CN107485714A - A kind of smooth thermotherapeutic agent/photoacoustic contrast agent and its preparation method and application - Google Patents
A kind of smooth thermotherapeutic agent/photoacoustic contrast agent and its preparation method and application Download PDFInfo
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- CN107485714A CN107485714A CN201610413964.8A CN201610413964A CN107485714A CN 107485714 A CN107485714 A CN 107485714A CN 201610413964 A CN201610413964 A CN 201610413964A CN 107485714 A CN107485714 A CN 107485714A
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Classifications
-
- 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
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Radiology & Medical Imaging (AREA)
- Physics & Mathematics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Acoustics & Sound (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to a kind of smooth thermotherapeutic agent/photoacoustic contrast agent and its preparation method and application, there is provided a kind of light thermotherapeutic agent and/or photoacoustic contrast agent containing molybdenum base polyoxometallate.The present invention utilizes the variable characteristic of molybdenum ionic valence condition, obtain it is a kind of can be according to the nano material of tumor microenvironment Intelligent adjustment photo-thermal efficiency, reversible regulation and control of its photo-thermal efficiency by external environment oxidation-reduction potential, reduction-state is rendered as in the reduction atmosphere of tumor lesion area, with efficient photo-thermal therapy function, and oxidation state is rendered as in the normal tissue, photo-thermal effect is very weak；Simultaneously; the grain size of molybdenum base polyoxometallate nanocluster with pH value reduce and self assembly is grown up; utilize this proton capture self aggregation effect under tumour slightly acidic condition; for improving intravenous injection diagnosis and treatment Ji Liu areas enriching quantity; normal structure is farthest protected while thereby guaranteeing that tumour efficient thermotherapy, to realize the high accuracy classification treatment of malignant tumour.
Description
Technical field
The present invention relates to one kind to have the dual more metals of environmental response molybdenum base of tumor microenvironment (faintly acid and week reduction)
Oxygen hydrochlorate and preparation method thereof, the molybdenum base polyoxometallate have optoacoustic radiography and light thermotherapeutic function, can be used as and be used to realize
The early diagnosis of tumour and the photoacoustic contrast agent and light thermotherapeutic agent of specific photo-thermal therapy, belong to Nano biomedical material technology
Field.
Background technology
In recent years, also begin to be faced with increasingly sternness, some emerging oncotherapy technologies of tumor development situation
The concern of bed.Because treatment time is short, therapeutic effect is obvious and the characteristics of to human body Small side effects, the light based near infrared light
Technique for hyperthermia is gradually favored by researcher, therefore, substantial amounts of correlative study work focuses primarily on design and exploitation can
Meet clinical demand near infrared light thermotherapeutic agent.Near infrared light thermotherapeutic agent is broadly divided into three classes at present：1. the noble metal of special appearance
Nano material.2. transition metal oxide and sulfide nano-material.3. conducting polymer nano material.Although these photo-thermal are treated
Agent shows good biological safety and efficient therapeutic effect in the lab, but a kind of can move towards clinical
Light thermotherapeutic agent must meet first：It is cheap, can be mass, be storage-stable etc. and require, and these minimum requirements are to work as
What preceding few light thermotherapeutic agent can be fully met.Secondly as most therapeutic processes need to be injected intravenously light thermotherapeutic agent, and it is in body
Interior circulation lacks specificity, can not be highly enriched in focal zone, and extraneous laser is difficult to ensure that high-precision focal zone irradiation, makes
Into inevitable normal tissue injury.Therefore, it is a kind of it is economical, can batch, stable and high specific light thermotherapeutic agent research and development
It is extremely urgent.
To realize the high specific of oncotherapy, the therapeutic strategy based on tumor microenvironment, it is increasingly becoming in recent years new
The main thought of diagnosis and treatment agent research and development.Tumor microenvironment mainly includes：(1) because active anaerobic glycolysis produces a large amount of acids
Subacidity caused by matter；(2) increasing for reduced glutathione causes tumour that week reduction is presented.This two big tumor microenvironment
Feature is often used as the stimulation switch for Nano medication transport system under study for action, reaches the mesh of controlled release in chemotherapeutics knurl
, specificity of the drug delivery system to tumour is improved with this.For existing smooth thermotherapeutic agent, its photothermal conversion ability only depends on
In its concentration and extraneous laser power density, up to now, still without a kind of light thermotherapeutic agent that can respond tumor microenvironment.And
In actual photo-thermal therapy implementation process, optical-thermal conversion material is inevitably distributed in the normal structure around tumour, extraneous
The irradiation of laser is also inevitably irradiated to these non-focal zones, also just produces great toxic side effect.Therefore, design and develop
A kind of high specific light thermotherapeutic agent with tumor microenvironment response, by with important actual meaning and clinical value.
The content of the invention
In view of the above-mentioned problems, it is an object of the invention to provide it is a kind of it is economical, can batch, stable and high specific photo-thermal
Treat agent and/or photoacoustic contrast agent and its preparation method and application.
On the one hand, the present invention provides a kind of light thermotherapeutic agent and/or photoacoustic contrast agent containing molybdenum base polyoxometallate.
Polyoxometallate (polyoxometalates, abbreviation POM) refers to some early transition metal elements (such as Mo) with MOx
(x can be 4,6 etc.) is the inorganic metal oxygen cluster compound that one kind that unit polycondensation is formed has special nature and structure.It is more golden
Category oxygen hydrochlorate can be divided into isopolyoxometallate (isopolyacid) and heteropolyoxometallate (heteropoly acid) according to composition difference, with more
Acid is to be formed by a kind of condensation dehydration of oxysalt, and heteropoly acid is to be formed by the condensation dehydration of two or more oxysalt
, wherein heteropoly acid includes miscellaneous element and with element (such as Mo).In the present invention, " molybdenum base polyoxometallate " refers at least contain
There is the polyoxometallate of molybdenum ion.For the present invention using the variable characteristic of molybdenum ionic valence condition, obtaining one kind can be according to tumour
The nano material of microenvironment Intelligent adjustment photo-thermal efficiency, its photo-thermal efficiency are being swollen by the reversible regulation and control of external environment oxidation-reduction potential
Reduction-state is rendered as in the reduction atmosphere of knurl focal zone, there is efficient photo-thermal therapy function, and is rendered as in the normal tissue
Oxidation state, photo-thermal effect are very weak；Meanwhile the grain size of molybdenum base polyoxometallate nanocluster with pH value reduce and from group
Dress is grown up, and using this proton capture self aggregation effect under tumour slightly acidic condition, diagnosis and treatment agent is injected intravenously for improving
In knurl area enriching quantity, normal structure is farthest protected while thereby guaranteeing that tumour efficient thermotherapy, to realize malignant tumour
High accuracy classification treatment.The intelligent thermotherapeutic agent of this self feed back regulation has for the clinicalization process of promotion photo-thermal therapy technology
Significance.In addition, molybdenum base polyoxometallate also has optoacoustic radiography function.Therefore molybdenum base polyoxometallate can be used for
Prepare light thermotherapeutic agent and/or photoacoustic contrast agent.
It is preferred that the molybdenum base polyoxometallate is molybdenum base heteropoly acid.In the present invention, " molybdenum base heteropoly acid " refer to by with
The oxygen-containing polyacid that element (Mo) and miscellaneous element different from molybdenum element are made up of by certain structure oxygen atom ligand bridging.
It is preferred that miscellaneous element in the molybdenum base polyoxometallate is P, Si, B, Al, Ga, Ge, Sn, As, Sb, Bi,
At least one of Se, Tc, I and all first, second, third transition series elements.The First Transition series elements be Sc, Ti,
V, Cr, Mn, Fe, Co, Ni, Cu, Zn, second transition series elements are Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, described
3rd transition series elements are La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg and all lanthanide series.
It is preferred that the molybdenum base polyoxometallate is molybdenum blue.The molybdenum blue is molybdenum base polyoxometallate in reproducibility
Under environment, part molybdenum element is reduced into lower valency, and color becomes au bleu.
It is preferred that the mol ratio of miscellaneous element and molybdenum element is 1 in the molybdenum base polyoxometallate：12,1：9,1：3,2：
3,2：5,1：11,2：17,3：4, or 1：6.
On the other hand, the present invention provides above-mentioned light thermotherapeutic agent and/or photoacoustic contrast agent containing molybdenum base polyoxometallate
Application in anti-tumor medicine is prepared.
The smooth thermotherapeutic agent, it is that after being enriched with tumor region, the light that specific light source is sent can be absorbed, such as 808nm laser,
Heat energy is converted light energy into, tumor temperature rise is reached the purpose of oncotherapy.
It is preferred that the molybdenum base polyoxometallate is molybdenum base heteropoly acid.
It is preferred that miscellaneous element in the molybdenum base polyoxometallate is P, Si, B, Al, Ga, Ge, Sn, As, Sb, Bi,
At least one of Se, Tc, I and all first, second, third transition series elements.
It is preferred that the molybdenum base polyoxometallate is molybdenum blue.
It is preferred that the mol ratio of miscellaneous element and molybdenum element is 1 in the molybdenum base polyoxometallate：12,1：9,1：3,2：
3,2：5,1：11,2：17,3：4, or 1：6.
Tumour of the present invention includes cutaneum carcinoma, breast cancer, lymthoma, glioma, prostate cancer, lung cancer, liver cancer, pancreas
Gland cancer, colorectal cancer etc..
Tumor microenvironment is respectively provided with subacidity and the property of week reduction, and described molybdenum base polyoxometallate, which has, to be directed to
The dual environment response characteristic of faintly acid and week reduction of tumor microenvironment, can respond tumor microenvironment pH, with pH value
Reduce and self assembly occurs, form nano vesicle, improve the enrichment degree in tumor region, there is tumor microenvironment redox again
Atmosphere response function, as reproducibility increases, its near infrared absorption also significantly improves, and can accordingly improve photothermal conversion efficiency.
The characteristics of using tumour faintly acid and week reduction, the present invention in molybdenum base polyoxometallate can be used as realize tumor microenvironment
The light thermotherapeutic agent of self feed back photo-thermal therapy, ensureing specificity and good efficacy while farthest protecting normal structure.
The anti-tumor medicine, can be different dosage forms, including solution, injection, tablet, powder, ointment, breast
Agent, capsule etc..
The anti-tumor medicine, can also include pharmaceutically acceptable excipient, and the excipient includes disintegrant, glued
Tie agent, filler, lubricant, antioxidant, lubricant, glidant, emulsifying agent, ointment etc..
The anti-tumor medicine, other drugs, such as chemotherapeutics can also be included, form combination drug.
Another further aspect, the present invention provides a kind of method for preparing the more metal heteropoly acids of above-mentioned molybdenum base, mainly including following step
Suddenly：
A) molybdenum source, miscellaneous element source and reducing agent are dissolved in solvent respectively, form homogeneous solution A, B and C；
B) under inert gas shielding, solution A and solution B are uniformly mixed, and the pH of reaction system is 4~8；
C) solution C is added into reaction system, be sufficiently mixed；
D) reaction produces molybdenum base polyoxometallate after product, washing, drying are isolated after terminating.
It is preferred that the solvent is included in water, acetone, dimethyl sulfoxide, at least one of DMF.It is described
Solvent has higher polarity, and to the molybdenum source, miscellaneous element source and reducing agent have preferable dissolubility.
It is preferred that in metal oxyacid salts of the molybdenum source including molybdenum, chlorate, nitrate or metal alkoxide extremely
Few one kind, the miscellaneous element source is miscellaneous element oxysalt.
It is preferred that the mol ratio of the miscellaneous element source and the molybdenum source is 1：100~1：1, preferably 1：10~1：1.
It is preferred that the reducing agent includes at least one of hydrazine hydrate, sodium borohydride, ascorbic acid and sodium hypophosphite,
The mol ratio of the reducing agent and the molybdenum source is 1：1~20：1.
It is preferred that the reaction temperature of the reaction system is 0~50 DEG C, preferably 20~40 DEG C.
The preparation method of molybdenum base polyoxometallate of the present invention has technique simple, is easy to produce in batches, can effectively reduce
The preparation cost of material.
Brief description of the drawings
Fig. 1 is the digital photograph figure of the molybdenum base polyoxometallate powder output displaying obtained by the embodiment of the present invention 1；
Fig. 2 is the transmission electron microscope that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is scattered in pH=7.4 solution
(TEM) picture (scale is 10nm in figure)；
Fig. 3 is the transmission electron microscope that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is scattered in pH=7.4 solution
High-resolution picture；
Fig. 4 is to show stability test result of the molybdenum base polyoxometallate in PBS solution obtained by the embodiment of the present invention 1
Figure；
Fig. 5 is the TEM photos (figure that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 4 is scattered in pH=7.4 solution
Middle scale is 5nm)；
Fig. 6 is the TEM pictures that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is scattered in pH=6.5 solution；
Fig. 7 is the TEM pictures that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is scattered in pH=4.5 solution；
Fig. 8 is what the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 was scattered in pH=7.4 solution and was progressively acidified
Dynamic light scattering (DLS) hydration kinetics diameter change figure；
Fig. 9 is the ultraviolet-visible that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is dispersed in different pH value
Abosrption spectrogram；
Figure 10 be the embodiment of the present invention 1 obtained by molybdenum base polyoxometallic acid salting liquid it is acidified-alkalization circulating treatment procedure in
The circulation change figure of absorbance at 808nm；
Figure 11 is the X-ray absorption essence of molybdenum base polyoxometallic acid salting liquid at various ph values obtained by the embodiment of the present invention 1
Fine texture spectrum (EXAFS)；
The schematic diagram that Figure 12 changes for molybdenum base polyoxometallate self assembly degree with pH intensity of variations；
Figure 13 is the XPS spectrum of the molybdenum base polyoxometallate of the different reducing degrees obtained by the embodiment of the present invention 1, in each figure
In, Ox is represented when not adding reducing agent, i.e., situation, R1, R2, R3, R4 under oxidation state represent to add respectively the amount of reducing agent by
Gradually four kinds of incremental situations, i.e. reducing degree gradually increase from R1 to R4；
Figure 14 is the EPR spectrums of the molybdenum base polyoxometallate of the different reducing degrees obtained by the embodiment of the present invention 1；
Figure 15 be the embodiment of the present invention 1 obtained by different reducing degrees molybdenum base polyoxometallate be dispersed in pH=5.0,
6.0th, the ultraviolet-visible absorption spectroscopy figure in 6.5,7.4 solution, scheme a-d in curve sequentially consist of Ox, R1, R2, R3,
R4；
It is molten that the molybdenum base polyoxometallate of different reducing degrees of the Figure 16 obtained by the embodiment of the present invention 1 is dispersed in pH=5.0
In liquid, in 1.5W/cm2808 nanometer lasers irradiation under heating curve figure；
Figure 17 is the optoacoustic radiography figure of the molybdenum base polyoxometallic acid saline solution obtained by the embodiment of the present invention 1；
Figure 18 is after the molybdenum base polyoxometallic acid saline solution obtained by tail vein injection embodiment 1 is carried out to mouse, when different
Between after, the photo assembled in tumor region of the molybdenum base polyoxometallate, US represents ultrasonic imaging in figure, PA represent optoacoustic into
Picture；
Figure 19 is after the molybdenum base polyoxometallic acid saline solution obtained by tail vein injection embodiment 1 is carried out to mouse, with the time
Elapse the change of optoacoustic (PA) contrast intensity of molybdenum base polyoxometallate in tumor region；
In Figure 20, figure a is cell survival rate number of the molybdenum base polyoxometallate under oxidative environment obtained by embodiment 1
According to molybdenum base polyoxometallates of the figure b obtained by embodiment 1 cell survival rate data under deep reproducibility environment；
Figure 21 is the molybdenum base polyoxometallate (80mg obtained by the Balb/c small white mouse tail vein injections embodiment of the present invention 1
Mo/kg) changes of weight contrasts with blank group in one month；
Figure 22 is the molybdenum base polyoxometallate (80mg obtained by the Balb/c small white mouse tail vein injections embodiment of the present invention 1
Mo/kg) 7 days with after 30 days, the slice maps of each organs and tissues contrasts with blank group；
Molybdenum base polyoxometallate obtained by Figure 23 various concentrations embodiment of the present invention 1 is in different capacity density 808nm laser
Suppression block diagram under irradiation to MCF-7 cytoactives；
Figure 24 is with copolymerization Jiao's picture of propidium iodide and the amphophilic MCF-7 cells of calcein under the conditions of different disposal；
Figure 25 is to show that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is downloaded at 808nm in different oxygen-containing atmospheres
Light absorbs figure；
Molybdenum base polyoxometallates of the Figure 26 obtained by the embodiment of the present invention 1 is with MCF-7 cells respectively in normoxia
Incubation 12 hours in (21%O2) and low oxygen content (2%) atmosphere, then irradiated under 808nm near-infrared lasers 5 minutes
Heating curve；
Figure 27 is progress 808nm in knurl area after molybdenum base polyoxometallate or physiological saline obtained by the injection embodiment of the present invention 1
Thermograph after laser irradiation 5min；
Figure 28 is progress 808nm in knurl area after molybdenum base polyoxometallate or physiological saline obtained by the injection embodiment of the present invention 1
Heating curve during laser irradiation 5min；
Figure 29 is to inject the molybdenum base polyoxometallate or physiological saline obtained by the embodiment of the present invention 1, and knurl area is carried out
After 808nm laser irradiation 5min, the relative tumour volume growth curve of different disposal group；
Figure 30 is after the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 injects two hours, using Soviet Union under different situations
The tumor tissues photo of another name for and eosin stains；
Molybdenum base polyoxometallates of the Figure 31 obtained by the embodiment of the present invention 1 is in tumor tissues after being injected intravenously 1 hour
Distribution map in knurl；
Figure 32 is the figure for showing to be carried out the result of photo-thermal treatment experiment with three tumor experimental models；
Figure 33 is the optoacoustic oxygen saturation picture of subcutaneous 4T1 tumours and the figure of High-resolution ultrasound imaging；
After Figure 34 is the molybdenum base polyoxometallate 1h obtained by the intravenous injection embodiment of the present invention 1, to tumor region and its week
The musculature and skin histology on side carry out XPS signs；
After Figure 35 is the molybdenum base polyoxometallate 1h obtained by the intravenous injection embodiment of the present invention 1, to tumor region and its week
The musculature on side carries out the sign of optoacoustic (PA) signal intensity；
Figure 36 is haemoconcentration metabolic chart, urine and the excrement of the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1
Metabolic condition and the accumulation in different organ and tissue；
Figure 37 is clearance rate curve of the molybdenum base polyoxometallate in tumour and heart obtained by the embodiment of the present invention 1.
Embodiment
Embodiment is enumerated further below to describe the present invention in detail.It should be understood that following examples are served only for the present invention
It is further described, it is impossible to be interpreted as limiting the scope of the invention, those skilled in the art is according to the present invention's
Some nonessential modifications and adaptations that the above is made belong to protection scope of the present invention.Following specific techniques of example
Parameter etc. is also only an example in OK range, i.e. those skilled in the art can do suitable model by this paper explanation
Interior selection is enclosed, and does not really want to be defined in the concrete numerical value of hereafter example.
Embodiment 1
0.06mol sodium molybdates, 0.012mol sodium phosphates and 0.6mol ascorbic acid are weighed, is dissolved in respectively in 20ml deionized waters,
Room temperature, which is sufficiently stirred, is completely dissolved it, and formation homogeneous solution A, B and C, stand-by respectively；Under argon gas protection, rapidly by solution B
Add in solution A, be heated to 40 DEG C, insulated and stirred 10min, make it well mixed；By solution C by syringe pump with 1ml/min
Speed be slowly added dropwise and be gradually changed into blue-green into reaction system, solution from transparent, finish, continue to stir 1h；Reaction end is treated
System temperature is down to room temperature, after adding 40ml ethanol stirring 20min, repeatedly centrifuges and cleans, be finally freeze-dried, obtain
Molybdenum base polyoxometallic acid salt powder, is sealed, stand-by.
Fig. 1 is the digital photograph figure of the molybdenum base polyoxometallate powder output displaying obtained by the embodiment of the present invention 1, its
Quality is 5.5208g, it can be seen that molybdenum base polyoxometallate proposed by the invention can realize batch production, can effectively drop
Its low preparation cost as clinical light thermotherapeutic agent.
Fig. 2 is the transmission electricity that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is scattered in pH=7.4 solution
Mirror picture, it can be seen that about 1nm is presented under the conditions of pH=7.4 in the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1
Ultra-small grain size, and size uniformity, favorable dispersibility.
Fig. 3 is the transmission electricity that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is scattered in pH=7.4 solution
The high-resolution picture of mirror, should be apparent that the crystal face of nano particle from figure.
The element ratio of molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is as shown in the table, wherein P/Mo's
Ratio is close to 1：12.
Fig. 4 is stability test of the molybdenum base polyoxometallate in PBS solution obtained by the embodiment of the present invention 1, from
The it can be seen from the figure that molybdenum base polyoxometallate deposits substantially unchanged, no precipitation generation in 1 year in PBS solution.Storage one
Slightly higher absorption should be the volatilization of solution and cause after year.The hydration radius of particle is substantially unchanged after figure b illustrates 1 year.Illustrate this
Molybdenum base polyoxometallate is well dispersed in physiological saline, and grain diameter is homogeneous, and storage has for more than 1 year without significant change
Good stability.
Embodiment 2
0.12mol sodium molybdates, 0.012mol sodium phosphates and 0.8mol ascorbic acid are weighed, is dissolved in respectively in 20ml deionized waters,
Room temperature, which is sufficiently stirred, is completely dissolved it, and formation homogeneous solution A, B and C, stand-by respectively；Under argon gas protection, rapidly by solution B
Add in solution A, temperature is 20 DEG C, constant temperature stirring 10min, makes it well mixed；By solution C by syringe pump with 1ml/min
Speed be slowly added dropwise and be gradually changed into blue-green into reaction system, solution from transparent, finish, continue to stir 1h；Reaction end is treated
System temperature is down to room temperature, after adding 40ml ethanol stirring 20min, repeatedly centrifuges and cleans, be finally freeze-dried, obtain
Molybdenum base polyoxometallic acid salt powder, is sealed, stand-by.
Embodiment 3
0.1mol sodium molybdates, 0.015mol sodium phosphates and 0.6mol sodium hypophosphites are weighed, is dissolved in respectively in 20ml deionized waters, room
Temperature, which is sufficiently stirred, is completely dissolved it, and formation homogeneous solution A, B and C, stand-by respectively；Under argon gas protection, solution B is added rapidly
Enter in solution A, be heated to 40 DEG C, insulated and stirred 10min, make it well mixed；By solution C by syringe pump with 1ml/min's
Speed is slowly added dropwise gradually to be changed into blue-green from transparent, finishes into reaction system, solution, continues to stir 1h；Body is treated in reaction end
It is that temperature is down to room temperature, after adding 40ml ethanol stirring 20min, repeatedly centrifuges and clean, be finally freeze-dried, obtain molybdenum
Quito oxometallic acid salt powder, is sealed, stand-by.
The molybdenum base polyoxometallate being prepared in embodiment 2 and 3, its P：Mo ratio is close to 1：12, with reference to reality
Example 1 is applied as can be seen that the ratio for changing P and Mo in reactant does not influence the P in final molybdenum base polyoxometallate product：Mo ratios
Example.
Embodiment 4
0.08mol sodium molybdates, 0.02mol sodium metasilicate and 1mol hydrazine hydrates are weighed, is dissolved in respectively in 20ml deionized waters, room temperature is filled
Stirring is divided to be completely dissolved it, formation homogeneous solution A, B and C, stand-by respectively；Under argon gas protection, solution B is added rapidly molten
In liquid A, 30 DEG C, insulated and stirred 10min are heated to, makes it well mixed；By solution C by syringe pump with 1ml/min speed
It is slowly added dropwise and is gradually changed into blue-green into reaction system, solution from transparent, finishes, continues to stir 0.5h；System is treated in reaction end
Temperature is down to room temperature, after adding 60ml ethanol stirring 20min, repeatedly centrifuges and cleans, be finally freeze-dried, obtain molybdenum base
Polyoxometallic acid salt powder, is sealed, stand-by.
Fig. 5 is that the TEM that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 4 is scattered in pH=7.4 solution shines
Piece, it can be seen that the molybdenum base polyoxometallate obtained by the present embodiment, under the conditions of pH=7.4, about 2nm extra small grain is presented
Footpath, and size uniformity, favorable dispersibility.
Embodiment 5
PH response experiments
Experiment material and instrument：
Molybdenum base polyoxometallic acid salting liquid (pH=7.4, concentration 1.5mg/ml) obtained by the embodiment of the present invention 1, hydrochloric acid is molten
Liquid, sodium hydroxide solution, liquid-transfering gun, pH meter, dynamic light scattering particle size instrument, transmission electron microscope, ultraviolet-visible absorption spectroscopy
Instrument.
Experimental method：
Molybdenum base polyoxometallic acid salting liquid is progressively acidified with hydrochloric acid, monitors its hydration kinetics diameter, and use transmission electron microscopy
Its metamorphosis of sem observation.Hydrochloric acid is progressively neutralized with sodium hydroxide, regulation molybdenum base polyoxometallic acid salting liquid is past to pH=7.4
Multiple 5 above steps, monitor the circulation change of its absorption spectrum.
Experimental result：
Fig. 6 is the TEM pictures that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is scattered in pH=6.5 solution, can
To find out that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 under the conditions of pH=6.5, can be self-assembly of particle diameter
Size about 20nm nano vesicle.
Fig. 7 is the TEM figures that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is scattered in pH=4.5 solution
Piece, it can be seen that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1, can be with self assembly shape under the conditions of pH=4.5
Exceed 50nm nano particle into particle diameter.
Fig. 8 be the embodiment of the present invention 1 obtained by molybdenum base polyoxometallate be scattered in pH=7.4 solution and progressively acid
Dynamic light scattering (DLS) hydration kinetics diameter change figure of change, it can be seen that how golden the molybdenum base obtained by the embodiment of the present invention 1 is
Belong to oxygen hydrochlorate, with acid degree raising can progressively self assembly, form larger sized nano particle.This pH responses are special
Property can realize its self assembly in faintly acid tumor region, and increased hydration kinetics diameter can effectively improve EPR effects,
Its enriching quantity in tumor region is finally improved, good basis is established in the implementation for follow-up efficient photo-thermal therapy.
Molybdenum base polyoxometallates of the Fig. 9 obtained by the embodiment of the present invention 1 is dispersed in ultraviolet in different pH value
Visible absorption spectra figure, it can be seen that with the increase of solution acidic degree, the more metals of molybdenum base obtained by the embodiment of the present invention 1
Absorption of the oxygen hydrochlorate at 808nm dramatically increases.
Figure 10 be the embodiment of the present invention 1 obtained by molybdenum base polyoxometallic acid salting liquid it is acidified-alkalization circular treatment mistake
The circulation change figure of absorbance in journey at 808nm, it can be seen that the molybdenum base polyoxometallic acid obtained by the embodiment of the present invention 1
The acid enhancing near infrared absorption characteristic completely reversibility of salt.It is this to be changed and the generation spy that rapidly absorption changes according to external environment pH
Property, the sensor that makes it be expected to be used as environment pH only need to test absorption spectrum, can be according to pH with absorbing high peak position
Relation deduces environmental pH.
Figure 11 is that the X ray of molybdenum base polyoxometallic acid salting liquid at various ph values obtained by the embodiment of the present invention 1 is inhaled
Fine structure spectroscopy (EXAFS) is received, is found by analysis, Fourier trasform spectroscopy such as Figure 11 of Mo k2 weighting K-edge vibrations
Shown, the limited scattering peak of no higher order dependencies demonstrates the clustering properties of the molybdenum base polyoxometallate.With solution acid
Change, the bond distance of the Mo=Ot (terminal oxygen) in material is gradually shortened, and the ligancy of terminal oxygen can also be reduced；Mo-Oe (sides altogether
Oxygen) bond distance also gradually shorten, but the ligancy of side oxygen then increased altogether.In addition, the bond distance of Mo-Mo keys and ligancy are kept
It is constant.The power that driving nano-particle carries out self assembly should be the balance of short-range attractive force and electrostatic repulsion forces between adjacent ions.
Which demonstrate the protonation of side oxygen atom altogether after acidifying, and then directly form hydrogen bond in Oe or Ot and proton.Another kind understands
Mode, in the neutral environment that pH is 7.4, the big ion of the nanoscale ionizes and between each other because Coulomb repulsion makes him completely
It is stable into small particles；After solution is acidified, electrostatic repulsion forces reduce, and the attraction enhancing that the hydrogen bond formed introduces, this two
The balance of kind of power make it that self assembly occurs in the case of low ph value obtains for nano-particle, and self assembly degree with pH intensity of variations and
Change, as shown in figure 12.
Figure 13 is the XPS spectrum of the molybdenum base polyoxometallate of the different reducing degrees obtained by the embodiment of the present invention 1, by scheming
In understand, in oxidative environment, Mo exists material in the form of+6 valencys.When in reproducibility environment, can also detect be+
5 valency Mo signal, the valency of declaratives+6 Mo are reduced into+5 valencys so that are with mixed valence under the Mo reproducibility environments in material
It is existing.
Figure 14 is the EPR spectrums of the molybdenum base polyoxometallate of the different reducing degrees obtained by the embodiment of the present invention 1, by scheming
In understand, material in reproducibility environment, g=1.92 at can see+5 valency Mo signal, in addition, at g=2.0023
Also it is observed that the signal of free electron, illustrates the electricity that can move freely under reducing environment in molybdenum base polyoxometallate be present
Son.
Reproducibility response experiment
Experiment material and instrument：
Molybdenum base polyoxometallic acid salting liquid (pH=5.0, concentration 1.5mg/ml) obtained by the embodiment of the present invention 1, Vitamin C
Acid solution, liquid-transfering gun, ultraviolet-visible absorption spectroscopy instrument, 808nm lasers, infrared thermography.
Experimental method：
Ascorbic acid solution is progressively added dropwise in molybdenum base polyoxometallic acid salting liquid, wherein sample when not adding ascorbic acid is i.e.
For Ox, with the increase of ascorbic acid addition, four samples are taken respectively, are designated as R1, R2, R3, R4, how golden molybdenum base is from R1 to R4
The reducing degree of category oxygen hydrochlorate is gradually deepened, and monitors the change of its absorption spectrum.Colorimetric is placed at different moments, taking 1ml solution
In ware, 1.5W/cm is used2808nm laser irradiation 5min, record different reducing degree molybdenum base multi-metal oxygens with infrared thermography
The heating curve of acid salt solution.
Experimental result：
Figure 15 be the embodiment of the present invention 1 obtained by different reducing degrees molybdenum base polyoxometallate be dispersed in pH=5.0,
6.0th, the ultraviolet-visible absorption spectroscopy figure in 6.5,7.4 solution.It can be seen that the more metals of molybdenum base obtained by the embodiment of the present invention 1
Oxygen hydrochlorate, with the increase of reducing degree, its near infrared absorption dramatically increases.
Figure 16 is that the molybdenum base polyoxometallate of the different reducing degrees obtained by the embodiment of the present invention 1 is dispersed in pH=
In 5.0 solution, in 1.5W/cm2808nm laser irradiation under heating curve figure.It can be seen that obtained by the embodiment of the present invention 1
Molybdenum base polyoxometallate, with the increase of reducing degree, its photothermal conversion efficiency significantly improves.
Molybdenum base polyoxometallate in the present invention has the characteristics of pH responses and reproducibility response, with reference to tumor microenvironment
The environmental properties of middle faintly acid and week reduction, the molybdenum base polyoxometallic acid in the present invention in the present invention can be used as photo-thermal
Agent is treated, applied in anti-tumor medicine.As shown in this embodiment, the grain size of molybdenum base polyoxometallate can be with pH
Value is reduced and self assembly is grown up (proton capture self aggregation effect).Its pH respective range can be 3 to 8, with acidic cancer microenvironment
Match.Particle diameter of the molybdenum base polyoxometallate under the conditions of pH=7.4 is 0.5~2nm, the self assembly under the conditions of pH=6.5
15~25nm of particle size nano vesicle is formed, the nanometer that particle diameter exceedes 50nm is self-assembly of under the conditions of pH=4.5
Grain.Therefore this pH response characteristics can realize its self assembly in faintly acid tumor region, increased hydration kinetics diameter
EPR effects can be effectively improved, finally improve its enriching quantity in tumor region.Meanwhile the molybdenum base multi-metal oxygen in the present invention
The molybdenum element valence state of hydrochlorate is variable, its photo-thermal efficiency by external environment oxidation-reduction potential reversible regulation and control, tumor lesion area also
Reduction-state is rendered as in former atmosphere, there is efficient photo-thermal effect, and is rendered as oxidation state in the normal tissue, photo-thermal effect is very
It is weak.Therefore, the molybdenum base polyoxometallate in the present invention can realize tumor microenvironment (faintly acid and week reduction) dual ring
Border responds, and has high specificity, so as to realize tumour high specific photo-thermal therapy.
Embodiment 6
Optoacoustic radiography performance test
Experiment material and equipment
Molybdenum base polyoxometallate obtained by the embodiment of the present invention 1,1.5ml EP pipes, photoacoustic imaging instrument.
Experimental method：
Molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 of various concentrations is placed in EP pipes, tested at its 825nm
Optoacoustic radiography performance.
Experimental result：
Figure 17 is the optoacoustic radiography figure of the molybdenum base polyoxometallic acid saline solution obtained by the embodiment of the present invention 1, it can be seen that real
The molybdenum base polyoxometallate obtained by example 1 is applied, the photoacoustic signal for having obvious concentration dependant, shows that it has potential optoacoustic
Radiography function.
Figure 18 is after the molybdenum base polyoxometallic acid saline solution obtained by tail vein injection embodiment 1 is carried out to mouse, no
With after the time, the photo that the molybdenum base polyoxometallate is assembled in tumor region, can be seen that molybdenum base from the second row and the third line
Polyoxometallate is after tumor region aggregation, if can be embodied with optoacoustic radiography Performance Observation to its distribution and aggregation situation
Go out its optoacoustic radiography performance.
After Figure 19 is carries out the molybdenum base polyoxometallic acid saline solution obtained by tail vein injection embodiment 1 to mouse, with
The change of time passage optoacoustic contrast intensity of molybdenum base polyoxometallate in tumor region, illustrates molybdenum base polyoxometallate
Aggregation can be realized in knurl in a short time, and embodies preferable optoacoustic radiography performance.
Embodiment 7
Cytotoxic evaluation is tested
Experiment material：
Molybdenum base polyoxometallate obtained by the embodiment of the present invention 1；
Cell model：
BRL-3A rat hepatocytes, RK-52E rat kidney cells and MCF-7 breast cancer cell models.
Experimental method：
Cell survival rate is evaluated using standard MTT methods, specific experiment method is：(1) inoculating cell：With containing the small ox blood of 10% tire
Clear nutrient solution is made into individual cells suspension, and 96 orifice plates are inoculated into every 3000 cells in hole, per the μ l of hole nutrient solution volume 100,
It is placed in 37 DEG C of cell culture incubators and cultivates.(2) cell is cultivated：After cell attachment, the molybdenum base multi-metal oxygen of various concentrations is added
After hydrochlorate co-cultures 48h with cell, carefully cleaned for several times with PBS, continue to co-culture 4h.(3) it is quantitative：MTT liquid is removed, is added per hole
Enter the 100 dissolving crystallized purples of μ l dimethyl sulfoxides, select 490nm wavelength, each hole absorbance value is determined on enzyme linked immunological monitor, remember
Record result.
Experimental result：
It is the cell survival rate data under oxidative environment that a is schemed in Figure 20, and figure b is cell survival rate number under deep reproducibility environment
According to.Test respectively to BRL-3A rat hepatocytes, NRK-52E rat kidney cells and MCF-7 breast cancer cell survival rate shadows
Ring, it can be seen that the material is under 500 μ g/mL higher concentration, and after co-culturing 48h, the survival rate of each cell can still maintain
More than 85%, show the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 in oxidative environment and deep reproducibility environment
Under be respectively provided with relatively low cell toxicant.
Embodiment 8
Live body safety experiment
Experiment material：
Molybdenum base polyoxometallate obtained by the embodiment of the present invention 1；
Experimental animal：
Balb/c female small white mouses, average weight 20g, 7 week old, purchased from Medical Center of Fudan University's Animal House.
Experimental method：
(dosage is the normal saline solution of molybdenum base polyoxometallate obtained by the μ l embodiment of the present invention 1 of tail vein injection 150
80mg Mo/kg).Weigh in, detect one month every three days, and the H＆E for passing through routine observes 7 and before injecting, after injection
The histotomy of 30 days.
Experimental result：
Figure 21 is the molybdenum base polyoxometallate (80mg obtained by the Balb/c small white mouse tail vein injections embodiment of the present invention 1
Mo/kg) changes of weight contrasts with blank group in one month, and injection material group changes of weight is with blank group without significant difference.
Figure 22 is the molybdenum base polyoxometallate obtained by the Balb/c small white mouse tail vein injections embodiment of the present invention 1
(80mg Mo/kg) 7 days with after 30 days, slice map and the blank group of each organs and tissues contrast, it can be seen that mouse is real in injection
Each organ of conscience spleen and lung kidney for applying (up to 30 days) before and after the molybdenum base polyoxometallate obtained by example 1 is anti-without overt toxicity
Should, not only without stress liver renal toxicity but also without long-term tissue toxicity, show good biocompatibility of the material in live body level.
Embodiment 9
Cell therapy is tested
Experiment material and instrument：
Molybdenum base polyoxometallate obtained by the embodiment of the present invention 1,808nm lasers；
Cell model：
MCF-7 breast cancer cell models.
Experimental method：
Cell survival rate is evaluated using standard MTT methods, specific experiment method is：(1) inoculating cell：With containing the small ox blood of 10% tire
Clear nutrient solution is made into individual cells suspension, with every hole 1 × 104Individual cell is inoculated into 96 orifice plates, per the μ of hole nutrient solution volume 100
L, it is placed in 37 DEG C of cell culture incubators and cultivates.(2) cell is cultivated：After 12h cell attachments, add more comprising various concentrations molybdenum base
The new culture medium of oxometallate.(3) with the 808nm lasers of different capacity density hole-specifically irradiating cell 5min, after it is every
Hole adds the 0.6mg/ml μ l of MTT kits solution 100, continues to co-culture 4h.(3) it is quantitative：MTT liquid is removed, 100 μ l are added per hole
The dissolving crystallized purple of dimethyl sulfoxide, 490nm wavelength is selected, each hole absorbance value is determined on enzyme linked immunological monitor, record result.
Experimental result：
Figure 23 is that the molybdenum base polyoxometallate obtained by the various concentrations embodiment of the present invention 1 swashs in different capacity density 808nm
Suppression block diagram under light irradiation to MCF-7 cytoactives, it can be seen that under laser irradiation, obtained by the embodiment of the present invention 1
Molybdenum base polyoxometallate, there is good cancer cell killing-efficiency, and killing rate and its concentration and laser power are into positive
Pass relation.
Figure 24 is with the common focused view of propidium iodide and the amphophilic MCF-7 cells of calcein under the conditions of different disposal
Piece, four kinds of conditions are respectively：Control group, POM injections group (25 μ g ml-1Mo), infrared laser (NIR) irradiation group (1.5W cm-2,
5min), POM injections+infrared laser irradiation group.The figure shows when tumour cell only has molybdenum base polyoxometallic acid salt treatment or red
During outer laser emission processing, the death of tumour cell can not be caused, when only meeting two conditions simultaneously, kill could be realized
The effect of tumour cell.
Figure 25 is that the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 is downloaded at 808nm in different oxygen-containing atmospheres
Light absorbs, it can be seen that with the gradual reduction of oxygen content in ambiance, light absorbs of the material at 808nm gradually increase
By force.Figure b show molybdenum base polyoxometallate recycling storage and inhaled in oxygen content for the UV, visible light in 21% and 2% ambiance
Receive spectrum, it can be seen that when oxygen content is 2% ambiance, its main absworption peak blue shift, and overall absorption intensity enhancing,
It is stronger in the ambiance of its absorption high oxygen content at 808nm in the ambiance of low oxygen content.
Molybdenum base polyoxometallates of the Figure 26 obtained by the embodiment of the present invention 1 is with MCF-7 cells respectively normal oxygen-containing
Incubation 12 hours in (21%O2) and low oxygen content (2%) atmosphere are measured, then are irradiated 5 minutes under 808nm near-infrared lasers
Heating curve, it can be seen that more good heating performance is embodied in the sample cultivated in low oxygen content atmosphere, than just
The sample temperature rise cultivated in normal oxygen content atmosphere is higher by 6 DEG C (figure a).Compare controlling in two groups of samples using cell apoptosis assay
Therapeutic effect (figure b), it can be found that the mortality of its MCF-7 cell of the sample cultivated in low oxygen content atmosphere substantially normally contains
One times of sample in oxygen amount atmosphere, illustrate the photo-thermal therapy agent that the molybdenum base polyoxometallate is the enhancing of typical low oxygen content.
Embodiment 10
Live body Experiment on therapy
Experiment material：
Molybdenum base polyoxometallate obtained by the embodiment of the present invention 1,808nm lasers and infrared thermography；
Experimental animal：
Balb/c female small white mouses, average weight 20g, 7 week old, purchased from Medical Center of Fudan University's Animal House.
Experimental method：
Single tumor model：(1) 4T1 tumor inoculations：In the thigh of mouse or so two, subcutaneously injection contains 1 × 10 respectively64T1 cells
The μ l of PBS suspensions 100, tumour growth to 100~130mm3Afterwards, it is stand-by.(2) mouse is arbitrarily divided into 4 groups, it is every group 7, different
Treatment group is：A. physiological saline group, the μ l physiological saline of tail vein injection 150；B. molybdenum base polyoxometallate group, tail vein injection
Molybdenum base polyoxometallate (30mg Mo/kg) obtained by the embodiment of the present invention 1；C. physiological saline+near-infrared irradiation group, tail
After being injected intravenously physiological saline 1h, with 1.5W/cm2808nm laser irradiation tumour 5min；D. molybdenum base polyoxometallate+near
Infrared radiation group, after the molybdenum base polyoxometallate 1h obtained by the tail vein injection embodiment of the present invention 1, with 1.5W/cm2's
808 laser irradiation tumour 5min.In processing procedure, changed with infrared thermography monitoring tumor temperature.(3) after processing terminates,
Tumour length (L) and wide (W) are measured within every two days, according to formula：V=L × W2/ 2 calculate tumor size, and divided by initial gross tumor volume
Obtain relative tumour volume；
Three tumor models：Similar with single tumor model, difference is in the subcutaneous three diverse locations inoculation of the thigh of mouse or so two
4T1 tumours.
Experimental result：
Figure 27 is progress 808nm in knurl area after molybdenum base polyoxometallate or physiological saline obtained by the injection embodiment of the present invention 1
Thermograph after laser irradiation 5min, it can be seen that the molybdenum base polyoxometallate obtained by the injection embodiment of the present invention 1
Afterwards, the irradiation of 808nm laser can effectively improve tumor temperature to 52 DEG C, and peritumoral tissues temperature improves without violent, shows this
The photo-thermal therapy of molybdenum base polyoxometallic acid Salt treatment obtained by inventive embodiments 1 specificity good to tumor tissues.
Figure 28 is knurl area progress after molybdenum base polyoxometallate or physiological saline obtained by the injection embodiment of the present invention 1
Heating curve during 808nm laser irradiation 5min.It is it can be seen that how golden in the molybdenum base obtained by the injection embodiment of the present invention 1
After belonging to oxygen hydrochlorate, under the irradiation of 808nm laser, tumor temperature can increase to over 50 DEG C rapidly in 2min, and control group swells
Although knurl temperature also increases, always below 40 DEG C, cell burn purpose is unable to reach.
Figure 29 is to inject the molybdenum base polyoxometallate or physiological saline obtained by the embodiment of the present invention 1, and knurl area is entered
After row 808nm laser irradiation 5min, the relative tumour volume growth curve of different disposal group.As a result show, the embodiment of the present invention 1
The near infrared light heat cure that obtained molybdenum base polyoxometallate is induced can effectively suppress the growth of tumour, and at 4 days
Complete tumor eradication, no longer recurs in two weeks, and other control group tumor growth rates do not make significant difference, and shows to utilize the present invention
Feasibility of the molybdenum base polyoxometallate as efficient photo-thermal therapy obtained by embodiment 1.
Figure 30 is after the molybdenum base polyoxometallate obtained by the embodiment of the present invention 1 injects two hours, to be adopted under different situations
The tumor tissues photo dyed with h and E, if there it can be seen that only with molybdenum base polyoxometallate or red
Outer light is handled, and tumor tissues do not receive destruction substantially.And the sample handled simultaneously using nano material and infrared light
Product, tumor tissues are then by serious damage.
Molybdenum base polyoxometallates of the Figure 31 obtained by the embodiment of the present invention 1 tumor tissues after being injected intravenously 1 hour
In knurl in distribution map, it can be seen that despite the presence of very high knurl inner tissue hydraulic pressure, molybdenum base polyoxometallate still can be
Intravenous injection penetrates into whole tumor region after 1 hour, illustrates that the molybdenum base polyoxometallate has good permeability.
Figure 32 is three tumor experimental models, is injected intravenously the molybdenum base polyoxometallate 1h obtained by the embodiment of the present invention 1
Afterwards, illumination is carried out to tumor region with 808nm laser, and laser illumination range covers all three tumours.Irradiate within 5 minutes
Afterwards, for the contrast experiment of intravenous injection salt solution, temperature heats warm area than more uniform, and can only be increased to less than 40 DEG C (figure b),
The temperature is relatively low, it is impossible to reaches significant thermotherapy effect.Figure c is shown, is injected intravenously in the experiment of molybdenum base polyoxometallate, is swollen
The obvious temperature difference between knurl region and normal structure be present, wherein tumor temperature is increased to 47 DEG C, and the temperature of normal structure then exists
Less than 42 DEG C.In this case it can realize out and tumour good therapeutic effect is damaged without normal tissue, show
Going out the molybdenum base polyoxometallate, there is very high specific tumour to treat.
Figure 33 is the optoacoustic oxygen saturation picture of subcutaneous 4T1 tumours and the figure product of High-resolution ultrasound imaging, and wherein US represents super
Acoustic imaging, PA represent photoacoustic imaging, from photoacoustic imaging oxygen content collection of illustrative plates, it can be seen that the oxygen saturation concentration of tumor region is very
It is low, hence it is evident that less than the oxygen saturation concentration of neighbouring normal structure, to illustrate the reproducibility microenvironment being well known in hypoxic tumors.
After Figure 34 is the molybdenum base polyoxometallate 1h obtained by the intravenous injection embodiment of the present invention 1, to tumor region and
The musculature and skin histology on its periphery carry out XPS signs, and the S elements observed in collection of illustrative plates should come from tissue
Protein.As can be seen that molybdenum base polyoxometallate is not detected substantially in skin histology.It is worth noting that, tumour
Region not only has higher molybdenum base polyoxometallate aggregate amount, and pentavalent Mo ratio compared to normal muscle tissues region
Example is also apparently higher than normal muscle tissues region, and pentavalent Mo contents increase the rise for being beneficial to absorption intensity, so as to be beneficial to
The raising of photo-thermal conversion efficiency.
After Figure 35 is the molybdenum base polyoxometallate 1h obtained by the intravenous injection embodiment of the present invention 1, to tumor region and
The musculature on its periphery carries out the sign of optoacoustic (PA) signal intensity, it can be seen that the higher PA signal hypothesis of tumor region
Bright molybdenum base polyoxometallate has higher enrichment compared to normal muscle tissues region in tumor region, in addition, tumor area
The signal peak of PA signals is located at 860nm in domain, close to absorption peak position during pH=6.5, compared to normal muscle tissues
Middle 881nm peak position has obvious blue shift, illustrates the slightly acidic environment of tumour so that it has the blue shift of absworption peak.
It should be noted that the faintly acid and week reduction in tumor microenvironment are the microenvironment that different tumours have jointly
Feature, the present invention in molybdenum base polyoxometallate the mechanism of action be based on the faintly acid and week reduction in tumor microenvironment,
I.e. molybdenum base polyoxometallate is self-assembly of big particle in weakly acidic tumor environment, so as to form richness in tumor region
Collection, the week reduction in microenvironment is recycled, strengthens the absorption at 808nm laser, so as to improve its photo-thermal heating properties, from
And realize effective tumour-specific photo-thermal therapy.The type of tumour can be it is a variety of, as cutaneum carcinoma, breast cancer, lymthoma,
Glioma, prostate cancer, lung cancer, liver cancer, cancer of pancreas, colorectal cancer etc., as an embodiment of the invention, implementing
From breast cancer as experimental subjects in example 10.
Embodiment 11
Pharmacokinetics experiment
Experiment material：
Molybdenum base polyoxometallate obtained by the embodiment of the present invention 1；
Experimental animal：
Balb/c female small white mouses, average weight 20g, 7 week old, purchased from Medical Center of Fudan University's Animal House.
Experimental method：
Molybdenum base polyoxometallate (30mg Mo/kg) obtained by the tail vein injection embodiment of the present invention 1, (1) selects 3 mouse,
It it is 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 40 hours and 72 hours in injection length
Afterwards, the change in concentration of 20 μ L blood measuring molybdenum bases polyoxometallates in blood is extracted from tail vein；(2) 3 mouse are selected,
Mouse is collected within the time that injection length is 1 hour, 4 hours, 8 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days and 7 days
Excrement and urine, measure the metabolism discharge rate of molybdenum base polyoxometallate；(3) mouse is divided into 6 groups, every group 3, in injection
Between be to put to death one group of mouse respectively after 30 minutes, 1 hour, 3 hours, 24 hours, 48 hours and 7 days, analyze mouse major organs
The content of the molybdenum base polyoxometallate of (heart, liver, spleen, lung, kidney, tumour and brain).
Figure 36 be the haemoconcentration metabolic chart of molybdenum base polyoxometallate obtained by the embodiment of the present invention 1, urine and
Excrement metabolic condition and the accumulation in different organ and tissue.Figure a is the song that the Mo concentration of element in blood changes over time
Line, concentration reduce the two-component pharmacokinetic model that rule meets classics, the terminal elimination of the center portion thereof point and periphery
Half-life period is respectively 25 minutes and 9.9 hours.It can be seen that the Mo contents in urine are quick in the Mo content analysis of excreta
Reduce, the Mo contents discharged after 7 days by urine account for 73% (figure b and c) of total injection dosage, and this metabolism illustrates that the molybdenum base is more
Oxometallate can by quick kidney filter and urine drains go out in vitro, this because have benefited from the material in neutral environment it is non-
Normal small hydrated diameter (1.7nm) and excellent hydrophily.Comparatively speaking, the Mo concentration among excrement is then relatively low,
Reach concentration peaks within second day after injection.Mo discharge total amount accounts for the 18% of injection dosage in excrement after 7 days, illustrates the molybdenum
Quito oxometallate can be metabolized by liver.It is worth noting that, most molybdenum base polyoxometallates can be 7
Discharge (considering inevitably to lose in excreta collection, existing 91% molybdenum base polyoxometallate is excluded) in it.
Have benefited from excellent metabolism performance, the material can avoid internal potential long term toxicity, show excellent biological safety.
Figure 37 is that clearance rate of the molybdenum base polyoxometallate in tumour and heart obtained by the embodiment of the present invention 1 is bent
Line, compared to the heart of non-mesh endothelial tissue, retention effect of the molybdenum base polyoxometallate in tumor tissues is clearly.
This has benefited from molybdenum base polyoxometallate EPR passive targets after tumor region, and self assembly is by small in tumour slightly acidic environment
Become big effect.
Visible in summary, molybdenum base polyoxometallate provided by the invention has excellent stability, good dispersiveness
Higher biological safety, it can realize the efficient photoacoustic imaging diagnosis of (1) malignant tumour；(2) according to tumor microenvironment
The specific near infrared light heat cure of self-control feedback.In terms of near infrared light heat cure, with tradition based on special appearance
Noble metal nano light thermotherapeutic agent is compared, and the present invention is cheap, good dispersion, degree of controllability are high；Compared to transition metal oxide
Or sulfide nanometer light thermotherapeutic agent, preparation process of the present invention is nontoxic to environment, and storability is high；With conducting polymer nanometer
Light thermotherapeutic agent is compared, and good thermal stability of the present invention, is not susceptible to heat inactivation.Rung with faintly acid and the dual environment of week reduction
Characteristic is answered, normal surrounding tissue is farthest protected while curative effect is improved.And there can be pole by kidney tachymetabolism
Good biocompatibility and organization security.The preparation technology simple economy, batch production can be achieved, be expected to clinical conversion,
Development and application to biomedical sector have important value and meaning.
Claims (10)
1. a kind of light thermotherapeutic agent and/or photoacoustic contrast agent containing molybdenum base polyoxometallate.
2. light thermotherapeutic agent and/or photoacoustic contrast agent according to claim 1 containing molybdenum base polyoxometallate, its feature
It is, the molybdenum base polyoxometallate is molybdenum base heteropoly acid.
3. light thermotherapeutic agent and/or photoacoustic contrast agent according to claim 2 containing molybdenum base polyoxometallate, its feature
It is, the miscellaneous element in the molybdenum base polyoxometallate is P, Si, B, Al, Ga, Ge, Sn, As, Sb, Bi, Se, Tc, I and institute
There are at least one of first, second, third transition series elements.
4. light thermotherapeutic agent and/or photoacoustic contrast agent according to claim 3 containing molybdenum base polyoxometallate, its feature
It is, the molybdenum base polyoxometallate is molybdenum blue.
5. the light thermotherapeutic agent according to any one of claim 1 to 4 containing molybdenum base polyoxometallate and/or optoacoustic are made
Shadow agent, it is characterised in that the mol ratio of miscellaneous element and molybdenum element is 1 in the molybdenum base polyoxometallate：12,1：9,1：3,2：
3,2：5,1：11,2：17,3：4, or 1：6.
6. prepared by the light thermotherapeutic agent containing molybdenum base polyoxometallate and/or photoacoustic contrast agent described in a kind of claim 1
Application in anti-tumor medicine.
A kind of 7. method of the molybdenum base polyoxometallate prepared described in claim 1, it is characterised in that mainly including following step
Suddenly：
a）Molybdenum source, miscellaneous element source and reducing agent are dissolved in solvent respectively, form homogeneous solution A, B and C；
b）Under inert gas shielding, solution A and solution B are uniformly mixed, and the pH of reaction system is 4~8；
c）Solution C is added into reaction system, is sufficiently mixed；
d）Reaction produces molybdenum base polyoxometallate after product, washing, drying are isolated after terminating.
8. according to the method for claim 7, it is characterised in that the solvent includes water, acetone, dimethyl sulfoxide, N, N- bis-
At least one of NMF.
9. according to the method for claim 7, it is characterised in that the molybdenum source includes metal oxyacid salts, the chlorine of molybdenum
At least one of salt dissolving, nitrate or metal alkoxide, the miscellaneous element source are miscellaneous element oxysalt, the miscellaneous element source with
The mol ratio of the molybdenum source is 1：100~1：1.
10. according to the method for claim 7, it is characterised in that the reducing agent includes hydrazine hydrate, sodium borohydride, anti-bad
The mol ratio of at least one of hematic acid and sodium hypophosphite, the reducing agent and the molybdenum source is 1：1~20：1.
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| CN114469992B (en) * | 2021-11-18 | 2022-11-08 | 中山大学附属第五医院 | Application of molybdenum-based polyoxometallate cluster in preparation of medicine for treating ulcerative colitis |
| CN114377128A (en) * | 2022-01-12 | 2022-04-22 | 中南大学 | Preparation and anti-tumor application of composite hydrogel co-loaded with near-infrared photothermal agent and immune drug |
| CN114377128B (en) * | 2022-01-12 | 2023-01-06 | 中南大学 | Preparation and anti-tumor application of composite hydrogel co-loaded with near-infrared photothermal agent and immune drug |
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