CN108939072A - A kind of nano-carrier and preparation method thereof for photodynamic therapy - Google Patents
A kind of nano-carrier and preparation method thereof for photodynamic therapy Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5115—Inorganic compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
- A61K49/143—Peptides, e.g. proteins the protein being an albumin, e.g. HSA, BSA, ovalbumin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The present invention provides the preparation methods of the nano-carrier for photodynamic therapy, comprising: by Fe3+Metal salt is dissolved in DMF, and photosensitizer TCPP is added, obtains particle NMOFs；Then ultrasonic disperse in water is added crosslinking agent EDC and NHS, BSA and sulphadiazine SDs fully reacting, particle NMOFs@BSA/SDs is obtained after dialysis；It is redispersed in distilled water, Mn is added2+Metal salt adjusts pH, carrier NMOFs@BSA/SDs@MnO is obtained after dialysis2.The present invention coats PROTEIN B SA and sulphadiazine SDs based on nano level metal organic frame particle, then particle needed for being obtained by mineralising in situ, SDs have specific recognition to the carbonic anhydrase in solid tumor, can active targeting to weary oxygen tumor locus；The MnO that mineralising generates2H can be catalyzed2O2It decomposes to improve tumor locus oxygen content, enhances optical dynamic therapy efficiency.
Description
Technical field
The present invention relates to biological targeting nanometer pharmaceutical technology field more particularly to a kind of receiving for photodynamic therapy
Meter Zai Ti and preparation method thereof.
Background technique
China is multiple one of the country of tumor disease, during the cancer mortality case of about a quarter appears in the world
State.Personal deep tumor, as primary hepatocellular carcinoma (HCC) occupies high mortality tumour second, most of China in China
HCC patient has hepatitis B and cirrhosis background, and onset concealment, how unobvious early symptom is, and early detective rate is low, surgical resection margins are difficult
It defines, Postoperative recurrent rate is high, chemotherapy and postoperative chemotherapy targeting is not strong and toxicity is big.So deep tumor treatment targeting
It improves, minimally-invasive treatment reduces skin phototoxicity, prevents postoperative metastasis and recurrence is the key problem that urgent clinical needs solve.
Photodynamic therapy (PhotodynamicTherapy, PDT) has just been referred to as in the early 1980s
" promising novel cancer mode ".This can be partly due to this attractive concept of PDT --- three kinds of treatments
The combination of composition: photosensitive drug, light and oxygen.Three itself is relative harmless, but triplicity will be generated with thin
The singlet oxygen (ozone) of cellular toxicity kill and do not develop drug resistance to tumour.Photodynamic therapy is dynamic using the light of drug
Stress effect carries out a kind of new technology of disease treatment, it uses the laser excitation photosensitizer (photo-dynamical medicine) of specific wavelength, swashs
The photosensitizer of state is sent out again energy transmission to the oxygen of surrounding, generates highly active singlet oxygen, on the one hand singlet oxygen can be made
At the capilary acute injury in carcinoma, angiemphraxis is caused to cause ischaemic；On the other hand tumour cell can be directly resulted in
Death, to achieve the purpose that local treatment tumour.Moreover, external source light is only focused on tumor locus, it can just make light power
Drug generates toxic action to tumour cell；For the position that do not arrived by illumination, such as normal tissue and cell are not generated then
Toxic action.Therefore, the toxic side effect very little of optical dynamic therapy, and it will not damage human body hemopoietic system and immune system
Function.Although optical dynamic therapy has many advantages in the treatment of tumour, it is to be also faced with many ask that acquirement, which is widely applied,
Topic: the effect of existing optical dynamic therapy is influenced by some factors, mainly the environment of tumour itself anoxic, low concentration
Photosensitizer and low ROS sphere of action, the optical dynamic therapy of tumour are the processes of an oxygen consumption, lead to oxygen concentration in tumour cell
It further decreases, lacks photosensitizer, be just difficult to generate necrosis or the apoptosis of sufficient reactive oxygen species and inducing cell, lead to light
The inefficiency of dynamic therapy.
Therefore, a kind of optical dynamic therapy carrier how is developed, which can increase tumor locus oxygen
Content becomes urgent problem to be solved to improve the efficiency of optical dynamic therapy.
Summary of the invention
It is an object of the invention to overcome deficiency in the prior art, a kind of receiving for photodynamic therapy is provided
Meter Zai Ti and preparation method thereof, this is used for the nano-carrier of photodynamic therapy using nano level metal organic frame particle as base
Plinth coats protein (BSA) and sulphadiazine (SDs), then obtains required particle by mineralising in situ.SDs is in solid tumor
Carbonic anhydrase (CAIX) has specific recognition, can active targeting to weary oxygen tumor locus；The MnO that mineralising generates2H can be catalyzed2O2
It decomposes and generates sufficient reactive oxygen species enhancing optical dynamic therapy efficiency to improve tumor locus oxygen content；MnO simultaneously2Tool
Diagnoses and treatment integration may be implemented in standby Magnetic resonance imaging function.
The present invention is implemented as follows:
One of the objects of the present invention is to provide a kind of preparation method of nano-carrier for photodynamic therapy, tools
Body includes the following steps:
The formation of step 1, nano metal organic frame particle: by Fe3+Metal salt is dissolved in n,N-Dimethylformamide, then
Photosensitizer TCPP is added dropwise, the pH for adjusting solution reaches acidic environment and is centrifuged after stirring to fully reacting, it washs,
Nano metal organic frame particle NMOFs is obtained, is stored for future use, the reaction carries out in the dark；
The formation of step 2, biocompatibility nano metal particles: the nano metal organic frame particle that step 1 is obtained
NMOFs ultrasonic disperse, and addition crosslinking agent N- ethyl-carbodiimide hydrochloride and N- hydroxyl amber under agitation in water
The mixed liquor of bovine serum albumin BSA and sulphadiazine SDs, stirring to fully reacting, after dialysis is added in amber acid imide after being stirred for
Obtain biocompatibility nano metal particles NMOFs@BSA/SDs；
Step 3, for photodynamic therapy nano-carrier formation: biocompatibility obtained in step 2 is received
Rice metallic NMOFs@BSA/SDs is dispersed in distilled water, and Mn is added2+Metal salt adjusts pH value of solution to 8.5- after stirring
9.5, until solution becomes orange, stirring obtains the nano-carrier NMOFs@BSA/ for photodynamic therapy after dialysis
SDs@MnO2。
The second object of the present invention is to provide a kind of receiving for photodynamic therapy that the method is prepared
Meter Zai Ti.
The invention has the advantages that:
1, the preparation method of a kind of nano-carrier for photodynamic therapy provided by the invention in step 2, utilizes
Cheap bovine serum albumin assigns material more excellent biocompatibility, and carry sulphadiazine (SDs) as bridge
Targeting is provided, carbonic anhydrase IX (CAIX) concentration can be lowered and then inhibits the expression of hypoxia inducible factor (HIF-1), is increased
Add tumor locus oxygen content, improves the efficiency of optical dynamic therapy.
2, the preparation method of a kind of nano-carrier for photodynamic therapy provided by the invention in step 3, utilizes
The MnO that mineralising generates2It is catalyzed H2O2Generate O2, inside tumor oxygen content can be improved, can produce when optical dynamic therapy more
Reactive oxygen species, achieve the effect that enhance optical dynamic therapy.
3、MnO2Have the function of Magnetic resonance imaging simultaneously, higher than the relaxation time of clinical nuclear magnetic resonance, may be implemented
The diagnoses and treatment integration of cancer, is expected to the curative effect obtained in the treatment of malignant tumour.
4, the preparation method of a kind of nano-carrier for photodynamic therapy provided by the invention, passes through nanoscale
Metal-organic framework, in conjunction with the property of inorganic metal and organic photosensitive ligand (TCPP), have it is suitably sized, well
Biocompatibility and biological degradability, photosensitive material content can be improved for optical dynamic therapy, assigned by EPR effect
The more photosensitizers of tumor locus；Wherein EPR effect, that is, solid tumor high-permeability and retention effect (enhanced
Permeability and retention effect) it refers to relative to normal tissue, the molecule or particle of certain sizes
Tend to the property for being gathered in tumor tissues.Microvascular endothelial gap in normal tissue is fine and close, structural integrity, macromolecular and
Lipid granule is not easy through vascular wall, and solid tumor mass medium vessels are abundant, vascular wall gap is wider, poor structural integrity, leaching
Ba Huiliu missing causes macromolecular substance and lipid granule that there is selective high-permeability and anelasticity, this phenomenon to be claimed
Make the high-permeability and retention effect of solid tumor mass, abbreviation EPR effect.EPR effect promotes macromolecular substance in tumour
The selective distribution of tissue can increase drug effect and reduce system side effect.
Detailed description of the invention
Fig. 1 is the nano-carrier NMOFs@BSA/SDs@for photodynamic therapy that experimental example 1 of the present invention provides
MnO2Transmission electron microscope (TEM) figure；
Fig. 2 is the nano-carrier NMOFs@BSA/SDs@for photodynamic therapy that experimental example 2 of the present invention provides
MnO2Ultraviolet spectra absorb figure；
Fig. 3 is the nano-carrier NMOFs@BSA/SDs@for photodynamic therapy that experimental example 3 of the present invention provides
MnO2It is catalyzed H2O2It decomposes and generates O2Amount change with time figure；
Fig. 4 is the nano-carrier NMOFs@BSA/SDs@for photodynamic therapy that experimental example 4 of the present invention provides
MnO2Mimetic enzyme catalytic performance time dynamic curve figure；
Fig. 5 is the MRI analysis figure that experimental example 5 of the present invention provides；
Fig. 6 is the nano-carrier NMOFs@BSA/SDs@for photodynamic therapy that experimental example 6 of the present invention provides
MnO2To the immunoblotting assay of cell expression CAIX；
Fig. 7 is that the different treatment group tumors volumes that application examples of the present invention provides change over time figure.
Specific embodiment
Embodiment 1
1, in 250mL flask, 2mLFe3+Solution (0.0125mM) enters to 10mLDMF, then the TCPP solution of 2mL
(0.0125mM) is added dropwise, while the acetic acid of 0.4mL is added the pH for being used to adjust mixed solution and reaches acidic environment.At room temperature
After being vigorously stirred 2 hours, mixed solution is heated to 80 DEG C and is slowly stirred 24 hours.Solution cooled to room temperature after reaction,
It is centrifuged, washs removal residual solvent with DMF, ethyl alcohol and deionized water respectively, NMOFs after purification is stored at 4 DEG C.
All reactions carry out in the dark.
2, it takes the BSA solution (0.1mM) of 2mL to be added into 800 microlitres of SDs solution (1mM), stirs 12 hours at room temperature,
Obtain BSA/SDs mixed liquor.Ultrasonic disperse 2 hours in deionized water the NMOFs prepared in the S1 of 100mg, then at 40 DEG C
It is added immediately 40mgEDC and 30mgNHS under the conditions of lower magnetic agitation, BSA/SDs mixed liquor is added after stirring 2 hours, at room temperature
Be stirred for 24 hours, the mixed solution after reaction be placed in bag filter placement dialyse in deionized water, change within every 4 hours once go from
Sub- water continues three days, obtains NMOFs@BSA/SDs particle and stores for future use at 4 DEG C.
3, the NMOFs@BSA/SDs particle of 25mg is taken to be dispersed in 10mL deionized water, the manganese chloride of 100 microlitres of 100mM
Solution is placed in together in the flask of 25mL, and after stirring 2 minutes at room temperature, the sodium hydroxide solution of 50 microlitres of 1mol/L is added,
Solution colour becomes orange at once.Obtain NMOFs BSA/SDs MnO2 nano platform after stirring 6 hours, the solution spend from
Sub- water dialyses 48 hours and removes unreacted manganese ion and sodium hydroxide, and finally obtained solution is placed at 4 DEG C and saves.
Embodiment 2
Step 1, in 250mL flask, 2mLFe3+Solution (0.0127mM) enters to 15mLDMF, then the TCPP solution of 2mL
(0.0127mM) is added dropwise, while the acetic acid of 0.5mL is added the pH for being used to adjust mixed solution and reaches acidic environment.At room temperature
After being vigorously stirred 2 hours, mixed solution is heated to 80 DEG C and is slowly stirred 24 hours.Solution cooled to room temperature after reaction,
It is centrifuged, washs removal residual solvent with DMF, ethyl alcohol and deionized water respectively, NMOFs after purification is stored at 4 DEG C.
All reactions carry out in the dark.
Step 2 takes the BSA solution (0.1mM) of 2mL to be added into 800 microlitres of SDs solution (1mM), and it is small to stir 12 at room temperature
When, obtain BSA/SDs mixed liquor.Ultrasonic disperse 2 hours in deionized water the NMOFs prepared in the S1 of 100mg, then 40
40mgEDC and 30mgNHS are added immediately at DEG C under the conditions of magnetic agitation, BSA/SDs mixed liquor, room temperature is added after stirring 2 hours
Under be stirred for 24 hours, the mixed solution after reaction be placed in bag filter placement dialyse in deionized water, change within every 4 hours and once go
Ionized water continues three days, obtains NMOFs@BSA/SDs particle and stores for future use at 4 DEG C.
Step 3 takes the NMOFs@BSA/SDs particle of 25mg to be dispersed in 10mL deionized water, the chlorination of 100 microlitres of 50mM
Manganese solution is placed in together in the flask of 25mL, and after stirring 2 minutes at room temperature, the sodium hydroxide that 50 microlitres of 1mol/L is added is molten
Liquid, solution colour become orange at once.NMOFs BSA/SDs MnO2 nano platform is obtained after stirring 6 hours, which uses
Remove unreacted manganese ion and sodium hydroxide within deionized water dialysis 48 hours, finally obtained solution is placed at 4 DEG C and saves.
Embodiment 3
1, in 250mL flask, 2mLFe3+Solution (0.013mM) enters to 15mLDMF, then the TCPP solution of 2mL
(0.013mM) is added dropwise, while the acetic acid of 0.5mL is added the pH for being used to adjust mixed solution and reaches acidic environment.At room temperature
After being vigorously stirred 2 hours, mixed solution is heated to 80 DEG C and is slowly stirred 24 hours.Solution cooled to room temperature after reaction,
It is centrifuged, washs removal residual solvent with DMF, ethyl alcohol and deionized water respectively, NMOFs after purification is stored at 4 DEG C.
All reactions carry out in the dark.
2, it takes the BSA solution (0.1mM) of 2mL to be added into 800 microlitres of SDs solution (1mM), stirs 12 hours at room temperature,
Obtain BSA/SDs mixed liquor.Ultrasonic disperse 2 hours in deionized water the NMOFs prepared in the S1 of 100mg, then at 40 DEG C
It is added immediately 40mgEDC and 30mgNHS under the conditions of lower magnetic agitation, BSA/SDs mixed liquor is added after stirring 2 hours, at room temperature
Be stirred for 24 hours, the mixed solution after reaction be placed in bag filter placement dialyse in deionized water, change within every 4 hours once go from
Sub- water continues three days, obtains NMOFs@BSA/SDs particle and stores for future use at 4 DEG C.
3, the NMOFs@BSA/SDs particle of 25mg is taken to be dispersed in 10mL deionized water, the manganese chloride of 100 microlitres of 100mM
Solution is placed in together in the flask of 25mL, and after stirring 2 minutes at room temperature, the sodium hydroxide solution of 50 microlitres of 1mol/L is added,
Solution colour becomes orange at once.Obtain NMOFs BSA/SDs MnO2 nano platform after stirring 6 hours, the solution spend from
Sub- water dialyses 48 hours and removes unreacted manganese ion and sodium hydroxide, and finally obtained solution is placed at 4 DEG C and saves.
Experimental example 1
Using transmission electron microscope (Transmission electron microscopy, TEM) to embodiment-implementation
Obtained this of example 3 is used for the nano-carrier NMOFs@BSA/SDs@MnO of photodynamic therapy2Pattern characterized.First
Sample is placed in dehydrated alcohol, ultrasonic vibration makes its dispersion, by dispersant liquid drop on the small copper mesh of oiling carbon film, dries.?
The pattern of sample is characterized under different resolution, result is as shown in Figure 1.Gained nano-particles size is on the left side 40nm
It is right.
Experimental example 2
This experiment detects nanometer golden surface plasma effect using diffusing reflection ultraviolet spectra.Due to the d-d of transition metal
Electron transition produces absorption signal, so can study transition metal element particle in the sample using this absorption signal
It is coordinated situation.It takes this as a foundation to judge whether Fe is really embedded into nano metal organic frame particle NMOFs.This experiment makes
With the Lambda750 type ultraviolet-uisible spectrophotometer of PerkinElmer company of the U.S., with BaSO4For blank reference, model is scanned
Enclose 200nm-800nm, scanning speed 2nm/s.Its result is as shown in Figure 2.The characteristic absorption peak of porphyrin (TCPP) compound,
Nearby strong absworption peak is known as Soret band to 420nm, several weak absorbings of 500~750nm range are known as Q band.
Experimental example 3
Analyze the nano-carrier NMOFs@BSA/SDs@MnO provided in an embodiment of the present invention for photodynamic therapy2
Catalytic action, if oxygen content can be increased.By the NMOFs@BSA/SDs@MnO of different content2It is added to H2O2, detection
Generation O under different time2Amount, as a result as shown in Figure 3.
The NMOFs@BSA/SDs@MnO2 of different content is catalyzed H in Fig. 32O2It decomposes and generates O2Amount change with time, add
After entering sample, O2Yield obviously increases, and shows the nano-carrier for photodynamic therapy that inventive embodiments provide
NMOFs@BSA/SDs@MnO2With catalytic action.
Experimental example 4
The nano-carrier NMOFs@BSA/SDs@MnO for photodynamic therapy that experimental example of the present invention provides2Mould
Quasi- peroxidase activity.
Peroxidase is with hydrogen peroxide H2O2For the enzyme of electron acceptor catalysis substrate oxidation, hydrogen peroxide oxidation is utilized
Various to provide the substrate of electronics, such as 3,3', the oxidation intermediate state of 5,5'- tetramethyl benzidines (abbreviation TMB), TMB is
Blue has preferable absorbance in 652nm, so being here that substrate carries out test characterization with TMB.In order to prove NMOFs@
BSA/SDs@MnO2Activity with simulation oxide enzyme, rather than the material itself is reacted with TMB, we design TMB and not
Commaterial forms solution, observes whether it reacts, and carries out time dynamics examination in 652nm using ultraviolet-uisible spectrophotometer
It tests, as a result as shown in Figure 4.
As shown in Figure 4, only in H2O2Under existence condition, solution absorbance under 652nm absorbing wavelength does not increase, meaning
TMB there is no oxidation reactions, only in NMOFs@BSA/SDs@MnO2In the presence of TMB, also do not react.It has only
NMOFs@BSA/SDs@MnO2, H2O2The peroxidase similar with HRP occurs with can just be catalyzed TMB under the common existence condition of TMB
Catalysis reaction, makes solution under 652nm wavelength, absorbance increases as time increases, it was demonstrated that TMB is in NMOFs@BSA/
SDs@MnO2By H under catalysis2O2Oxidation.
Experimental example 5
Magnetic resonance imaging (MRI) is widely used at present in medicine detection imaging, the safety with radiationless damage,
Can the technologies flexibility such as arbitrary orientation tomoscan, covered proton density, relaxation weighted imaging and multi-parameter feature
Advantage, it has also become most strong one of detection means in contemporary clinical diagnosis, however the certain different tissues of clinical discovery or tumour
The relaxation time of tissue is overlapped, leads to difficult diagnosis.Therefore people begin one's study contrast agent, and enhancing signal contrast improves
Image resolution ratio.It, which is acted on, mainly changes tissue local relaxation characteristic by injecting contrast agent and opening, and improves image contrast, from
And improve the accuracy of diagnosis.Contrast agent is the substance that its a kind of chemically synthesized density is higher than living tissue, contrast agent itself
Signal is not generated, by changing the relaxation efficiency of water proton in internal local organization, is contrasted with surrounding tissue, to reach
The purpose of radiography.
It is clinical contrast agent as control, NMOFs@BSA/SDs@MnO provided by the invention that this experiment, which uses Gd-DTPA,2
As experimental group, using the relaxation time of MRI analysis instrument test experiments group and control group.As a result as shown in Figure 5.
Abscissa Mn/Gd indicates the concentration of Mn or Gd in Fig. 5 curve, and two curves respectively indicate 2 dispersion of NMOFs@BSA/SDs@MnO
1/T1 and Mn concentration relationship；The relationship of 1/T1 and the Gd concentration of Gd-DTPA dispersion.
As shown in Figure 5, NMOFs@BSA/SDs@MnO provided by the invention2T1 relaxation rate be 6.09mM-1s-1, higher than facing
The 4.33mM of the contrast agent of bed application-1s-1, there is better external imaging effect.
Experimental example 6
Fig. 6 is NMOFs@BSA/SDs@MnO under anoxia condition24t1 cell expression CAIX is immunized in nanocomposite
Engram analysis.As shown in Figure 6 with NMOFs@BSA/SDs@MnO2The raising of concentration, CAIX signal strength reduce, explanation
NMOFs@BSA/SDs@MnO2It is inhibited to CAIX, to prove that one kind provided by the invention is controlled for photodynamic tumor
The nano-carrier for the treatment of can lower carbonic anhydrase IX (CAIX) concentration and then inhibit the expression of hypoxia inducible factor (HIF-1), increase
Add tumor locus oxygen content, improves the efficiency of optical dynamic therapy.
The internal antitumous effect of application examples NMOFs@BSA/SDs@MnO2
By the monitoring to gross tumor volume after different treatments, NMOFs@BSA/SDs@MnO is evaluated2Cylinder therapeutic effect.
For phosphate buffered saline solution (PBS) as control, mouse is randomly divided into 4 groups of (irradiations of PBS, 660nm wavelength laser, NMOFs@BSA/
SDs@MnO2With NMOFs@BSA/SDs@MnO2660nm laser irradiation group) verify optical dynamic therapy (PDT) effect, tail vein note
Penetrate 20mg/kg, the image observed after 30 minutes with IVIS animal imaging.As a result such as Fig. 7.
Compared with control group (PBS), no sample but tumour growth is had no significant effect using laser (660nm)；And
NMOFs@BSA/SDs@MnO2Group (experimental group) gross tumor volume slightly reduces, the OH of part reaction-It is by being catalyzed part H2O2It is raw
At, another factor is NMOFs@BSA/SDs@MnO2There is adjustment effect to hypoxemia microenvironment, to inhibit tumour growth；And
Laser (660nm) irradiates NMOFs@BSA/SDs@MnO2There is more obvious inhibiting effect to tumour, illustrates that specific wavelength laser swashs
Send out NMOFs@BSA/SDs@MnO2PDT significant effect.
Symbol@in NMOFs@BSA/SDs involved in text shows that NMOF is wrapped up by BSA/SDs；Involved in text
NMOFs@BSA/SDs@MnO2In symbol@show that NMOF is wrapped up by BSA/SDs, then BSA/SDs is again by MnO2Package.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (9)
1. a kind of preparation method of the nano-carrier for photodynamic therapy, which is characterized in that specifically comprise the following steps:
The formation of step 1, nano metal organic frame particle: by Fe3+Metal salt is dissolved in n,N-Dimethylformamide, then dropwise
Photosensitizer TCPP is added, the pH for adjusting solution reaches acidic environment and is centrifuged after stirring to fully reacting, washs, obtains
Nano metal organic frame particle NMOFs, stores for future use, and the reaction carries out in the dark；
The formation of step 2, biocompatibility nano metal particles: the nano metal organic frame particle NMOFs that step 1 is obtained
Ultrasonic disperse in water, and crosslinking agent N- ethyl-carbodiimide hydrochloride and N- hydroxysuccinimidyl acyl Asia are added under agitation
The mixed liquor of bovine serum albumin BSA and sulphadiazine SDs is added in amine after being stirred for, stir to fully reacting, given birth to after dialysis
Object compatibility nano metallic NMOFs@BSA/SDs；
Step 3, for photodynamic therapy nano-carrier formation: by biocompatibility nanogold obtained in step 2
Belong to particle NMOFs@BSA/SDs to be dispersed in distilled water, Mn is added2+Metal salt adjusts pH value of solution to 8.5-9.5 after stirring, until
Solution becomes orange, and stirring obtains the nano-carrier NMOFs@BSA/SDs@MnO for photodynamic therapy after dialysis2。
2. the preparation method for the nano-carrier of photodynamic therapy as described in claim 1, which is characterized in that described
In step 1, Fe3+Metal salt is any one in iron chloride, ferric sulfate and ferric nitrate.
3. the preparation method for the nano-carrier of photodynamic therapy as described in claim 1, which is characterized in that described
In step 1, the pH that vinegar acid-conditioning solution is added reaches acidic environment.
4. the preparation method for the nano-carrier of photodynamic therapy as described in claim 1, which is characterized in that described
In step 1, after regulating pH, it is 2 hours that the time, which is stirred at room temperature, is again heated to 80 DEG C and is slowly stirred 24 hours, molten after reaction
Liquid natural cooling.
5. the preparation method for the nano-carrier of photodynamic therapy as described in claim 1, which is characterized in that described
In step 1, after being centrifuged, washed respectively with DMF, ethyl alcohol and deionized water.
6. the preparation method for the nano-carrier of photodynamic therapy as described in claim 1, which is characterized in that described
In step 2, BSA/SDs mixed liquor is added after being stirred for 2 hours after addition crosslinking agent, is stirred at room temperature 24 hours, dialyses 3 days
Obtain biocompatibility nano metal particles NMOFs@BSA/SDs.
7. the preparation method for the nano-carrier of photodynamic therapy as described in claim 1, which is characterized in that described
In step 3, the Mn2+Metal salt includes manganese chloride, manganese sulfate or manganese nitrate.
8. the preparation method for the nano-carrier of photodynamic therapy as described in claim 1, which is characterized in that described
In step 3, Mn is added2+Sodium hydrate regulator solution pH to 9 is added after stirring 2 minutes after metal salt, solution becomes orange, then stirs
It mixes 6 hours, the nano-carrier NMOFs@BSA/SDs@MnO for photodynamic therapy is obtained after dialysis2。
9. a kind of nano-carrier for photodynamic therapy being prepared such as any the method for claim 1-8.
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