CN105435248A - Multi-functional bismuth selenide nanocomposite and preparation method and application thereof - Google Patents
Multi-functional bismuth selenide nanocomposite and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of biomedicine, in particular to a multi-functional bismuth selenide nanocomposite and a preparation method and application thereof. The multi-functional bismuth selenide nanocomposite aims to solve the problems that the synthesis condition and process of the existing hyperthermia chemotherapy nano material are complex, the biological safety is poor, the drug loading capacity is low, the existing hyperthermia chemotherapy nano material is short of an appropriate imaging diagnosis function, the heat-light properties need to be improved, and the existing hyperthermia chemotherapy nano material is short of clinical experimental verification. The grain size of the multi-functional bismuth selenide nanocomposite is 50 nm to 200 nm, and the drug loading capacity for loading doxorubicin hydrochloride is 3% to 10%. The preparation method comprises a step 1 of preparing Bi2Se3 nanosheets; a step 2 of preparing Bi2Se3@PDA nano particle dispersion liquid; and a step 3 of preparing the multi-functional bismuth selenide nanocomposite. The multi-functional bismuth selenide nanocomposite serves as the hyperthermia chemotherapy nano material to be utilized in hyperthermia chemotherapy of a malignant tumor or serves as a CT imaging contrast agent to be utilized in CT imaging diagnosis of the malignant tumor.
Description
Technical field
The present invention relates to biomedical sector, be specifically related to a kind of multi-functional bismuth selenide nano-complex, its preparation method and application.
Background technology
Photo-thermal therapy be grew up in the last few years a kind of Noninvasive based on near-infrared laser, can the novel therapeutic technology of Fast Fixed-point killing tumor cells, its principle utilizes the nano material (photo-thermal therapy agent) with photo-thermal converting function to be that heat comes to heat tumor tissues by light energy conversion, when temperature reaches more than 42 degree, will be there is apoptosis or necrosis in tumor tissues, the normal structure of human body or organ then can not come to harm.But, the more effective and safety implemented to make photo-thermal therapy, people are in the urgent need to diagnosing tumour position, size and profile before carrying out photo-thermal therapy, also need to determine that photo-thermal therapy agent is in the enrichment condition of lesions position with to treatment situation Real-Time Monitoring over the course for the treatment of, and after treatment, curative effect is assessed.Therefore, just need when implementing photo-thermal therapy carry out guiding in real time in conjunction with Tomographic Diagnosis Technology (as CT imaging, MRI imaging and photoacoustic imaging etc.) and assist.In addition, because biological tissue is to the absorption of light and scattering process, the thorough eradicating cancer cells of photo-thermal therapy is only relied on to be very difficult.In order to overcome these problems, people need photo-thermal therapy and other therapies (as chemotherapy, physics radiotherapy etc.) to join together, more effectively to treat tumor up hill and dale.Wherein, because photo-thermal effect can either make tumor cell more responsive and significantly promote that tumor cell is to the picked-up of chemotherapeutics to chemotherapeutics, photo-thermal therapy and chemotherapy are joined together (abbreviation thermochemotherapy) make this two kinds of therapy synergism, under very low using dosage, just can obtain more effective therapeutic effect, this is significant for reducing the toxic and side effects produced in therapeutic process.
In the last few years, much there is the comparatively strong nano material (as gold nanorods, gold nanoshell, gold nanometer cage and CNT etc.) absorbed to be developed as thermochemotherapy nano material and to be widely used in the thermochemotherapy of tumor near infrared region.Although these thermochemotherapy Application of microns have achieved good effect when tumor therapy experiments, but when embody rule, also there is a lot of limitation in them, such as synthesis condition and process more complicated, biological safety is very poor, drug loading is low, lack suitable image-forming diagnose function and light thermal property has much room for improvement, and lacks clinical experiment checking etc.In addition, the kind of this kind of multi-functional thermochemotherapy nano material is still very limited.Therefore, the multi-functional thermochemotherapy nano material of development of new is necessary for the multi-modal diagnosis of tumor and thermochemotherapy.
Through retrieving relevant bismuth selenide (Bi both at home and abroad
2se
3) document of nano material aspect and patent results show, before this invention is filed, have no precedent Bi
2se
3nano material carries out the report of medicine carrying for Thermochemotherapy of Tumor aspect.
Summary of the invention
The present invention will solve the synthesis condition of existing thermochemotherapy nano material and process is complicated, biological safety is poor, drug loading is low, lack suitable image-forming diagnose function and light thermal property has much room for improvement, lack the problem of clinical experiment checking, and a kind of multi-functional bismuth selenide nano-complex, its preparation method and application are provided.
A kind of multi-functional bismuth selenide nano-complex, it with organic high molecular polymer, dihydroxylic alcohols, selenium source, bismuth salt, reducing agent, dopamine hydrochloride, Tri(Hydroxymethyl) Amino Methane Hydrochloride solution, doxorubicin hydrochloride and serum albumin aqueous solution for raw material is prepared from, the particle diameter of described multi-functional bismuth selenide nano-complex is 50nm ~ 200nm, and in described multi-functional bismuth selenide nano-complex, the drug loading of doxorubicin hydrochloride is 3% ~ 10%.
A kind of preparation method of multi-functional bismuth selenide nano-complex is carried out according to following steps:
One, organic high molecular polymer is dissolved in dihydroxylic alcohols completely, obtain reaction system, selenium source and bismuth salt is added in reaction system, after ultrasonic mix homogeneously, with the heating rate of 10 DEG C/min ~ 20 DEG C/min by the temperature of reaction system from room temperature to 100 DEG C ~ 250 DEG C, then in reaction system, reducing agent is added, be be cooled to room temperature after reacting 5min ~ 30min under the condition of 100 DEG C ~ 250 DEG C in temperature, adopt the mixed liquor of acetone and water centrifugal and wash 3 ~ 5 times, collect sample, vacuum drying, obtains Bi
2se
3nanometer sheet; In the mixed liquor of described acetone and water, the volume ratio of water and acetone is 1:(1 ~ 5); The quality of described organic high molecular polymer and the volume ratio of dihydroxylic alcohols are 1g:(100 ~ 200) mL; The quality of described bismuth salt and the volume ratio of dihydroxylic alcohols are 1g:(300 ~ 400) mL; The quality of described selenium source and the volume ratio of dihydroxylic alcohols are 1g:(600 ~ 700) mL; The volume ratio of described reducing agent and dihydroxylic alcohols is 1mL:(60 ~ 70) mL;
Two, dopamine hydrochloride is dissolved in Tri(Hydroxymethyl) Amino Methane Hydrochloride solution, after ultrasonic mix homogeneously, adds the Bi that step one obtains wherein
2se
3nanometer sheet, after stirring at normal temperature 3 ~ 9h, adopts deionized water centrifugal and washs 3 ~ 5 times, being then scattered in dimethyl sulfoxide, obtaining Bi
2se
3pDA nanoparticle dispersion liquid; Described Bi
2se
3the concentration of PDA nanoparticle dispersion liquid is (2 ~ 4) mg/mL; The quality of described dopamine hydrochloride and the volume ratio of Tri(Hydroxymethyl) Amino Methane Hydrochloride solution are 1g:(300 ~ 500) mL; Described Bi
2se
3the quality of nanometer sheet and the volume ratio of Tri(Hydroxymethyl) Amino Methane Hydrochloride solution are 1g:(1500 ~ 2500) mL; The pH of described Tri(Hydroxymethyl) Amino Methane Hydrochloride solution is 8 ~ 10;
Three, doxorubicin hydrochloride is dissolved in dimethyl sulfoxide, after ultrasonic mix homogeneously, obtains doxorubicin hydrochloride dispersion liquid; Doxorubicin hydrochloride dispersion liquid is joined the Bi that step 2 obtains
2se
3in PDA nanoparticle dispersion liquid, stirring at normal temperature 5 ~ 15min, obtain mixed solution, then mixed solution is dropwise added drop-wise in serum albumin aqueous solution under ultrasound condition, adopt deionized water centrifugal and wash 3 ~ 5 times, obtaining solid, by solid dispersal in phosphate buffer, being positioned over temperature is preserve in the refrigerator of 4 DEG C, obtains multi-functional bismuth selenide nano-complex; The concentration of described doxorubicin hydrochloride dispersion liquid is (5 ~ 20) mg/mL; Described doxorubicin hydrochloride dispersion liquid and Bi
2se
3the volume ratio of PDA nanoparticle dispersion liquid is 1:(1 ~ 4); The volume ratio of described mixed solution and serum albumin aqueous solution is 1:(2 ~ 6); The quality of described solid and the volume ratio of phosphate buffer are 1g:(1000 ~ 2000) mL; The concentration of the aqueous solution of serum albumin described in step 3 is 5.0mg/mL.
A kind of application of multi-functional bismuth selenide nano-complex is the thermochemotherapy multi-functional bismuth selenide nano-complex being used for malignant tumor as thermochemotherapy nano material.
A kind of application of multi-functional bismuth selenide nano-complex is the CT image-forming diagnose multi-functional bismuth selenide nano-complex being used for malignant tumor as CT image-forming contrast medium.
The invention has the beneficial effects as follows:
The preparation condition of multi-functional bismuth selenide nano-complex prepared by the present invention and process simple; The size of the multi-functional bismuth selenide nano-complex of preparation freely can control by changing the proportioning of reaction raw materials, required temperature and response time simply;
Multi-functional bismuth selenide nano-complex prepared by the present invention successfully loads chemotherapeutic drugs Doxorubicin, there is very high drug loading (3% ~ 10%), wherein drug loading freely can be controlled by the DOX amount controlling to add reaction, and there is pH and the light activated drug release character of near-infrared, to tumor cell, there is significant chemotherapy effect; Nano-complex has near infrared region and absorbs more by force, has excellent photo-thermal intensification performance and photo and thermal stability; Nano-complex, can killing tumor cell effectively under the irradiation of near-infrared laser, and thermochemotherapy Be very effective is better than independent photo-thermal therapy or chemotherapy effect; Nano-complex toxicity is low, has good biological safety; Nano-complex can remarkable CT imaging signal in outer, the body of reinforcement.
Accompanying drawing explanation
Fig. 1 is the TEM figure of the multi-functional bismuth selenide nano-complex that embodiment one step 3 obtains;
Fig. 2 is the grain size distribution of the multi-functional bismuth selenide nano-complex that embodiment one step 3 obtains;
Fig. 3 is the Bi that embodiment one step one obtains
2se
3the uv absorption correlation curve figure of the multi-functional bismuth selenide nano-complex that nanometer sheet and embodiment one step 3 obtain, wherein 1 is Bi
2se
3nanometer sheet, 2 is multi-functional bismuth selenide nano-complexes;
Fig. 4 is the Bi that embodiment one step one obtains
2se
3the fluorescence spectrum comparison diagram of the multi-functional bismuth selenide nano-complex dispersion liquid that nanometer sheet and variable concentrations embodiment one step 3 obtain, wherein 1 is Bi
2se
3nanometer sheet, 2 is concentration is the multi-functional bismuth selenide nano-complex dispersion liquid of 4 μ g/mL, and 3 is concentration is the multi-functional bismuth selenide nano-complex dispersion liquid of 8 μ g/mL, and 4 is concentration is the multi-functional bismuth selenide nano-complex dispersion liquid of 16 μ g/mL;
Fig. 5 is the Bi that embodiment one step one obtains
2se
3the Bi that nanometer sheet, embodiment one step 2 obtain
2se
3bi in PDA nanoparticle dispersion liquid
2se
3the FTIR spectrum figure of the multi-functional bismuth selenide nano-complex that PDA nanoparticle and embodiment one step 3 obtain, wherein 1 is Bi
2se
3nanometer sheet, 2 is Bi
2se
3bi in PDA nanoparticle dispersion liquid
2se
3pDA nanoparticle, 3 is multi-functional bismuth selenide nano-complexes;
Fig. 6 is the drug release patterns of pH sensitivity, wherein 1 is the drug release patterns of pure DOX under pH=7.4 condition, and 2 are multi-functional bismuth selenide nano-complex drug release patterns under pH=7.4 condition, 3 are multi-functional bismuth selenide nano-complex drug release patterns under pH=5.5 condition, 4 is multi-functional bismuth selenide nano-complex drug release patterns under pH=4.5 condition;
Fig. 7 is the light activated drug release correlation curve of multi-functional bismuth selenide nano-complex dispersion liquid near-infrared of the PBS dispersion of different pH, wherein 1 be pH=4.5 PBS dispersion multi-functional bismuth selenide nano-complex dispersion liquid, 2 be pH=5.5 PBS dispersion multi-functional bismuth selenide nano-complex dispersion liquid, 3 be pH=7.4 PBS dispersion multi-functional bismuth selenide nano-complex dispersion liquid, black arrow indication is laser irradiation time section;
Fig. 8 is that the multi-functional bismuth selenide nano-complex dispersion liquid of variable concentrations and HeLa cell hatch the cell viability figure after 24 and 48 hours jointly, and wherein 1 is 24 hours, and 2 is 48 hours;
Fig. 9 is the photo-thermal heating curve of the multi-functional bismuth selenide nano-complex dispersion liquid of variable concentrations, and wherein 1 is 0 μ g/mL, and 2 is 5 μ g/mL, and 3 is 20 μ g/mL, and 4 is 50 μ g/mL, and 5 is 100 μ g/mL, and 6 is 200 μ g/mL;
Figure 10 is the photo-thermal intensification temperature difference figure of the multi-functional bismuth selenide nano-complex dispersion liquid of variable concentrations;
Figure 11 is the photo-thermal ramp cycle figure of multi-functional bismuth selenide nano-complex dispersion liquid, and wherein 1 is that laser is opened, and 2 is laser shutdowns;
Figure 12 is the Bi of multi-functional bismuth selenide nano-complex, non-medicine carrying
2se
3nano-complex (Bi
2se
3pDA/HSA) and pure DOX to cell viability comparison diagram after HeLa cell thermochemotherapy, wherein 1 is multi-functional bismuth selenide nano-complex, and 2 is Bi of non-medicine carrying
2se
3nano-complex (Bi
2se
3pDA/HSA), 3 is pure DOX;
Figure 13 is the external CT image of multi-functional bismuth selenide nano-complex, and wherein 1 be Bi concentration of element be 0mmol/L, 2 are Bi concentration of element be 4.56mmol/L, 3 are Bi concentration of element be 13.7mmol/L, 4 are Bi concentration of element be 27.4mmol/L, 5 are Bi concentration of element be 36.5mmol/L, 6 are Bi concentration of element is 45.6mmol/L;
Figure 14 is that the external CT imaging signal (CT value, HU) of multi-functional bismuth selenide nano-complex strengthens block diagram;
Figure 15 be injection multi-functional bismuth selenide nano-complex before mice CT image;
Figure 16 be injection multi-functional bismuth selenide nano-complex after mice CT image, wherein 1 is tumor.
Detailed description of the invention
Detailed description of the invention one: a kind of multi-functional bismuth selenide nano-complex of present embodiment, it with organic high molecular polymer, dihydroxylic alcohols, selenium source, bismuth salt, reducing agent, dopamine hydrochloride, Tri(Hydroxymethyl) Amino Methane Hydrochloride solution, doxorubicin hydrochloride and serum albumin aqueous solution for raw material is prepared from, the particle diameter of described multi-functional bismuth selenide nano-complex is 50nm ~ 200nm, and in described multi-functional bismuth selenide nano-complex, the drug loading of doxorubicin hydrochloride is 3% ~ 10%.
Detailed description of the invention two: present embodiment and detailed description of the invention one are one or both the mixture in polyvinylpyrrolidone and polyacrylic acid unlike: described organic high molecular polymer; Described dihydroxylic alcohols is a kind of or wherein several mixture in ethylene glycol, propylene glycol and butanediol; Described selenium source is a kind of or wherein several mixture in sodium selenite, potassium selenite and selenium dioxide; Described bismuth salt is a kind of or wherein several mixture in bismuth nitrate, bismuth chloride and bismuth acetate; Described reducing agent is mixture a kind of or wherein several in azanol, morpholine borine, sodium borohydride, glucose and ascorbic acid; The pH of described Tri(Hydroxymethyl) Amino Methane Hydrochloride solution is 8.0 ~ 10; One or both mixture in described serum albumin aqueous solution behaviour serum albumin aqueous solution and Bovine Serum Albumin in Aqueous Solution, the concentration of described serum albumin aqueous solution is 5.0mg/mL.Other are identical with detailed description of the invention one.
Detailed description of the invention three: the preparation method of a kind of multi-functional bismuth selenide nano-complex of present embodiment is carried out according to following steps:
One, organic high molecular polymer is dissolved in dihydroxylic alcohols completely, obtain reaction system, selenium source and bismuth salt is added in reaction system, after ultrasonic mix homogeneously, with the heating rate of 10 DEG C/min ~ 20 DEG C/min by the temperature of reaction system from room temperature to 100 DEG C ~ 250 DEG C, then in reaction system, reducing agent is added, be be cooled to room temperature after reacting 5min ~ 30min under the condition of 100 DEG C ~ 250 DEG C in temperature, adopt the mixed liquor of acetone and water centrifugal and wash 3 ~ 5 times, collect sample, vacuum drying, obtains Bi
2se
3nanometer sheet; In the mixed liquor of described acetone and water, the volume ratio of water and acetone is 1:(1 ~ 5); The quality of described organic high molecular polymer and the volume ratio of dihydroxylic alcohols are 1g:(100 ~ 200) mL; The quality of described bismuth salt and the volume ratio of dihydroxylic alcohols are 1g:(300 ~ 400) mL; The quality of described selenium source and the volume ratio of dihydroxylic alcohols are 1g:(600 ~ 700) mL; The volume ratio of described reducing agent and dihydroxylic alcohols is 1mL:(60 ~ 70) mL;
Two, dopamine hydrochloride is dissolved in Tri(Hydroxymethyl) Amino Methane Hydrochloride solution, after ultrasonic mix homogeneously, adds the Bi that step one obtains wherein
2se
3nanometer sheet, after stirring at normal temperature 3 ~ 9h, adopts deionized water centrifugal and washs 3 ~ 5 times, being then scattered in dimethyl sulfoxide, obtaining Bi
2se
3pDA nanoparticle dispersion liquid; Described Bi
2se
3the concentration of PDA nanoparticle dispersion liquid is (2 ~ 4) mg/mL; The quality of described dopamine hydrochloride and the volume ratio of Tri(Hydroxymethyl) Amino Methane Hydrochloride solution are 1g:(300 ~ 500) mL; Described Bi
2se
3the quality of nanometer sheet and the volume ratio of Tri(Hydroxymethyl) Amino Methane Hydrochloride solution are 1g:(1500 ~ 2500) mL; The pH of described Tri(Hydroxymethyl) Amino Methane Hydrochloride solution is 8 ~ 10;
Three, doxorubicin hydrochloride is dissolved in dimethyl sulfoxide, after ultrasonic mix homogeneously, obtains doxorubicin hydrochloride dispersion liquid; Doxorubicin hydrochloride dispersion liquid is joined the Bi that step 2 obtains
2se
3in PDA nanoparticle dispersion liquid, stirring at normal temperature 5 ~ 15min, obtain mixed solution, then mixed solution is dropwise added drop-wise in serum albumin aqueous solution under ultrasound condition, adopt deionized water centrifugal and wash 3 ~ 5 times, obtaining solid, by solid dispersal in phosphate buffer, being positioned over temperature is preserve in the refrigerator of 4 DEG C, obtains multi-functional bismuth selenide nano-complex; The concentration of described doxorubicin hydrochloride dispersion liquid is (5 ~ 20) mg/mL; Described doxorubicin hydrochloride dispersion liquid and Bi
2se
3the volume ratio of PDA nanoparticle dispersion liquid is 1:(1 ~ 4); The volume ratio of described mixed solution and serum albumin aqueous solution is 1:(2 ~ 6); The quality of described solid and the volume ratio of phosphate buffer are 1g:(1000 ~ 2000) mL; The concentration of the aqueous solution of serum albumin described in step 3 is 5.0mg/mL.Detailed description of the invention four: present embodiment and detailed description of the invention three are one or both the mixture in polyvinylpyrrolidone and polyacrylic acid unlike: organic high molecular polymer described in step one.Other are identical with detailed description of the invention three.
Detailed description of the invention five: present embodiment and detailed description of the invention three or four unlike: dihydroxylic alcohols described in step one is a kind of or wherein several mixture in ethylene glycol, propylene glycol and butanediol.Other are identical with detailed description of the invention three or four.
Detailed description of the invention six: one of present embodiment and detailed description of the invention three to five unlike: selenium source described in step one is a kind of or wherein several mixture in sodium selenite, potassium selenite and selenium dioxide; The salt of bismuth described in step one is a kind of or wherein several mixture in bismuth nitrate, bismuth chloride and bismuth acetate.Other are identical with one of detailed description of the invention three to five.
Detailed description of the invention seven: one of present embodiment and detailed description of the invention three to six unlike: reducing agent described in step one is mixture a kind of or wherein several in azanol, morpholine borine, sodium borohydride, glucose and ascorbic acid.Other are identical with one of detailed description of the invention three to six.
Detailed description of the invention eight: one of present embodiment and detailed description of the invention three to seven are unlike one or both the mixture in: the aqueous solution of serum albumin described in step 3 behaviour serum albumin aqueous solution and Bovine Serum Albumin in Aqueous Solution.Other are identical with one of detailed description of the invention three to seven.
Detailed description of the invention nine: the application of a kind of multi-functional bismuth selenide nano-complex of present embodiment is the thermochemotherapy multi-functional bismuth selenide nano-complex being used for malignant tumor as thermochemotherapy nano material.
Detailed description of the invention ten: the application of a kind of multi-functional bismuth selenide nano-complex of present embodiment is the CT image-forming diagnose multi-functional bismuth selenide nano-complex being used for malignant tumor as CT image-forming contrast medium.
Following examples are adopted to verify beneficial effect of the present invention:
Embodiment one: a kind of preparation method of multi-functional bismuth selenide nano-complex is carried out according to following steps:
One, 0.25gPVP is dissolved in 40.0mL dihydroxylic alcohols completely, obtains reaction system, in reaction system, add 60mgNa
2seO
3with 112.5mgBi (NO
3)
35H
2o, after ultrasonic mix homogeneously, with the heating rate of 15 DEG C/min by the temperature of reaction system from room temperature to 180 DEG C, then in reaction system, 0.6mL hydroxylamine solution is added, be be cooled to room temperature after reacting 10min under the condition of 180 DEG C in temperature, adopt the mixed liquor of acetone and water centrifugal and wash 3 ~ 5 times, collecting sample, vacuum drying, obtains Bi
2se
3nanometer sheet; In the mixed liquor of described acetone and water, the volume ratio of water and acetone is 1:5;
Two, pH 24.76mg dopamine hydrochloride being dissolved in 10.0mL is the Tri(Hydroxymethyl) Amino Methane Hydrochloride solution of 8.5, after ultrasonic mix homogeneously, adds the Bi that 5mL step one obtains wherein
2se
3nanometer sheet, after stirring at normal temperature 6h, adopts deionized water centrifugal and washs 3 ~ 5 times, being then scattered in dimethyl sulfoxide, obtaining Bi
2se
3pDA nanoparticle dispersion liquid;
Three, 10mg doxorubicin hydrochloride is dissolved in 1mL dimethyl sulfoxide, after ultrasonic mix homogeneously, obtains doxorubicin hydrochloride dispersion liquid; Doxorubicin hydrochloride dispersion liquid is joined the Bi that step 2 obtains
2se
3in PDA nanoparticle dispersion liquid, stirring at normal temperature 10min, obtain mixed solution, then concentration mixed solution being dropwise added drop-wise under ultrasound condition 12.0mL is in the serum albumin aqueous solution of 5.0mg/mL, adopt deionized water centrifugal and wash 3 ~ 5 times, obtaining solid, by solid dispersal in phosphate buffer, being positioned over temperature is preserve in the refrigerator of 4 DEG C, obtains multi-functional bismuth selenide nano-complex.
Fig. 1 is the TEM figure of the multi-functional bismuth selenide nano-complex that embodiment one step 3 obtains; Fig. 2 is the grain size distribution of the multi-functional bismuth selenide nano-complex that embodiment one step 3 obtains; Fig. 3 is the Bi that embodiment one step one obtains
2se
3the uv absorption correlation curve figure of the multi-functional bismuth selenide nano-complex that nanometer sheet and embodiment one step 3 obtain, wherein 1 is Bi
2se
3nanometer sheet, 2 is multi-functional bismuth selenide nano-complexes; Fig. 4 is the Bi that embodiment one step one obtains
2se
3the fluorescence spectrum comparison diagram of the multi-functional bismuth selenide nano-complex dispersion liquid that nanometer sheet and variable concentrations embodiment one step 3 obtain, wherein 1 is Bi
2se
3nanometer sheet, 2 is concentration is the multi-functional bismuth selenide nano-complex dispersion liquid of 4 μ g/mL, and 3 is concentration is the multi-functional bismuth selenide nano-complex dispersion liquid of 8 μ g/mL, and 4 is concentration is the multi-functional bismuth selenide nano-complex dispersion liquid of 16 μ g/mL; Fig. 5 is the Bi that embodiment one step one obtains
2se
3the Bi that nanometer sheet, embodiment one step 2 obtain
2se
3bi in PDA nanoparticle dispersion liquid
2se
3the FTIR spectrum figure of the multi-functional bismuth selenide nano-complex that PDA nanoparticle and embodiment one step 3 obtain, wherein 1 is Bi
2se
3nanometer sheet, 2 is Bi
2se
3bi in PDA nanoparticle dispersion liquid
2se
3pDA nanoparticle, 3 is multi-functional bismuth selenide nano-complexes.Result shows, multi-functional bismuth selenide nano-complex presents irregularly shaped, mean diameter 112nm, and particle size distribution is homogeneous; Have near infrared region and absorb more by force, absorption value is higher than Bi
2se
3nanometer sheet; Fluorescence spectrum and FTIR spectrum show that DOX is successfully loaded in multi-functional bismuth selenide nano-complex.
Embodiment two: the vitro drug release experiment of multi-functional bismuth selenide nano-complex:
Drug loading test and calculating: the 1.0mg/mL multi-functional bismuth selenide nano-complex dispersion liquid of 100 μ L is joined (pH=5) in 3.0mL dilute hydrochloric acid solution, be placed in darkroom stirring to spend the night, utilize spectrofluorophotometer to test its fluorescence spectrum, utilize DOX fluorescence standard curve to calculate drug loading.Result of calculation shows, the drug loading of multi-functional bismuth selenide nano-complex is 3.25%.
The drug release experiment of pH sensitivity: the multi-functional bismuth selenide nano-complex dispersion liquid of the PBS dispersion of different for 1.0mL pH (4.5,5.5,7.4) is loaded in Dialysis tubing, be immersed in the PBS dialysis solution of the corresponding pH of 80mL respectively, be placed in 37 DEG C of darkroom gentle agitation, at selected time point, 2.0mL solution is taken out respectively from system, utilize spectrofluorophotometer to test its fluorescence spectrum, utilize DOX fluorescence standard curve to calculate drug accumulation burst size, draw drug release patterns.Fig. 6 is the drug release patterns of pH sensitivity, wherein 1 is the drug release patterns of pure DOX under pH=7.4 condition, and 2 are multi-functional bismuth selenide nano-complex drug release patterns under pH=7.4 condition, 3 are multi-functional bismuth selenide nano-complex drug release patterns under pH=5.5 condition, 4 is multi-functional bismuth selenide nano-complex drug release patterns under pH=4.5 condition.As can be seen from the figure, compared with pure DOX, multi-functional bismuth selenide nano-complex can realize medicament slow release, and along with the reduction of pH, drug release rate increases, and illustrates that multi-functional bismuth selenide nano-complex has the drug release character of pH sensitivity.
The light activated drug release experiment of near-infrared: the multi-functional bismuth selenide nano-complex dispersion liquid of the PBS dispersion of different for 2.0mL pH (4.5,5.5,7.4) is irradiated 8min (laser unlatching) under 808nm laser, cultivate 1h (laser shutdown) at being placed in dark 37 DEG C, so circulate.At selected time point, after Centrifuge A sample, measure the medicine fluorescence spectrum discharged in supernatant, utilize DOX fluorescence standard curve to calculate drug accumulation burst size, draw drug release patterns.Fig. 7 is the light activated drug release correlation curve of multi-functional bismuth selenide nano-complex dispersion liquid near-infrared of the PBS dispersion of different pH, wherein 1 be pH=4.5 PBS dispersion multi-functional bismuth selenide nano-complex dispersion liquid, 2 be pH=5.5 PBS dispersion multi-functional bismuth selenide nano-complex dispersion liquid, 3 be pH=7.4 PBS dispersion multi-functional bismuth selenide nano-complex dispersion liquid, black arrow indication is laser irradiation time section.Experimental result, when opening laser and irradiating, the drug release rate of multi-functional bismuth selenide nano-complex significantly increases, and after closing laser instrument, rate of release reduces, and pH is lower, this phenomenon is more obvious, and this illustrates that multi-functional bismuth selenide nano-complex has the light activated drug release character of near-infrared.
Embodiment three: multi-functional bismuth selenide nano-complex is to the cellularised therapeutic effect test experiments of HeLa:
HeLa cell is placed in overnight incubation on 96 well culture plates, adds the multi-functional bismuth selenide nano-complex dispersion liquid (0,2,5 of variable concentrations, 10,20,50,100,150,200 μ g/mL) continue cultivation 24 and after 48 hours respectively, with CCK-8 kit measurement cell viability.Fig. 8 is that the multi-functional bismuth selenide nano-complex dispersion liquid of variable concentrations and HeLa cell hatch the cell viability figure after 24 and 48 hours jointly, and wherein 1 is 24 hours, and 2 is 48 hours.As can be seen from the figure, along with the increase of multi-functional bismuth selenide nano-complex dispersion liquid concentration and incubation time, it is better to the fragmentation effect of HeLa cell, illustrates that multi-functional bismuth selenide nano-complex is to the significant chemotherapy effect of tumor cell.
Embodiment four: multi-functional bismuth selenide nano-complex light thermal property test:
Photo-thermal temperature rise effect is tested: the variable concentrations multi-functional bismuth selenide nano-complex dispersion liquid (0,5,20 by cumulative volume being 3.0mL, 50,100,200 μ g/mL) irradiate 10 minutes with the laser of 808nm, period utilizes thermocouple to measure system temperature every 10 seconds.Fig. 9 is the photo-thermal heating curve of the multi-functional bismuth selenide nano-complex dispersion liquid of variable concentrations, and wherein 1 is 0 μ g/mL, and 2 is 5 μ g/mL, and 3 is 20 μ g/mL, and 4 is 50 μ g/mL, and 5 is 100 μ g/mL, and 6 is 200 μ g/mL; Figure 10 is the photo-thermal intensification temperature difference figure of the multi-functional bismuth selenide nano-complex dispersion liquid of variable concentrations.As can be seen from the figure, multi-functional bismuth selenide nano-complex dispersion liquid can be rapidly heated under the irradiation of 808nm laser instrument, and along with the increase of concentration, its temperature rise effect significantly increases, this illustrates that multi-functional bismuth selenide nano-complex has excellent photo-thermal intensification performance.
Photo and thermal stability is tested: utilize 808nm laser to irradiate 10 minutes the multi-functional bismuth selenide nano-complex dispersion liquid of the 100 μ g/mL of 3.0mL, then naturally cool to room temperature, again open laser illumination 10 minutes afterwards, natural cooling, circulation like this 5 times, thermocouple record variations in temperature.Figure 11 is the photo-thermal ramp cycle figure of multi-functional bismuth selenide nano-complex dispersion liquid, and wherein 1 is that laser is opened, and 2 is laser shutdowns.Result shows, multi-functional bismuth selenide nano-complex its photo-thermal intensification performance after use 808nm laser instrument irradiates repeatedly remains unchanged, and this illustrates that multi-functional bismuth selenide nano-complex has excellent photo and thermal stability.
Embodiment five: multi-functional bismuth selenide nano-complex is tested HeLa cell thermochemotherapy measure of merit:
HeLa cell is placed in overnight incubation on 96 well culture plates, adds the Bi of the DOX of variable concentrations, non-medicine carrying
2se
3nano-complex (Bi
2se
3pDA/HSA), multi-functional bismuth selenide nano-complex dispersion liquid (0,5,10,20,50,100 μ g/mL) hatch cultivation 12 hours after, discard old culture medium, wash 3 times, add fresh culture, utilize 808nm laser illumination 5min, after cell continues to cultivate 24h, with CCK-8 kit measurement cell viability.Figure 12 is the Bi of multi-functional bismuth selenide nano-complex, non-medicine carrying
2se
3nano-complex (Bi
2se
3pDA/HSA) and pure DOX to cell viability comparison diagram after HeLa cell thermochemotherapy, wherein 1 is multi-functional bismuth selenide nano-complex, and 2 is Bi of non-medicine carrying
2se
3nano-complex (Bi
2se
3pDA/HSA), 3 is pure DOX.As can be seen from the figure, under the irradiation of near-infrared laser, multi-functional bismuth selenide nano-complex is to the Bi of the fragmentation effect of HeLa cell apparently higher than non-medicine carrying
2se
3nano-complex (Bi
2se
3pDA/HSA) or pure DOX, illustrate that the thermochemotherapy Be very effective of multi-functional bismuth selenide nano-complex to tumor cell is better than independent photo-thermal therapy or chemotherapy effect.
Embodiment six: multi-functional bismuth selenide nano-complex is external, CT imaging test experiment in body:
External CT imaging test: by the multi-functional bismuth selenide nano-complex of variable concentrations (Bi concentration of element: 0,4.56,13.7,27.4,36.5,45.6mmol/L) be placed in 1.5mL centrifuge tube, utilize toy CT Image-forming instrument to carry out scanning computed tomography signal, utilize supporting CT software to carry out the calculating of graphical analysis and CT value.Figure 13 is the external CT image of multi-functional bismuth selenide nano-complex, and wherein 1 be Bi concentration of element be 0mmol/L, 2 are Bi concentration of element be 4.56mmol/L, 3 are Bi concentration of element be 13.7mmol/L, 4 are Bi concentration of element be 27.4mmol/L, 5 are Bi concentration of element be 36.5mmol/L, 6 are Bi concentration of element is 45.6mmol/L; Figure 14 is that the external CT imaging signal (CT value, HU) of multi-functional bismuth selenide nano-complex strengthens block diagram.Result shows, multi-functional bismuth selenide nano-complex can significantly strengthen system CT signal intensity, and along with the increase of solution concentration, CT value (HU) increases, and wherein CT value becomes positive correlation with system concentration.As calculated, multi-functional bismuth selenide nano-complex is 7.53HUmmolBi/L to X-ray absorption coefficient, apparently higher than the absorptance (3.93HUmmolI/L) of clinical conventional CT contrast agent iohexol, illustrate that the CT imaging effect of multi-functional bismuth selenide nano-complex is better than comparing iohexol.
CT imaging test in body: the PBS dispersion liquid (5.0mg/mL) being built with the multi-functional bismuth selenide nano-complex of nude mice intratumor injection 100 μ L of tumor model, mice is placed in toy CT imaging system instrument with isoflurane anesthesia and carries out CT scan, carries out image reconstruction after collecting data.Figure 15 be injection multi-functional bismuth selenide nano-complex before mice CT image, Figure 16 be injection multi-functional bismuth selenide nano-complex after mice CT image, wherein 1 is tumor.Result shows, before injection, mouse tumor region does not find CT signal, and after the multi-functional bismuth selenide nano-complex dispersion liquid of injection, mouse tumor region list reveals bright CT signal, the position of tumor and size are all high-visible, illustrate that multi-functional bismuth selenide nano-complex can significantly strengthen in vivo CT imaging signal.
Claims (10)
1. a multi-functional bismuth selenide nano-complex, it is characterized in that it with organic high molecular polymer, dihydroxylic alcohols, selenium source, bismuth salt, reducing agent, dopamine hydrochloride, Tri(Hydroxymethyl) Amino Methane Hydrochloride solution, doxorubicin hydrochloride and serum albumin aqueous solution for raw material is prepared from, the particle diameter of described multi-functional bismuth selenide nano-complex is 50nm ~ 200nm, and in described multi-functional bismuth selenide nano-complex, the drug loading of doxorubicin hydrochloride is 3% ~ 10%.
2. the multi-functional bismuth selenide nano-complex of one according to claim 1, is characterized in that described organic high molecular polymer is one or both the mixture in polyvinylpyrrolidone and polyacrylic acid; Described dihydroxylic alcohols is a kind of or wherein several mixture in ethylene glycol, propylene glycol and butanediol; Described selenium source is a kind of or wherein several mixture in sodium selenite, potassium selenite and selenium dioxide; Described bismuth salt is a kind of or wherein several mixture in bismuth nitrate, bismuth chloride and bismuth acetate; Described reducing agent is mixture a kind of or wherein several in azanol, morpholine borine, sodium borohydride, glucose and ascorbic acid; The pH of described Tri(Hydroxymethyl) Amino Methane Hydrochloride solution is 8.0 ~ 10; One or both mixture in described serum albumin aqueous solution behaviour serum albumin aqueous solution and Bovine Serum Albumin in Aqueous Solution, the concentration of described serum albumin aqueous solution is 5.0mg/mL.
3. the preparation method of a kind of multi-functional bismuth selenide nano-complex as claimed in claim 1, is characterized in that the preparation method of multi-functional bismuth selenide nano-complex is carried out according to following steps:
One, organic high molecular polymer is dissolved in dihydroxylic alcohols completely, obtain reaction system, selenium source and bismuth salt is added in reaction system, after ultrasonic mix homogeneously, with the heating rate of 10 DEG C/min ~ 20 DEG C/min by the temperature of reaction system from room temperature to 100 DEG C ~ 250 DEG C, then in reaction system, reducing agent is added, be be cooled to room temperature after reacting 5min ~ 30min under the condition of 100 DEG C ~ 250 DEG C in temperature, adopt the mixed liquor of acetone and water centrifugal and wash 3 ~ 5 times, collect sample, vacuum drying, obtains Bi
2se
3nanometer sheet; In the mixed liquor of described acetone and water, the volume ratio of water and acetone is 1:(1 ~ 5); The quality of described organic high molecular polymer and the volume ratio of dihydroxylic alcohols are 1g:(100 ~ 200) mL; The quality of described bismuth salt and the volume ratio of dihydroxylic alcohols are 1g:(300 ~ 400) mL; The quality of described selenium source and the volume ratio of dihydroxylic alcohols are 1g:(600 ~ 700) mL; The volume ratio of described reducing agent and dihydroxylic alcohols is 1mL:(60 ~ 70) mL;
Two, dopamine hydrochloride is dissolved in Tri(Hydroxymethyl) Amino Methane Hydrochloride solution, after ultrasonic mix homogeneously, adds the Bi that step one obtains wherein
2se
3nanometer sheet, after stirring at normal temperature 3 ~ 9h, adopts deionized water centrifugal and washs 3 ~ 5 times, being then scattered in dimethyl sulfoxide, obtaining Bi
2se
3pDA nanoparticle dispersion liquid; Described Bi
2se
3the concentration of PDA nanoparticle dispersion liquid is (2 ~ 4) mg/mL; The quality of described dopamine hydrochloride and the volume ratio of Tri(Hydroxymethyl) Amino Methane Hydrochloride solution are 1g:(300 ~ 500) mL; Described Bi
2se
3the quality of nanometer sheet and the volume ratio of Tri(Hydroxymethyl) Amino Methane Hydrochloride solution are 1g:(1500 ~ 2500) mL; The pH of described Tri(Hydroxymethyl) Amino Methane Hydrochloride solution is 8 ~ 10;
Three, doxorubicin hydrochloride is dissolved in dimethyl sulfoxide, after ultrasonic mix homogeneously, obtains doxorubicin hydrochloride dispersion liquid; Doxorubicin hydrochloride dispersion liquid is joined the Bi that step 2 obtains
2se
3in PDA nanoparticle dispersion liquid, stirring at normal temperature 5 ~ 15min, obtain mixed solution, then mixed solution is dropwise added drop-wise in serum albumin aqueous solution under ultrasound condition, adopt deionized water centrifugal and wash 3 ~ 5 times, obtaining solid, by solid dispersal in phosphate buffer, being positioned over temperature is preserve in the refrigerator of 4 DEG C, obtains multi-functional bismuth selenide nano-complex; The concentration of described doxorubicin hydrochloride dispersion liquid is (5 ~ 20) mg/mL; Described doxorubicin hydrochloride dispersion liquid and Bi
2se
3the volume ratio of PDA nanoparticle dispersion liquid is 1:(1 ~ 4); The volume ratio of described mixed solution and serum albumin aqueous solution is 1:(2 ~ 6); The quality of described solid and the volume ratio of phosphate buffer are 1g:(1000 ~ 2000) mL; The concentration of the aqueous solution of serum albumin described in step 3 is 5.0mg/mL.
4. the preparation method of a kind of multi-functional bismuth selenide nano-complex according to claim 3, is characterized in that organic high molecular polymer described in step one is one or both the mixture in polyvinylpyrrolidone and polyacrylic acid.
5. the preparation method of a kind of multi-functional bismuth selenide nano-complex according to claim 3, is characterized in that dihydroxylic alcohols described in step one is a kind of or wherein several mixture in ethylene glycol, propylene glycol and butanediol.
6. the preparation method of a kind of multi-functional bismuth selenide nano-complex according to claim 3, is characterized in that selenium source described in step one is a kind of or wherein several mixture in sodium selenite, potassium selenite and selenium dioxide; The salt of bismuth described in step one is a kind of or wherein several mixture in bismuth nitrate, bismuth chloride and bismuth acetate.
7. the preparation method of a kind of multi-functional bismuth selenide nano-complex according to claim 3, is characterized in that reducing agent described in step one is mixture a kind of or wherein several in azanol, morpholine borine, sodium borohydride, glucose and ascorbic acid.
8. the preparation method of a kind of multi-functional bismuth selenide nano-complex according to claim 3, is characterized in that one or both the mixture in the aqueous solution of serum albumin described in step 3 behaviour serum albumin aqueous solution and Bovine Serum Albumin in Aqueous Solution.
9. the application of a kind of multi-functional bismuth selenide nano-complex as claimed in claim 1, it is characterized in that the thermochemotherapy multi-functional bismuth selenide nano-complex being used for malignant tumor as thermochemotherapy nano material.
10. the application of a kind of multi-functional bismuth selenide nano-complex as claimed in claim 1, it is characterized in that the CT image-forming diagnose multi-functional bismuth selenide nano-complex being used for malignant tumor as CT image-forming contrast medium.
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