, be mounted with antitumor drug and/or gene.
5. the multi-functional preparation method containing the hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium according to any one of Claims 1-4, is characterized in that, comprise the following steps:
(1) by dispersedly having gadolinium source, source of iron, there is the organic polymer protective agent of good biocompatibility and reproducibility and the mixed solution of acid after 60 ~ 120 DEG C of insulation a period of times, isolate solid, obtain the prussian blue nano particle containing gadolinium;
(2) by gained containing gadolinium prussian blue nano particle with there is the organic polymer protective agent of good biocompatibility and reproducibility and sourly mix homogeneously and after being incubated a period of time in 100 ~ 160 DEG C, isolating solid, obtain described nanometer diagnosis and treatment agent.
6. preparation method according to claim 5; it is characterized in that; in step (1); described gadolinium source is the water soluble salt of gadolinium; described source of iron is at least one in the potassium ferricyanide, sodium ferricyanide and potassium ferrocyanide; the described organic polymer protective agent with reproducibility is polyvinylpyrrolidone and/or chitosan, and described acid is hydrochloric acid and/or sulphuric acid.
7. the preparation method according to claim 5 or 6; it is characterized in that; in step (1); in described mixed solution; gadolinium source, source of iron, the protectant mass ratio of organic polymer with reproducibility are 1:(0.2 ~ 100): (100 ~ 2000); the concentration in described gadolinium source is 0.01 ~ 0.5mol/L, and the concentration of described acid is 0.0001 ~ 2mol/L, and temperature retention time is 4 ~ 72 hours.
8. the preparation method according to any one of claim 5 to 7, is characterized in that, in step (1), the preparation of described mixed solution comprises the following steps:
A) gadolinium source, polyvinylpyrrolidone and acid are thoroughly mixed to form gadolinium source, and source of iron, polyvinylpyrrolidone and acid are thoroughly mixed to form source of iron solution;
B) under agitation gadolinium source solution is added drop-wise in source of iron solution, dropwises rear continuation stirring 1 ~ 6 hour.
9. the preparation method according to any one of claim 5 to 8; it is characterized in that, in step (2), described in there is reproducibility organic polymer protective agent be polyvinylpyrrolidone and/or chitosan; described acid is hydrochloric acid and/or sulphuric acid, and the concentration of described acid is 1 ~ 4mol/L.
10. the preparation method according to any one of claim 5 to 9; it is characterized in that; in step (2), be 1:(0.5 ~ 10 containing the prussian blue nano particle of gadolinium, the organic polymer protective agent with reproducibility, sour mass ratio): (0.5 ~ 5), temperature retention time is 1 ~ 5 hour.
The multi-functional application had concurrently in preparation containing the hollow mesoporous prussian blue nano diagnosis and treatment agent of gadolinium in the nanometer diagnosis and treatment agent of NMR (Nuclear Magnetic Resonance)-imaging, photoacoustic imaging and photo-thermal therapy effect according to any one of 11. 1 kinds of Claims 1-4, or preparing the application in medium refraction index sensor.
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