CN106668879A - Preparation method of nano simple-substance bismuth diagnosis and treatment agent for CT (computed tomography)/PAT (pericardial adipose tissue) imaging - Google Patents
Preparation method of nano simple-substance bismuth diagnosis and treatment agent for CT (computed tomography)/PAT (pericardial adipose tissue) imaging Download PDFInfo
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- CN106668879A CN106668879A CN201710004818.4A CN201710004818A CN106668879A CN 106668879 A CN106668879 A CN 106668879A CN 201710004818 A CN201710004818 A CN 201710004818A CN 106668879 A CN106668879 A CN 106668879A
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- 229910052797 bismuth Inorganic materials 0.000 title claims abstract description 74
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 238000011282 treatment Methods 0.000 title claims abstract description 57
- 239000000126 substance Substances 0.000 title claims abstract description 54
- 238000003745 diagnosis Methods 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000003384 imaging method Methods 0.000 title abstract description 10
- 238000002591 computed tomography Methods 0.000 title abstract 4
- 210000000577 adipose tissue Anatomy 0.000 title abstract 2
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 45
- 239000013078 crystal Substances 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 10
- 239000011259 mixed solution Substances 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- 238000007626 photothermal therapy Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- -1 n- dodecyl Chemical group 0.000 claims description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims description 7
- 150000005846 sugar alcohols Polymers 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- QGLWBTPVKHMVHM-KTKRTIGZSA-N (z)-octadec-9-en-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCN QGLWBTPVKHMVHM-KTKRTIGZSA-N 0.000 claims description 5
- YAJYJWXEWKRTPO-UHFFFAOYSA-N 2,3,3,4,4,5-hexamethylhexane-2-thiol Chemical compound CC(C)C(C)(C)C(C)(C)C(C)(C)S YAJYJWXEWKRTPO-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 229920000151 polyglycol Polymers 0.000 claims description 4
- 239000010695 polyglycol Substances 0.000 claims description 4
- 238000002601 radiography Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 2
- 239000003125 aqueous solvent Substances 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 14
- 238000000034 method Methods 0.000 abstract description 9
- 230000008569 process Effects 0.000 abstract description 5
- 238000013170 computed tomography imaging Methods 0.000 abstract description 2
- 238000011156 evaluation Methods 0.000 abstract description 2
- 229920000642 polymer Polymers 0.000 abstract description 2
- PPNKDDZCLDMRHS-UHFFFAOYSA-N dinitrooxybismuthanyl nitrate Chemical compound [Bi+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O PPNKDDZCLDMRHS-UHFFFAOYSA-N 0.000 abstract 2
- 230000002349 favourable effect Effects 0.000 abstract 2
- 230000002787 reinforcement Effects 0.000 abstract 2
- 230000002980 postoperative effect Effects 0.000 abstract 1
- 238000010882 preoperative diagnosis Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 9
- 239000002086 nanomaterial Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000002872 contrast media Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 235000013339 cereals Nutrition 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000013007 heat curing Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 230000001235 sensitizing effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- ZQUAVILLCXTKTF-UHFFFAOYSA-H bismuth;tripotassium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[K+].[K+].[Bi+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O ZQUAVILLCXTKTF-UHFFFAOYSA-H 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000007773 growth pattern Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000011337 individualized treatment Methods 0.000 description 1
- 239000000193 iodinated contrast media Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000002082 metal nanoparticle Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000003333 near-infrared imaging Methods 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
Classifications
-
- 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
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/225—Microparticles, microcapsules
-
- 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
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
Abstract
The invention discloses a preparation method of a nano simple-substance bismuth diagnosis and treatment agent for CT (computed tomography)/PAT (pericardial adipose tissue) imaging. The method comprises the following steps: carrying out reaction on a hydrophobic reducing organic solvent and Bi(NO3)3 to generate a hydrophobic-molecule-coated nano simple-substance bismuth crystal, and carrying out reaction on the hydrophobic-molecule-coated nano simple-substance bismuth crystal and an amphiphilic polymer in a hydrophobic organic solvent-water mixed solution. The nano simple-substance bismuth diagnosis and treatment agent has the functions of CT imaging reinforcement and PAT imaging reinforcement, has favorable photothermal effects, can simultaneously implement the integrated diagnosis and treatment process composed of tumor preoperative diagnosis, intraoperative tracking, post-operative evaluation and the like, and thus, has favorable development potential.
Description
Technical field
The invention belongs to nano material and molecular medicine technical field, and in particular to a kind of system of nano simple substance bismuth diagnosis and treatment agent
Preparation Method.
Background technology
For the treatment of tumor patient, the limitation of traditional three big treatment means radiotherapies, chemotherapy and operative treatment is increasingly
Substantially, as lacked the selectivity to diseased region, wound is big, it is impossible to realize individualized treatment etc., therefore in the urgent need to exploitation is new
The treatment means of type are solved.Current photo-thermal therapy (photothermal therapy, PTT) is to develop rapidly in recent years
A kind of minimally invasive oncotherapy technology, it is considered to be a kind of great potential substitutes the tumor therapeuticing method of operation.Target tumor portion
The sensitising agent of position produces heat in the case where incident light is excited using its photothermal deformation effect, and tumor by local temperature can be made to raise and reach
Uniform temperature (42℃More than), so as to realize the effect of killing tumor cell.Due to the cancer target using targeted nano sensitising agent
Transmission and the irradiation to tumor locus selectivity, can significantly reduce whole body system toxicity, simultaneously as near red for what is excited
Outer smooth tissue penetration is strong, and whole therapeutic process can be combined completely by laser controlling with iconography means, be given
Targeted elimination focus while pathological tissues image, forms the diagnosis and treatment integrated carrier for having diagnosis and treatment ability of medicine concurrently, causes
The extensive concern in oncology treatments fields.
Targeting development is all the time the weakness of CT imaging techniques, simple organic iodine contrast medium cell phagocytosis amount pole
It is low, and without substantially selectivity, it is impossible to realize this purpose.Occur going out for inorganic metal nano-particle CT contrast agent in recent years
It is existing, this problem is solved to a certain extent.However, current metal nano contrast agent generally existing is expensive, prepare work
The problems such as skill is complicated, biocompatibility is not enough.Bismuth has been widely used in clinical system as a kind of generally the least expensive heavy metal element
Agent, such as colloidal bismuth subcitrate, are a kind of selections being extremely secure.Bi2S3Nanometer has been demonstrated to be imaged with preferable CT
Effect, and the present invention constructs a kind of bismuth with elementary nano particle, and using hydrophily transformation has been carried out, toxicity is reduced, have
Good biocompatibility.Compared to early-stage Study, with significantly improving.Simultaneously present invention firstly discovers that bismuth with elementary nanometer
Grain has preferable photo-thermal effect and photoacoustic imaging effect, its clinical practice has been widened significantly, with bigger clinical meaning.
The content of the invention
For above demand, it is an object of the invention to provide a kind of while making in receiving for CT/PAT radiographies and photo-thermal therapy
The preparation method of rice bismuth with elementary diagnosis and treatment agent.
The preparation method that the present invention is provided is comprised the following steps：
1) by hydrophobicity reproducibility organic solvent and Bi (NO3)3By 1：1~20 mixed in molar ratio, is then heated to 170
~180 DEG C react, and naturally cool to 20~40 DEG C, filtering, after gained solid is eluted through ethanol and chloroform, as hydrophobicity
The nano simple substance bismuth crystal of molecule parcel；
2) nano simple substance bismuth crystal is distributed in mixed solution of the hydrophobic organic solvent with water, in the mixed solution
The concentration of nano simple substance bismuth crystal is 20~100mg/ml, adds amphipathic nature polyalcohol, and 10~30min of ultrasonic reaction, revolving is removed
Hydrophobic solvent is removed, the solution for obtaining as nano simple substance bismuth diagnosis and treatment agent.
Preferably, the hydrophobicity reproducibility organic solvent is n- dodecyl mereaptan, tert-dodecyl mercaptan, in oleyl amine at least one
Kind.
Preferably, the amphipathic nature polyalcohol is at least in phosphatide polyethylene glycol, polyethylene glycol, mercapto-polyglycol
Kind.
Preferably, hydrophobic organic solvent and the volume ratio of water are 1 in the mixed solution：1~5, most preferably 1：3.
Preferably, the concentration of nano simple substance bismuth crystal is 50~80mg/ml, most preferably 60mg/ml in the mixed solution.
As kernel, outer layer wraps up one to the nano simple substance bismuth crystal that the diagnosis and treatment agent that the present invention is provided is wrapped up with hydrophobic molecule again
Layer amphipathic nature polyalcohol (polymer containing hydrophilic radical and hydrophobic grouping simultaneously in molecular structure) molecule, the particle diameter ＜ of kernel
50nm, the particle diameter after amphipathic nature polyalcohol parcel is 100-200nm.
The present invention there is obvious advantage in CT/PAT imaging contrasts and photo-thermal therapy diagnosis and treatment agent, such as 1. bismuth with elementary have compared with
Big relative atomic mass, X-ray absorption ability is strong, and x-ray attenuation coefficient is big, and CT organizes high resolution；2. bismuth with elementary is near
Infrared band has stronger absorption, can simultaneously be used as the contrast agent that photo-thermal therapy and PAT are imaged.3. bismuth with elementary synthesis material is cheap
It is easy to get, synthesis technique is simple and easy to apply.
The present invention is Matrix absorption near infrared light with bismuth with elementary, and the heat energy that can be exchanged into high-energy makes it have preferable light
Heat cure and photoacoustic imaging effect, while the bismuth effect with CT contrast agent in itself.The presence of amphipathic nature polyalcohol overcomes to be received
Rice bismuth with elementary crystal toxic and side effect and hydrophobicity in itself, makes it have good dispersiveness and biocompatibility, can answer extensively
For the diagnosis and treatment of tumour-specific, it is of great value in clinical practice, can simultaneously realizes tumour CT, art
The integrated diagnosis and treatment process such as middle tracking and POE, with preferable development potentiality.
Brief description of the drawings
Fig. 1 is the images of transmissive electron microscope of the nano simple substance bismuth crystal of n- dodecyl mereaptan parcel.
Fig. 2 is the images of transmissive electron microscope of nano simple substance bismuth diagnosis and treatment agent.
Fig. 3 is the nano simple substance bismuth crystal of n- dodecyl mereaptan parcel and the grain size distribution of nano simple substance bismuth diagnosis and treatment agent.
Fig. 4 is temperature variation curve of the nano simple substance bismuth diagnosis and treatment agent under different light intensity.
Fig. 5 is influence of the nano simple substance bismuth diagnosis and treatment agent to C6 cells (glioma cell) survival rate.
Fig. 6 is CT value curve of the nano simple substance bismuth diagnosis and treatment agent in various concentrations.
Fig. 7 is PAT signal value curve of the nano simple substance bismuth diagnosis and treatment agent in various concentrations.
Fig. 8 is relative growth curve of the mice with tumor tumour under the conditions of different disposal.
Specific embodiment
The present invention is described in detail below by embodiment.
Embodiment 1
A kind of preparation method of nano simple substance bismuth diagnosis and treatment agent, comprises the following steps：
1) by n- dodecyl mereaptan and Bi (NO3)3·5H2O presses 1：3 mixed in molar ratio, using heating mantle heats to 178 DEG C,
Kept for one minute, 30 DEG C are cooled under natural conditions, whole process carries out logical nitrogen simultaneously under stirring.Filtering, by institute
Solid with anhydrous ethanol elution 3 times (rotating speed 8000r/min, 15min/ time), chloroform wash-out 1 time (rotating speed 3000r/min,
8min/ times), 40 DEG C are evaporated removing chloroform, the nano simple substance bismuth crystal of the product for obtaining as n- dodecyl mereaptan parcel.
2) the nano simple substance bismuth crystal that gained n- dodecyl mereaptan is wrapped up is scattered in the mixed solvent (hexamethylene of hexamethylene and water
The volume ratio 1 of alkane and water：3) in, make crystal concentration for 60mg/ml, after ultrasonic 30min, add phosphatide polyethylene glycol (DSPE-
PEG2000), phosphatide polyethylene glycol is 1 with the mol ratio of bismuth with elementary：5, ultrasonic reaction 30min, reaction solution through 0.45um filter membrane
Filtering, removes big aggregate, and filtrate revolving removes hexamethylene, and remaining solution is nano simple substance bismuth diagnosis and treatment agent.
As can be seen that step 1 from the transmission electron microscope picture of Fig. 1, Fig. 2) obtained in nano simple substance bismuth crystal and step 2) system
The nano simple substance bismuth diagnosis and treatment agent particle diameter for obtaining is more homogeneous, is shaped as the circle of rule, and dispersiveness is preferably.
As can be seen that nanometer bismuth material particle size obtained in the present embodiment is homogeneous from the grain size distribution of Fig. 3, monodispersity
(PDI) it is smaller, respectively less than 0.1.
Embodiment 2
A kind of preparation method of nano simple substance bismuth diagnosis and treatment agent, comprises the following steps：
1) by oleyl amine and Bi (NO3)3·5H2O presses 1：7 mixed in molar ratio, using heating mantle heats to 170 DEG C, keeps 2
Minute, 40 DEG C are cooled under natural conditions, whole process carries out logical nitrogen simultaneously under stirring.Filtering, by gained solid
With anhydrous ethanol elution 2 times, chloroform is eluted 2 times, is evaporated removing chloroform, the nano simple substance bismuth of the product for obtaining as oleyl amine parcel
Crystal.
2) the nano simple substance bismuth crystal that gained oleyl amine is wrapped up is scattered in the mixed solvent (body of chloroform and water of chloroform and water
Product compares 1：1) in, make crystal concentration for 20mg/ml, after ultrasonic 30min, add mercapto-polyglycol, mercapto-polyglycol and list
The mol ratio of matter bismuth is 1：1, ultrasonic reaction 20min, reaction solution remove big aggregate, filtrate through the membrane filtration of 0.45um
Revolving removes chloroform, and remaining solution is nano simple substance bismuth diagnosis and treatment agent.
Embodiment 3
A kind of preparation method of nano simple substance bismuth diagnosis and treatment agent, comprises the following steps：
1) by tert-dodecyl mercaptan and Bi (NO3)3·5H2O presses 1：1 mixed in molar ratio, using heating mantle heats to 180 DEG C,
Kept for 1 minute, be naturally cooling to 20 DEG C, whole process carries out logical nitrogen simultaneously under stirring.Filtering, gained solid is used
Anhydrous ethanol elution 1 time, chloroform is eluted 1 time, is evaporated removing chloroform, the nanometer list of the product for obtaining as tert-dodecyl mercaptan parcel
Matter bismuth crystal.
2) by the nano simple substance bismuth crystal that gained tert-dodecyl mercaptan is wrapped up be scattered in toluene and water mixed solvent (toluene with
The volume ratio 1 of water：5) in, make crystal concentration for 100mg/ml, after ultrasonic 30min, add phosphatide polyethylene glycol, the poly- second two of phosphatide
Alcohol is 1 with the mol ratio of bismuth with elementary：8, ultrasonic reaction 10min, reaction solution remove big aggregate, filtrate rotation through membrane filtration
Toluene is evaporated off, remaining solution is nano simple substance bismuth diagnosis and treatment agent.
Embodiment 4
The photothermal deformation merit rating of bismuth with elementary nano material：
Nano simple substance bismuth diagnosis and treatment agent obtained in 1mL (1mg/mL) embodiment 1 is taken in PE pipes, respectively 0.5,1.0,
1.5W/cm2Light intensity under irradiated through 808nm laser, using different time points near infrared imaging system record observing time
Temperature, draws temperature time curve.
As can be seen from Figure 4:In 1W/cm2And 1.5W/cm2Light intensity under, in 1 minute the nano material temperature rise 30
More than degree Celsius, illustrate that the material has good photothermal deformation ability under above-mentioned light-intensity conditions, can be good at for light
Heat cure and photoacoustic imaging.
Embodiment 5
Nano simple substance bismuth diagnosis and treatment agent is used as CT/PAT photoacoustic imagings：
Nano simple substance bismuth diagnosis and treatment obtained in the embodiment 1 of configuration various concentrations (12.0,9.0,6.0,4.0,1.0mg/mL)
Agent, pure water is compared, and 1mL is taken respectively in PE pipes, and various concentrations nano simple substance bismuth diagnosis and treatment agent is measured using small animal imaging CT
Hu values.
Nano simple substance bismuth diagnosis and treatment obtained in the embodiment 1 of configuration various concentrations (10,5,2.5,1.25,0.625mg/mL)
Agent, takes 1mL as in glass tube respectively, and photoacoustic signal value is measured using PA system Endra Nexus128.
As can be seen from Figure 6：Nano simple substance bismuth diagnosis and treatment agent CT value sizes in vitro are linearly increased with concentration, maximum dense
Spend corresponding CT values to be contrasted with pure water, differ 700Hu, illustrate that this nanometer of diagnosis and treatment agent preferably can be imaged for CT.
As can be seen from Figure 7：Nano simple substance bismuth diagnosis and treatment agent PAT signal value sizes in vitro are linearly increased with concentration,
It is about 9000a.u. in Cmax, illustrates that the nano material has good photoacoustic imaging ability.
Embodiment 6
Nano simple substance bismuth diagnosis and treatment agent is used for photo-thermal therapy：
1. external photo-thermal effect and Cytotoxic evaluation：C6 cells are inoculated in two 96 orifice plates, treat that cell is long to 20000
Individual/hole, adds the nano simple substance bismuth diagnosis and treatment agent of 100uL various concentrations (100,25,12.5,6.25,3.125ug/mL) with culture
After 24 hours, 96 orifice plates receive light intensity for 1W/cm2808nm laser irradiate 15 minutes, while not adding nano simple substance bismuth
The hole of diagnosis and treatment agent receives identical photo-irradiation treatment, adds 20mL MTT to co-culture after illumination 4 hours, takes out the culture medium containing MTT, plus
150mL DMSO, vortex oscillation 2 minutes, ELIASA measures absorbance of 96 orifice plates in 570nm, calculates survival rate.
2. photo-thermal therapy effect assessment in body:16 tumor-bearing mices are randomly divided into four groups, first group every other day tail it is quiet
Arteries and veins injection 200uL PBS；Second group is every other day 1W/cm in intensity2808nm laser under irradiate 15 minutes；3rd group every
Tail vein injection concentration is nano simple substance bismuth diagnosis and treatment agent (10mg/mL 200uL) of 10mg/mL every two days；4th group first every
One day tail vein injection concentration is the nano simple substance bismuth diagnosis and treatment agent of (10mg/mL 200uL), in intensity after half an hour to one hour
It is 1W/cm2808nm laser under irradiate 15 minutes.Processed through 6 different conditions, need to measure each after each receiving treatment
The major diameter and minor axis (a of tumour:Major diameter, b：Minor axis), calculate its volume size (V=a*b2/ 2), and record and processing data, obtain
The curve of relative tumour volume (V/V0).
As can be seen from Figure 5：The diagnosis and treatment agent vitro cytotoxicity and external photo-thermal are obtained by the cell survival rate for measuring
Curative effect.Through the cell of photo-irradiation treatment, 20% is only survived in the μ g/mL C6 cells of maximum concentration 100；Simultaneously without photo-irradiation treatment
Cell, in being co-cultured with the μ g/mL bismuth with elementary nano material of maximum concentration 100, survival rate can reach more than 85%.Illustrate this nanometer
Not only cytotoxicity is low for diagnosis and treatment agent, also with the effect of external photo-thermal tumor killing cell well.
As can be seen from Figure 8：Processed with illumination through 6 bismuth with elementary nano materials simultaneously after, tumour growth is substantially pressed down
System, or even be gradually reduced.And the basic linearly growth pattern of other three groups of tumours of control group, it is the 10 of experimental group tumor size
More than times.Confirm that the nano material has internal photo-thermal therapy effect well, can well suppress tumour growth.
Claims (5)
1. a kind of while the preparation method of the nano simple substance bismuth diagnosis and treatment agent as CT/PAT radiographies and photo-thermal therapy, it is characterised in that
Comprise the following steps：
1) by hydrophobicity reproducibility organic solvent and Bi (NO3)3By 1：1~20 mixed in molar ratio, is then heated to 170~180
DEG C react, naturally cool to 20~40 DEG C, filtering, after gained solid is eluted through ethanol and chloroform, as hydrophobic molecule
The nano simple substance bismuth crystal of parcel；
2) nano simple substance bismuth crystal is distributed in mixed solution of the hydrophobic organic solvent with water, nanometer in the mixed solution
The concentration of bismuth with elementary crystal is 20~100mg/ml, adds amphipathic nature polyalcohol, 10~30min of ultrasonic reaction, and revolving is removed dredges
Aqueous solvent, the solution for obtaining as nano simple substance bismuth diagnosis and treatment agent.
2. the preparation method of nano simple substance bismuth diagnosis and treatment agent as claimed in claim 1, it is characterised in that：The hydrophobicity reproducibility has
Machine solvent is n- dodecyl mereaptan, tert-dodecyl mercaptan, at least one in oleyl amine.
3. the preparation method of nano simple substance bismuth diagnosis and treatment agent as claimed in claim 1, it is characterised in that：The amphipathic nature polyalcohol is
At least one in phosphatide polyethylene glycol, polyethylene glycol, mercapto-polyglycol.
4. the preparation method of nano simple substance bismuth diagnosis and treatment agent as claimed in claim 1, it is characterised in that：It is hydrophobic in the mixed solution
Property organic solvent and water volume ratio be 1：1~5.
5. the preparation method of nano simple substance bismuth diagnosis and treatment agent as claimed in claim 1, it is characterised in that：Nanometer in the mixed solution
The concentration of bismuth with elementary crystal is 50~80mg/ml.
Priority Applications (1)
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| CN109157531A (en) * | 2018-08-31 | 2019-01-08 | 上海工程技术大学 | A kind of porous bismuth nanosphere and its preparation method and application |
| CN110917387A (en) * | 2019-12-04 | 2020-03-27 | 中山大学 | Developable embolism microsphere and preparation method thereof |
| CN112336858A (en) * | 2020-10-09 | 2021-02-09 | 华南理工大学 | Bismuth-manganese-based composite particle and preparation method and application thereof |
| CN115805063A (en) * | 2022-11-29 | 2023-03-17 | 浙江大学 | Multifunctional porous core-shell composite nano material and preparation method thereof |
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| CN109157531A (en) * | 2018-08-31 | 2019-01-08 | 上海工程技术大学 | A kind of porous bismuth nanosphere and its preparation method and application |
| CN109157531B (en) * | 2018-08-31 | 2021-03-09 | 上海工程技术大学 | Porous bismuth nano-microsphere and preparation method and application thereof |
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| CN112336858A (en) * | 2020-10-09 | 2021-02-09 | 华南理工大学 | Bismuth-manganese-based composite particle and preparation method and application thereof |
| CN112336858B (en) * | 2020-10-09 | 2021-09-21 | 华南理工大学 | Bismuth-manganese-based composite particle and preparation method and application thereof |
| CN115805063A (en) * | 2022-11-29 | 2023-03-17 | 浙江大学 | Multifunctional porous core-shell composite nano material and preparation method thereof |
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