CN108434462A - A kind of multifunctional nano diagnosis and treatment agent and the preparation method and application thereof of mesoporous poly-dopamine load manganese carbonyl - Google Patents
A kind of multifunctional nano diagnosis and treatment agent and the preparation method and application thereof of mesoporous poly-dopamine load manganese carbonyl Download PDFInfo
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- 238000011282 treatment Methods 0.000 title claims abstract description 64
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 46
- 238000003745 diagnosis Methods 0.000 title claims abstract description 46
- 229920001690 polydopamine Polymers 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- QFEOTYVTTQCYAZ-UHFFFAOYSA-N dimanganese decacarbonyl Chemical group [Mn].[Mn].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] QFEOTYVTTQCYAZ-UHFFFAOYSA-N 0.000 title claims abstract description 18
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 19
- 230000002195 synergetic effect Effects 0.000 abstract description 4
- 101100513612 Microdochium nivale MnCO gene Proteins 0.000 description 53
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- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 7
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
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- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- 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
- A61K49/1821—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
- 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
- A61K49/1827—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 having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1851—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 having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
- A61K49/1857—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 having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
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Abstract
The invention discloses the multifunctional nano diagnosis and treatment agent and the preparation method and application thereof that a kind of mesoporous poly-dopamine loads manganese carbonyl.Multifunctional nano diagnosis and treatment agent wraps up hydrophobic manganese carbonyl drug by water-soluble mesoporous poly-dopamine carrier；The mass ratio of mesoporous poly-dopamine and manganese carbonyl is 18：1.The multifunctional nano diagnosis and treatment agent realizes MRI and the gas under photoacoustic imaging guiding and photo-thermal synergistic treatment, is expected to improve oncotherapy effect and biocompatibility is good, have clinical application potentiality.
Description
Technical field
The invention belongs to field of biomedical materials, specifically, being related to a kind of multi-functional diagnosis and treatment agent and preparation method thereof.
Background technology
Currently, in order to realize Precise Diagnosis and efficiently treatment disease, designed diagnosis and treatment agent generally requires to be provided simultaneously with more
Mould is imaged and the functions such as treatment.Clinically generally using operation, radiotherapy, chemotherapy these traditional means treating cancers, not only pair
More and weak curative effect is acted on, it is difficult to thoroughly eradicate malignant tumour.The tumor thermal therapy that near infrared light mediates is as a kind of superior
Local therapeutic approaches attract attention in recent years.Photo-thermal therapy is because it is with deep tissue penetration and organization security, knot
The agent of closing light hot-cast socket can realize effective killing to profound tumor tissues by non-intruding means.Compared with traditional remedies, light
Heat cure has Non-Invasive, highly selective, high therapeutic efficiency, the advantages such as small to surrounding health tissue's damage.It has reported at present
A variety of photothermal conversion agent, including inorganic nano material, for example, gold nanosphere, silver nano-grain, two-dimentional transition metal sulfide,
Graphene, carbon nanotube etc. have been obtained for widely studying due to its good photothermal conversion efficiency.However, most of nothings
Machine nano material photostability is poor, biocompatibility is bad, and difficult to degrade and metabolism has genotoxic potential, these are greatly limited
The development of photo-thermal therapy.
In numerous emerging photothermal conversion agent, poly-dopamine（PDA）People are caused as a kind of photo-thermal material
Concern.Poly-dopamine is the main component of natural biological pigment melanin, so having excellent biocompatibility.With more
Bar amine is that the poly-dopamine nanoparticle that raw material is prepared is with good stability, biodegradability, can with carrying medicament,
Photothermal conversion preparation be can be used as photo-thermal therapy of cancer（PTT）, shown in the early diagnosis of disease and targeted drug conveying
Go out distinctive advantage.But poly-dopamine is as a kind of solid nano-particle, the load for hydrophobic drug, drugloading rate and packet
Envelope rate is not high.As a kind of new material in PDA material, mesoporous poly-dopamine（Mesoporous polydopamine,
MPDA）With pore passage structure, preparation process it is simple, it is of low cost and with high specific surface area, high photothermal conversion efficiency and
The advantages such as excellent biocompatibility and cause to pay close attention to.Guan in 2016 etc. is synthesized by the heterogeneous construction from part design in interface first
A kind of mesoporous poly-dopamine nano-particle with radial oriented duct can be made by the way that the volume of TMB is added in control system
MPDA takes on any of a number of shapes, such as bowl fills, is spherical, to meet different application demands.In addition, based on the excellent light of MPDA materials
Absorption characteristic can be used as photothermal conversion agent and be applied to photo-thermal therapy of cancer, builds multi-functional cancer diagnosis and treatment platform.But it there is no at present
Application report of the material in medical imaging and diagnosis and treatment agent.It would therefore be desirable to extend mesoporous poly-dopamine to a deeper level
Application.
Utilize gaseous signal molecule（Such as CO, NO）The Gases for Treating for replacing traditional chemotherapeutics, due to having selection
Property kill cancer cell and protect the anticancer property of normal cell, it is considered to be the oncotherapy means of a kind of emerging " green ",
It has broad application prospects.Carbon monoxide（CO）Being can not in one of endogenous metabolism object of normal body and physiological environment
Or scarce a kind of signaling molecule.The study found that the CO of low dosage has many diseases such as inflammation, cancer and angiocardiopathy etc.
Significant therapeutic effect.And have been reported proves that the direct use of CO can generate cancer cell cell apoptosis-promoting effect before, together
When reduce Chemotherapeutic Drugs On Normal cell toxicity.Current research is mainly concentrated in discharges molecule by CO（CORM）Safety is passed
It send to required action site, the release of CO is mostly spontaneous or is excited by ultraviolet/visible light.Spontaneous type is difficult to realize
Effective control of CO releases, CO burst sizes are few, are difficult to realize expected curative effect in vivo.In addition, ultraviolet/visible light excitated type is also deposited
It is big in the phototoxicity of skin, the limited defect of penetration depth, so treatment superficial foci is only used for, to the effect of deep tumor
Difference limits the development of CO Gases for Treating tumours.
In diagnosis and treatment agent designs and builds, visible diagnosis part is particularly critical.Researcher need by suitably at
Understand the position of tumour, the internal enrichment condition being distributed with it in tumor locus of size and therapeutic agent as technology.Nuclear-magnetism is total
It shakes imaging（MRI）It is a kind of more satisfactory imaging pattern that diagnostic assistance can be provided for oncotherapy and monitored in real time, tool
There is higher spatial resolution, not the limitation of tissue penetration depths, it has also become most strong diagnosis hand in contemporary clinical diagnosis
One of section.Current clinically common gadolinium（Gd）Contrast agent, after injection, gadolinium can have in brain and its hetero-organization centainly to retain,
It may cause potential risks.In recent years, the research emphasis of magnetic resonance contrast agent had been transferred to transiting state metal by researchers
On manganese, it is a kind of paramagnetic metal, there is 5 unpaired electrons, has stronger relaxation enhancing effect.Before this, there is document sharp
With the metal ion chelant ability that poly-dopamine is excellent, manganese ion is adsorbed in the poly-dopamine nano grain surface synthesized, into
Photo-thermal therapy under row MRI imaging guiding, achieves good effect.However, since manganese ion is to act on adsorbing by chelating
In nano grain surface, there is the risk to fall off, manganese ion itself also has larger toxicity in addition, is unfavorable for clinical application.
In conclusion in order to improve the accuracy of Gases for Treating and photo-thermal therapy, need to confirm tumour in body before the treatment
Interior size and location, and the process for the treatment of is monitored in real time.The nanometer diagnosis and treatment agent reported both at home and abroad at present is usual
It is related to a variety of chemical reagent and drug participates in, preparation process is complicated, of high cost, efficiency is low, repeatability is bad, it is difficult to realizes clinical
Using.By Mn in the present invention2(CO)10（Write a Chinese character in simplified form MnCO）High-efficient carrier builds a kind of tumor microenvironment in the duct of MPDA（H+
And H2O2）The nanometer diagnosis and treatment agent of response, magnetic resonance imaging（MRI）And photoacoustic imaging（PAI）The lower realization CO of guiding is efficiently transported and light
Heat cure synergistic treatment is expected to increase substantially the diagnosing and treating effect of cancer, mitigates the toxic side effect of systemic chemotherapy.
Invention content
The purpose of the present invention is the deficiencies for existing diagnosis and treatment preparation, provide a kind of high-efficiency multi-function nanometer diagnosis and treatment agent, can
Tumor thermal therapy and CO Gases for Treating for the guiding of MRI/PAI Double-mode imagings.The MnCO@that specifically present invention is built
MPDA diagnosis and treatment agent has following function and application：The first, MnCO and the endogenous stimulation H of tumour are utilized2O2Class Fenton occurs（Fenton）
Reaction, it is in situ to generate therapeutic CO gases kill cancer cell；The second, MnCO is in acidic cancer environment and H2O2It is raw under collective effect
At Mn2+（Efficient MRI contrast agent）, can be used for the magnetic resonance imaging of tumor locus, also solved while MRI is imaged manganese from
Son recycles this big problem of Poisoning in vivo, to realize the monitoring and assessment of therapeutic process；Third absorbs arteries and veins using MPDA
Pulsed optical energy converts light energy into thermal energy, and then generates ultrasonic signal, realizes the in vivo tissue photoacoustic imaging of deeper；The
Four, the near infrared light of absorption is generated into fuel factor using MPDA and carries out photo-thermal therapy, further improve therapeutic effect and safety
Property.
To achieve the goals above, the present invention provides the preparation method of above-mentioned multifunctional nano diagnosis and treatment agent：
A kind of multifunctional nano diagnosis and treatment agent of mesoporous poly-dopamine load manganese carbonyl, by water-soluble mesoporous poly-dopamine（MPDA）
Carrier wraps up hydrophobic manganese carbonyl（MnCO）Drug forms, and the mass ratio of the MnCO and MPDA are 1 ~ 8：1.
The preparation method of the multifunctional nano diagnosis and treatment agent of above-mentioned mesoporous poly-dopamine load manganese carbonyl, includes the following steps：
（1）MPDA is dissolved in 2-3mL organic solvents, though MPDA is water-soluble material, is also dissolved in the organic solvent of part.
（2）Manganese carbonyl is added into above-mentioned system, the system is statically placed in vacuum drying chamber after mixing, vapors away one
Part organic solvent, the remaining organic solvent of centrifugation removal；
（3）By step（3）Middle gained precipitation aqueous solution or organic solvent are washed 2-4 times, can be resuspended in solution, be loaded
The nanometer diagnosis and treatment agent particle of manganese carbonyl.
In above-mentioned preparation method（1）In, the organic solvent is chloroform, dichloromethane, tetrahydrofuran, dimethyl Asia
One or more mixing in sulfone, methanol, ethyl alcohol.
In above-mentioned preparation method（2）In, vacuum drying condition is room temperature, and removal organic solvent purpose is that concentration drug is dense
Degree enters MPDA holes conducive to drug, improves drugloading rate.Remaining organic solvent volume, which is the 1/5-1/4 of former solvent volume, to be advisable,
While conducive to collection of products, ensure that carrying medicine reaction fully carries out.
In above-mentioned preparation method（2）In, the parameter of the centrifugation is 8000-13000 rpm, 6-10min.
In above-mentioned preparation method（3）In, the aqueous solution can be water, PBS solution（pH 5.0-7.4）, culture medium
Deng, the organic solvent type and（1）Middle organic solvent is identical.
In above-mentioned preparation method, the mesoporous poly-dopamine（MPDA）The diameter of carrier between 50 ~ 400 nm,
Mesopore size is 1 ~ 50 nm.
The synthesis technology of above-mentioned mesoporous poly-dopamine load manganese carbonyl is simple and practicable, efficient and reproducible, Ke Yijin
Row large-scale production.
The present invention also provides above-mentioned multifunctional nano diagnosis and treatment agent for magnetic resonance imaging contrast, photoacoustic imaging contrast agent
And/or the application in treatment tumour gaseous medication, treatment tumor photo-thermal ablation preparation.
Compared with prior art, the present invention has the advantages that：
（1）MnCO is the very strong substance of lipophilicity, can not direct injection.The mesoporous poly-dopamine of carrier（MPDA）With higher ratio
Surface area and nano pore structure, wrapping up hydrophily or hydrophobic drug has the advantages that drugloading rate is high.MPDA due to it from
Body has very strong adsorption capacity and abundant nano pore, moreover it is possible to and π-π * electron transitions are generated, and hydrogen bond is formed with molecule, it can
To increase substantially the load efficiency of MnCO, to make CO gas burst sizes improve, and then cancer cell is killed.
（2）Manganese ion results from tumor locus by responding the hydrogen peroxide selectivity of tumor microenvironment, in MRI imagings
Manganese ion is also solved simultaneously recycles this big problem of toxicity in vivo.
（3）The mesoporous poly-dopamine of carrier（MPDA）Also there is good photothermal conversion efficiency and photostability, make it that can make
The treatment of tumour is used for for a kind of photo-thermal therapy agent.
（4）The diagnosis and treatment agent realizes magnetic resonance imaging and the CO gases under photoacoustic imaging guiding and photo-thermal synergistic treatment, has
It hopes raising oncotherapy effect and biocompatibility is good, there are clinical application potentiality.
Description of the drawings
Fig. 1 is the MnCO@MPDA that embodiment 1 synthesizes and its schematic diagram of application；
Fig. 2 is (a) of embodiment 1, (b) MPDA nitrogen adsorptions/desorption curve;(c) transmission electron microscope for being MnCO@MPDA
Figure;(d) it is dynamic light scattering grain size distribution；
Fig. 3 is photo-thermal of the nanometer diagnosis and treatment agent MnCO@MPDA aqueous solutions under (a) various concentration and (b) different laser powers
Heating figure；
Fig. 4 is the nanometer diagnosis and treatment agent MnCO@MPDA UV, visible light extinction figures that CO burst sizes change in different time points；
Fig. 5 is external (a) MRI figures of various concentration MnCO@MPDA aqueous dispersions and (b) relaxation rate calculates figure.
Fig. 6 be free MnCO and four kinds of cell incubations (a) for 24 hours, (b) after 48h cell activity and MnCO@MPDA and
Four kinds of cell incubations (c) for 24 hours, (d) cell activity after 48h.
Fig. 7 is after MnCO@MPDA PBS dispersion liquids inject tumor-bearing mice in a manner of tail vein injection, and (a) is HCT116
The T of tumor region different time points1- MRI schemes.(b) change for the magnetic resonance signal intensity of tumor region with (c)；
Fig. 8 is after MnCO@MPDA PBS dispersion liquids inject tumor-bearing mice in a manner of tail vein injection, and (a) is HCT116 tumours
The photoacoustic imaging figure of region different time points.(b) change for the photoacoustce signal intensity of tumor region；
Fig. 9 is after nanometer diagnosis and treatment agent MnCO@MPDA, MPDA and control group PBS intravenous administrations enter mice with tumor 9h, and (a) is small
The thermograph of mouse tumor locus;(b) it is the temperature variation of tumor region；
Figure 10 is nanometer diagnosis and treatment agent MnCO@MPDA, MPDA, dissociates MnCO and control group PBS after tail vein injection enters mice with tumor
Treatment, (a) is the tumor Volume Changes figure of different grouping mouse different time before and after treatment；(b) it is different points
The mouse weight variation diagram of group mouse different time before and after treatment;(c) be different grouping mouse after the treatment the 6th, 10 and
14 days pictures（Laser power is 1W/cm2）.
Specific implementation mode
Experimental method described in following embodiments is unless otherwise specified conventional method；The reagent and material, such as
Without specified otherwise, commercially obtain.
The synthesis of 1 nanometer of diagnosis and treatment agent MnCO@MPDA of embodiment
It is as follows：
（1）The synthesis of the mesoporous poly-dopamine MPDA of carrier is obtained with reference to prior art preparation, and grain size is 210 nm.
（2）The synthesis of MnCO@MPDA：It weighs 1.5 mg MnCO and is dissolved in 1 mL methanol, 300 μ g MPDA are dissolved in 1mL first
The two is uniformly mixed by alcohol, is statically placed in vacuum drying chamber, until solvent volume volatilization takes out centrifugation when being 500-600 μ L
13000 rpm, 10 min, gained precipitation is MnCO@MPDA, can be resuspended in water or PBS（PH is 7.4）In solution.
The synthesis of 2 nanometers of diagnosis and treatment agent MnCO@MPDA of embodiment
It is as follows：
（1）The synthesis of the mesoporous poly-dopamine MPDA of carrier is obtained with reference to prior art preparation, and grain size is 210 nm.
（2）The synthesis of MnCO@MPDA：It weighs 1.5 mg MnCO and is dissolved in 1 mL methanol, 1.5 mg MPDA are dissolved in 1mL first
Alcohol mixes the two, is statically placed in vacuum drying chamber, until solvent volume volatilization takes out centrifugation 13000 when being 500-600 μ L
Rpm, 10 min, gained precipitation is MnCO@MPDA, can be resuspended in water or PBS（PH is 7.4）In solution.
The characterization of 3 nanometers of diagnosis and treatment agent MnCO@MPDA of embodiment
It is as follows：
（1）MPDA nitrogen adsorptions/desorption curve measures：Take 100 mg MPDA samples of drying, Instrument measuring nitrogen adsorption/de-
Attached curve, (b) shown such as Fig. 2 (a), the specific surface area that the MPDA nano-particles of the preparation of embodiment 1 are calculated using BJH methods is
21.8603 m2/g, pore size are about 10 nm.
（2）Transmission electron microscope（TEM）Observe MnCO@MPDA patterns：10 μ L MnCO@MPDA dispersion liquids are taken, are added dropwise in surface carbon
Coated copper is online, under room temperature natural air drying.Under 200kV voltage conditions, the shape of transmission electron microscope observation nano particle
Looks and grain size.As shown in Fig. 2 (c), the transmission electron microscope results of nanoparticle MnCO@MPDA prepared by embodiment 1, it can be seen that receive
Rice corpuscles is spherical in shape and uniform particle diameter, the pore passage structure of regular distribution.
（3）Malvern nano particle size instrument measures MnCO@MPDA grain sizes：Take 1mL MnCO@MPDA dispersion liquids that sample cell is added
In, it is 250.6 ± 5.5 nm to measure its grain size, and obtains the dynamic light scattering grain size distribution such as Fig. 2 (d).By can in figure
See, MnCO MPDA particle size distribution ranges obtained are relatively narrow, show grain size than more uniform.
The external photo-thermal property research of 4 nanometers of diagnosis and treatment agent of embodiment is as follows：
（1）The MnCO@MPDA dispersion liquids for preparing different MPDA concentration, solution is moved in sample cell, uses power for 2W/cm2
808nm lasers solution is irradiated 10 minutes, while temperature when carrying out with electronic thermometer recording materials laser irradiation
Spend situation of change.It is depicted as temperature-time curve, the relationship of analytical solution temperature change and solution concentration.
（2）The MnCO@MPDA dispersion liquids for preparing a concentration of 100 μ g/mL of MPDA, solution is moved in sample cell, is adopted respectively
Dispersion liquid is irradiated 10 minutes with 808 nm lasers of different capacity, is disperseed when being irradiated with electronic thermometer recording laser
The temperature variations of liquid.It is depicted as temperature-time curve, the relationship of analytical solution temperature change and laser power.Such as Fig. 3
(a), shown in (b), under 808 nm laser irradiations, it is in concentration and laser power dependence that MnCO@MPDA dispersion liquid temperature, which increases,.
5 nanometers of diagnosis and treatment agent carbon monoxide release characterizations of embodiment
It is as follows：MnCO@MPDA are resuspended in PBS（PH is 7.4）In, a concentration of 300 μ g/mL.Take 200 μ L should
Dispersion liquid is added in the hemoglobin PBS solution configured, and a certain amount of hydrogenperoxide steam generator is added afterwards so that dispersion liquid is overall
Product is 4mL（Hemoglobin concentration is 4 μm of ol, and concentration of hydrogen peroxide is 100 μm of ol）.The dispersion liquid is placed in ultraviolet-visible
In spectrophotometer sample cell, absorbance value, measurement range 350-600nm are measured every 5 min.Draw extinction collection of illustrative plates such as Fig. 4
It is shown, with the extension of time, the CO gas generated is combined with hemoglobin, lead to hemoglobin absorption at 430 nm
Angle value gradually weakens, and carbonyl haemoglobin（CO gas and hemoglobin combination product）Extinction at 410 nm
Angle value gradually increases, and shows the generation of carbon monoxide.
6 nanometers of diagnosis and treatment agent magnetic resonance imaging performance characterizations of embodiment
It is as follows：MnCO@MPDA aqueous dispersions are subjected to gradient dilution, are swept under NMR imaging instrument
It retouches, detects its MRI imaging effect.It is (b) shown such as Fig. 5 (a), with Mn2+Concentration increases, the MRI reduction of contrast signal of MnCO@MPDA
Constantly enhancing, brightness is gradually increased, with Mn2+A concentration of abscissa of amount of ionic species, with longitudinal relaxation rate r1（1/T1）It is vertical
Coordinate carries out linear fit, and the longitudinal relaxation rate for obtaining MnCO@MPDA is 33.55 mM-1S-1, it is the vertical of commercial Magnevist Solution
To relaxation rate（5.35 mM-1S-1）6.27 times.Compared with commercial contrast agent, MnCO@MPDA diagnosis and treatment agent can be such that MRI radiographies believe
It number significantly increases.
7 nanometers of diagnosis and treatment agent Cytotoxic evaluations of embodiment
It is as follows：By four kinds of different cells（Human umbilical vein endothelial cells HUVEC, human liver cancer cell HepG2, people's knot
Colon-cancer cell HCT116, mouse colonic cell CT-26）It is seeded in 4 piece of 96 hole cell culture respectively with the quantity in 4000/hole
In plate.After cell is adherent, the free MnCO and MnCO@MPDA PBS dispersion liquids of various concentration gradient are separately added into, with cell
It is incubated 24 hours and 48 hours altogether, MTT experiment detects influence of the nanometer diagnosis and treatment agent to cell activity.The experimental results showed that free
The cytotoxicity of MnCO is very low, almost without the effect of killing cell（Fig. 6 (a), (b)）.HCT116 in four kinds of cells（Human colon carcinoma
Cell）Cell activity is substantially reduced（Fig. 6 (c), (d)）, show that MnCO@MPDA can effectively kill this tumour cells of HCT116,
The reason is that H in HCT116 cells2O2Level compares that other cells are higher, is conducive to the generation of CO gases, and then generate cell toxicant
Property, there are the potentiality for the treatment of colon cancer.
Magnetic resonance imaging in 8 nanometers of diagnosis and treatment agent Mice Bodies of embodiment
It is as follows：Using tail vein injection method, 125 μ L MnCO@MPDA (6mg/mL) tail veins are injected into lotus knurl
Mouse, different time points carry out magnetic resonance imaging to mouse before the injection, after injection respectively, compare the change of different time points MRI signal
Change situation.(b), (c) shown such as Fig. 7 (a), after MnCO@MPDA injection mice with tumor, tumor locus magnetic resonance signal gradually increases
By force, and at 9 hours or so reach peak value, show that nano-particle is at this moment most in tumor locus enriching quantity, light can be carried out in 9 hours
Heat cure.
Photoacoustic imaging is as follows in 9 nanometers of diagnosis and treatment agent Mice Bodies of embodiment：It is noted into Mice Body by tail vein
125 μ L MnCO@MPDA (6mg/mL) are penetrated, different time points carry out photoacoustic imaging scanning to mouse before and after injection respectively.Knot
Fruit such as Fig. 8 (a), (b) shown, after injected sample, mouse tumor position photoacoustic signal gradually increases, after 9 h, tumor locus optoacoustic
Signal reaches most strong；After for 24 hours, tumor imaging strength reduction, but it is still maintained at higher intensity levels.Show that MnCO@MPDA have
Higher stability and longer circulation time in vivo can effectively be enriched in tumor locus by EPR effects, be conducive to tumor locus
And its identification on boundary, provide golden hour and lesion information for photo-thermal therapy thereafter.
Thermal imaging of the 10 nanometers of diagnosis and treatment agent of embodiment at mouse tumor position is tested
Steps are as follows for specific experiment：PBS, MPDA and MnCO@MPDA are injected into mice with tumor through tail vein, in injection 9 hours
Afterwards, with different laser powers（1W/cm2And 0.5W/cm2）Tumor locus is irradiated 5 minutes, using infrared temperature monitor dynamic
Record tumor locus temperature change.It is (b) shown such as Fig. 9 (a), carry out laser irradiation, tumor locus temperature after injecting 9 hours
60 DEG C can be increased to, shows that diagnosis and treatment agent is enriched in tumor locus, there is good photothermal conversion effect.
The oncotherapy situation and curative effect monitoring of 11 nanometers of diagnosis and treatment agent MnCO@MPDA of embodiment
It is as follows：By 125 μ L (6mg/mL) MnCO@MPDA through tail vein inject mice with tumor, injection 9 hours it is laggard
Row photo-thermal therapy.It is grouped into untreated fish group, only gas, only laser therapy group and gas, laser synergistic treatment group.It need to carry out laser
The group for the treatment of is with different laser powers（1W/cm2And 0.5W/cm2）It irradiates tumor locus 5 minutes, every other day weighs one thereafter
Secondary mouse weight is used in combination vernier caliper measurement gross tumor volume and takes pictures to mouse.Dynamic monitoring different grouping mouse is being controlled
Treat the gross tumor volume and mouse weight of front and back different time points.It is (b), (c) shown such as Figure 10 (a), compared with the control group, gas
Treatment group's mouse tumor volume has a diminution, but and the mice with tumor tumour that receives laser irradiation group be obviously reduced.Each group mouse weight
Change no significant difference.
Claims (8)
1. a kind of multifunctional nano diagnosis and treatment agent of mesoporous poly-dopamine load manganese carbonyl, which is characterized in that by water-soluble mesoporous
Poly-dopamine carrier wraps up hydrophobic manganese carbonyl drug and forms；The mass ratio of mesoporous poly-dopamine and manganese carbonyl is 1-8：1.
2. the preparation method of the multifunctional nano diagnosis and treatment agent of mesoporous poly-dopamine load manganese carbonyl, feature described in claim 1
It is to include the following steps：
（1）Mesoporous poly-dopamine is dissolved in organic solvent；
（2）Manganese carbonyl is added into above-mentioned system, the system is statically placed in vacuum drying chamber after mixing, vapors away a part
Organic solvent, the remaining organic solvent of centrifugation removal；
（3）By step（3）Middle gained precipitation aqueous solution or organic solvent are washed 2-4 times, can be resuspended in solution, be loaded
The nanometer diagnosis and treatment agent particle of manganese carbonyl.
3. preparation method as described in claim 1, which is characterized in that step（1）Or（3）The organic solvent is three chloromethanes
One or more mixing in alkane, dichloromethane, tetrahydrofuran, dimethyl sulfoxide (DMSO), methanol, ethyl alcohol.
4. preparation method as described in claim 1, which is characterized in that step（2）The parameter of the centrifugation is 8000-13000
Rpm, 6-10min.
5. preparation method as described in claim 1, which is characterized in that step（2）The vacuum drying condition is room temperature, until
Stop drying when the organic solvent of remaining 1/5-1/4 volumes.
6. preparation method as described in claim 1, which is characterized in that the diameter of the mesoporous poly-dopamine carrier 50 ~
Between 400 nm, mesopore size is 1-50 nm.
7. preparation method as described in claim 1, which is characterized in that step（3）The aqueous solution be water, PBS solution or
Culture medium.
8. the multifunctional nano diagnosis and treatment agent of mesoporous poly-dopamine load manganese carbonyl described in claim 1 prepare for magnetic resonance at
As the application in contrast agent, photoacoustic imaging contrast agent and/or treatment tumour gaseous medication, treatment tumor photo-thermal ablation preparation.
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