CN102961337A - Preparation method of target compound nano particle - Google Patents

Preparation method of target compound nano particle Download PDF

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CN102961337A
CN102961337A CN2012105435903A CN201210543590A CN102961337A CN 102961337 A CN102961337 A CN 102961337A CN 2012105435903 A CN2012105435903 A CN 2012105435903A CN 201210543590 A CN201210543590 A CN 201210543590A CN 102961337 A CN102961337 A CN 102961337A
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CN102961337B (en
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郭喜明
郭斌
薄璇
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Harbin Institute of Technology
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Abstract

The invention provides a preparation method of a target compound nano particle, relating to a preparation method of target treatment integration compound nano particles. The invention solves the technical problems of poor carrier stability and small drug-loading quantity of the traditional antineoplastic drugs. The method comprises the following steps of: preparing a methanol solution of an integrated nano particle of a Fe3O4-HCPT@SiO2 coupling porphyrin photosensitizer; and stirring the methanol solution of the integrated nano particle of the Fe3O4-HCPT@SiO2 coupling porphyrin photosensitizer, N,N-dimethylformamide and target biomolecule or antitumor drug for reacting at the room temperature, and centrifuging to obtain the target compound nano particle. Polystyrolsulfon acid (PSS) and 10-hydroxycamptothecine are absorbed on a Fe3O4 magnetic nano particle through a self-assembly mode. The preparation method is high feasibility; the target compound nano particle has a physical target function of the magnetic nano particle and an active target function of further functionally modifying the biomolecule on the surface; and the medicine concentration can be increased under a dual-target function.

Description

The preparation method of targeting composite nanoparticle
Technical field
The present invention relates to the preparation method of the integrated composite nanoparticle of a kind of targeting diagnosis and treatment.
Background technology
Point out according to the official of World Health Organization (WHO): by 2010, malignant tumor will replace cardiovascular disease became the maximum disease of world's death toll.The clinical diagnosing tumour that can be used for has at present: optical imagery, positron emission tomography, Magnetic Resonance Imaging, ultrasonic and Computed tomography; The treatment tumor have: operation, radiotherapy, Drug therapy three large main method, the householder methods such as photodynamic therapy, thermotherapy, more than various therapies all received good treatment effect.As carrying out optical imagery with porphyrins, be to excite after the 405nm light absorption to produce 630nm and 690nm near infrared region fluorescence to the tumor tissues imaging by the stronger absorbing wavelength of its structure porphin ring, have the advantage of low-energy radiation, hypersensitivity etc.; With hydroxy camptothecin (HCPT) class medicine, by selectivity inhibition tumor cell DNA topoisomerase, cut off the dna single chain, disturb copying of DNA chain, have stronger anti-tumor activity; Carry out optical dynamic therapy with porphyrins, by optionally enrichment on tumor cell of porphyrin, the generation activated singlet oxygen of tool (O2) causes tumor cell dead because of the oxidation inactivation will bring out biological tissue when using the rayed tumor area of certain wavelength near, have that antitumor spectra is wide, indication is wide, the remarkable advantage of repetitive therapy repeatedly, and with chemotherapy combined use concertedness good, with the excellent oncotherapy effect of operation associating Reduction surgery scope and minimizing postoperative recurrence; And carry out photo-thermal therapy with golden core/shell nanoparticles, and by the near-infrared wavelength of its adjustable surface longitudinal plasma absorption with its resonance, kill tumor stem cell after the release heat, thus suppress neoplasm metastasis; When with the Drug therapy combined effect, have the chemical sensitization effect and can improve the blood circulation of tumor periphery and strengthen membrane passage, strengthen the inside tumor that penetrates into of medicine.
But exist in the diagnosing tumor medicine three totally two with problem are: one, target-oriented drug is poor; Take hydroxy camptothecin (HCPT) class medicine as example, there are two kinds of forms in HCPT under different pH conditions: Alpha-hydroxy-delta-lactone loop type and carboxylic acid, ethyl ester form, but in two kinds of forms only the lactone structure form have anti-tumor activity, and the water solublity of lactone structure form is relatively poor, how to improve lactone structure camptothecine target tumor cell and is the Research Challenges of this type of medicine always; Two, owing to the distinctive biotic environment of tumor tissues, make in diagnosis and treatment drug level difficulty to reach valid density; Three, in the diagnosis and treatment of tumor, use the monotherapy curative effect low, can't treat malignant tumor.Therefore two key problems are that the pharmaceutical carrier that How to choose is suitable improves various Therapeutic Method itself and makes up can science and the multiple therapy Comprehensive Treatment of reasonable combination tumour medicine in present tumor diagnosis and treatment research.
Along with the development of science and technology, the diagnosing tumor treatment technology take micro-nano manufacturing technology and nano material as the basis provides an effective way for solving this two large problems.Can make drug targeting act on tumor cell as behind the carrier nanoparticle, rear gathering focus, and can strengthen cell to the osmosis of its medicine.The nano-carrier that is developed out at present has polymer microballoon nanoparticle, microcapsule lipid and microemulsion, golden nanometer particle etc.; In many nanoparticles, golden nanometer particle has can be the further surface-functionalized advantage that tumor cell is had the biomolecule of targeting such as monoclonal antibody, folic acid, albumen, saccharide etc., can make nanoparticle accurately be positioned specific tumor cell after the modification, significantly improve medicine in the concentration of specific tumors tissue, further reduce side effect; And golden nanometer particle also can be prepared into and multiplely discharge controlled drug delivery system under specific part and condition, reduce simultaneously the consumption of medicine under the prerequisite that does not weaken the diagnosis and treatment curative effect, thereby golden nanometer particle is the desirable nano-carrier of a class.
In recent years on above-mentioned nano-carrier Research foundation, made up multiple targeting ability, and the integrated composite Nano of multiple diagnosis and treatment method combination can have been become a new study hotspot, as based on the liposome nano material with Fe 3O 4The magnetic targeting optical imagery composite nanoparticle that magnetic nano-particle and fluorescent dye make up; Treat composite nanoparticle based on optical imagery and nuclear magnetic resonance composite nanoparticle, photo-thermal therapy and conventional medicament that golden nanometer particle makes up.But the research of this type of composite nanoparticle is in the junior stage, and still has the defective of three aspects:, and first aspect is that the drug loading of this type of drug-loading system is less, stability and targeting are lower; Second aspect be need in the preparation process with an organic solvent, surfactant, ultrasonic or homogeneity, this all will limit the diagnosis and treatment process of tumour medicine; The third aspect is difficult to organically combine multiple diagnosis and treatment mode, has long consultation hours.
Summary of the invention
The present invention provides a kind of preparation method of targeting composite nanoparticle in order to solve present antineoplastic drug carrier poor stability, technical problem that drug loading is little.
The preparation method of targeting composite nanoparticle is carried out according to following steps:
One, preparation magnetic nano-particle:
Be the FeCl of 1mol/L with 10mL concentration 3Aqueous solution, 2.5mLFeSO 47H 2The HCl solution of O joins the NH that 125mL concentration is 0.7mol/L 37H 2O continue to stir 30min, and centrifugalize is also collected product in the supernatant, and the product in the supernatant with deionized water wash 3 times, and then is dispersed in the 150mL deionized water, obtains Fe 3O 4Nano-particle solution;
Described Fe8O 47H 2FeSO in the HCl solution of O 47H 2The concentration of O is that the concentration of 2mol/L, HCl is 2mol/L;
Two, preparation Fe 3O 4-HCPT nanoparticle:
With 10mLFe 3O 4Nano-particle solution is distributed in the NaCl aqueous solution of the poly-hydrogen chloropropene amine of 10ml, ultrasonic reaction 30min, and then magnetic separation is the NaCl solution washing of 0.51mol/L with concentration, is dispersed in water at last, obtaining concentration is the Fe of the PAH-parcel of 7.5mg/ml 3O 4Nano-particle solution;
Poly-hydrogen chloropropene amine concentration is 1mg/ml in the NaCl aqueous solution of the poly-hydrogen chloropropene amine described in the step 2, and the concentration of NaCl is 0.5mol/L;
Three, the Fe that 10mLPAH-is wrapped up 3O 4Nano-particle solution is distributed to ultrasonic reaction 30min in the NaCl aqueous solution of 10ml polystyrolsulfon acid acid sodium, obtains Fe 3O 4The magnetic nano-particle precursor;
The concentration of kayexalate is 1mg/ml in the NaCl aqueous solution of the polystyrolsulfon acid acid sodium described in the step 3, and the concentration of NaCl is 0.5mol/L;
Four, the 364mg10-hydroxy camptothecin is dissolved in the 150mLNaOH solution, regulating pH value is 11, add concentration be the HCl of 1mol/L to regulate pH value be 4.8, obtain the HCPT microemulsion, with 10mlFe 3O 4The magnetic nano-particle precursor joins in the 10mLHCPT microemulsion, stirring is also passed through the uv absorption monitoring reaction, when the characteristic absorption peak of 10-hydroxycamptothecine disappears, stopped reaction, the magnetic separation collecting precipitation, and be 4.8 HCl solution washing with pH value, then add in the 150mL deionized water, obtain the Fe of kayexalate/HCPT 3O 4The magnetic nano-particle aqueous solution;
Five, preparation Fe 3O 4-HCPT@SiO 2:
The 1mL ethyl orthosilicate is mixed with 30mL ethanol, obtain the alcoholic solution of ethyl orthosilicate, with 2.5mLNH 3H 2O, 38mLH 2The Fe of O, 38mL ethanol and 10mL kayexalate/HCPT 3O 4Then the magnetic nano-particle aqueous solution adds the alcoholic solution of ethyl orthosilicate, reacted 4 hours, and magnetic separation, collecting precipitation, and the mixed solution of water and ethanol washing 3 times, redispersion obtains Fe in the 100mL deionized water 3O 4-HCPT@SiO 2Aqueous solution;
Six, be centrifugal Fe under the condition of 10000rpm at rotating speed then 3O 4-HCPT@SiO 2Aqueous solution 30min removes supernatant, adds washing with alcohol, ultra-sonic dispersion 15-20min;
Seven, repeating step is six 3-4 time, and obtaining concentration is 7.5mg/mLFe 3O 4-HCPT@SiO 2Alcoholic solution;
Eight, with 10mLFe 3O 4-HCPT@SiO 2Alcoholic solution and 0.03ml aminopropyltriethoxywerene werene stirred 3 hours under 80 ℃ condition, then according at rotating speed being centrifugal 30min under the condition of 10000rpm, in precipitation, add ethanol, the order of ultra-sonic dispersion 15-20min, repeat 5 times, obtain the Fe that surface amination is modified 3O 4-HCPT@SiO 2Solution;
Nine, preparation golden nanometer particle:
Adding 0.01ml concentration in the 40mL distilled water is that 0.25mol/L aqueous solution of chloraurate, 0.2mL concentration are that 0.2mol/L wet chemical, 0.6mL concentration are the 0.5mol/L sodium borohydride aqueous solution, under the condition of 600rpm, stir 10min, add again the sodium borohydride aqueous solution that concentration is 0.5mol/L, until the bluish violet of solution becomes the orange red sodium borohydride aqueous solution that stops to add, restir 5min obtains solution of gold nanoparticles;
Ten, preparation strawberry shape gold nano compound particle:
Fe with the modification of 0.07ml surface amination 3O 4-HCPT@SiO 2Solution dilution is to 50ml, and then splashes in the solution of gold nanoparticles, then with the centrifugal 90min of the speed of 600rpm, obtains Au/SiO 2Solution;
11, preparation gold nanoshell:
The 25mg potassium carbonate is dissolved in the 100ml distilled water, and then the speed stirring 10min with 600rpm adds the aqueous solution of chloraurate that 1.5ml concentration is 0.25mol/L, continues to stir 30 minutes, gets mixed liquor, with 4ml mixed liquor and Au/SiO 2Solution mixes, and then with the centrifugal 30min of 5000rpm, and then is scattered in the 10mL water precipitation after centrifugal and ultrasonic 10min, obtains wrapping up the SiO of gold nanoshell 2The nanoparticle aqueous solution;
12, with 0.03g 1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 3～4ml oxolane join in the centrifuge tube, add the SiO that 1～5ml is wrapped up in gold nanoshell again 2Nanoparticle aqueous solution and 50mg Porphyrin-Based Sensitizer molecule reacted 72 hours, were under the condition of 6000rpm centrifugal 10 minutes at rotating speed after reaction finishes, collecting precipitation, and precipitation is dispersed in the methanol, obtain the Fe that concentration is 7.5mg/mL 3O 4-HCPT@SiO 2The methanol solution of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer;
13, with 50mg～100mg Fe 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours, then be that 14000rpm, temperature are centrifugal under 4 ℃ the condition at rotating speed, be dispersed in behind the collecting precipitation in the methanol, obtain the methanol solution of targeting composite nanoparticle;
Porphyrin-Based Sensitizer molecule described in the step 12 is 5-(4-chloroethene acyloxy phenyl)-10,15,20-three (4-carboxyl phenyl) porphyrin or tetrachloro acetoxyl group phenyl porphyrin;
Targeting biomolecule described in the step 13 is folic acid;
Antitumor drug described in the step 13 is monoclonal antibody Trastuzumab, paclitaxel, amycin, 5-fluorouracil or the cry of certain animals of first ammonia butterfly.
We are bright to be adsorbed on Fe with polystyrolsulfon acid (PSS) and 10-hydroxycamptothecine self assembly mode 3O 4Magnetic nano-particle, the present invention has at first obtained a kind of efficient dewatering medicament drug-loading system; This method feasibility is high; Has Fe own 3O 4The physics targeting of magnetic nano-particle and the active targeting of further surface-functionalized modified biological molecule, the remarkable drug level that increases diseased region under the condition that reaches the side effect minimum, has efficient treatment effect under the dual-target effect.The technical barrier that this kind preparation method can solve the poor drug loading of medicine-carried system biocompatibility and targeting is low, self assembly easily occurs in transportation medicine.
Other or a kind of novel targeting Integral rice corpuscles of this kind medicine-carried system: at Fe 3O 4-10-hydroxycamptothecine@SiO 2Coat gold nanoshell, first can by thermotherapy kill tumor cell and the tumor stem cell of gold nanoshell, not only can treat tumor and can suppress neoplasm metastasis; Second can strengthen the osmotic absorption that membrane passage improves medicine by the effect of thermotherapy chemical sensitization, and the blood circulation that improves the tumor periphery increases medicine and enters inside tumor to improve the drug level ratio of tumor/normal structure.The Porphyrin-Based Sensitizer of the biomolecule folic acid that is connected by cystine linkage makes Fe 3O 4-10-hydroxycamptothecine@SiO 2@Au possesses the effect of photodynamics diagnosis and treatment.
Description of drawings
Fig. 1 is the SEM image of the targeting composite nanoparticle of experiment one preparation;
Fig. 2 is step 2 gained Fe in the experiment one preparation targeting composite nanoparticle 3O 4-HCPT nanoparticle TEM image;
Fig. 3 is the TEM image of the targeting composite nanoparticle of experiment one preparation;
Fig. 4 is the dynamic laser light scattering diagram picture of the targeting composite nanoparticle of monodispersed experiment one preparation in aqueous solution;
Fig. 5 is the spontaneous release accumulation of the medicine of targeting composite nanoparticle in 37 ℃ PBS solution of different pH value of experiment one preparation behavior curve, wherein
Figure BDA00002589017000051
Represent pH value and be the spontaneous release accumulation of the medicine behavior curve in 9.2 37 ℃ the PBS solution,
Figure BDA00002589017000052
Represent pH value and be the spontaneous release accumulation of the medicine behavior curve in 8.0 37 ℃ the PBS solution,
Figure BDA00002589017000053
Represent pH value and be the spontaneous release accumulation of the medicine behavior curve in 7.4 37 ℃ the PBS solution.
The specific embodiment
Technical solution of the present invention is not limited to the following cited specific embodiment, also comprises the combination in any between each specific embodiment.
The specific embodiment one: the preparation method of present embodiment targeting composite nanoparticle is carried out according to following steps:
One, preparation magnetic nano-particle:
Be the FeCl of 1mol/L with 10mL concentration 3Aqueous solution, 2.5mLFeSO 47H 2The HCl solution of O joins the NH that 125mL concentration is 0.7mol/L 37H 2O continue to stir 30min, and centrifugalize is also collected product in the supernatant, and the product in the supernatant with deionized water wash 3 times, and then is dispersed in the 150mL deionized water, obtains Fe 3O 4Nano-particle solution;
Described FeSO 47H 2FeSO in the HCl solution of O 47H 2The concentration of O is that the concentration of 2mol/L, HCl is 2mol/L;
Two, preparation Fe 3O 4-HCPT nanoparticle:
With 10mLFe 3O 4Nano-particle solution is distributed in the NaCl aqueous solution of the poly-hydrogen chloropropene amine of 10ml, ultrasonic reaction 30min, and then magnetic separation is the NaCl solution washing of 0.51mol/L with concentration, is dispersed in water at last, obtaining concentration is the Fe of the PAH-parcel of 7.5mg/ml 3O 4Nano-particle solution;
Poly-hydrogen chloropropene amine concentration is 1mg/ml in the NaCl aqueous solution of the poly-hydrogen chloropropene amine described in the step 2, and the concentration of NaCl is 0.5mol/L;
Three, the Fe that 10mLPAH-is wrapped up 3O 4Nano-particle solution is distributed to ultrasonic reaction 30min in the NaCl aqueous solution of 10ml polystyrolsulfon acid acid sodium, obtains Fe 3O 4The magnetic nano-particle precursor;
The concentration of kayexalate is 1mg/ml in the NaCl aqueous solution of the polystyrolsulfon acid acid sodium described in the step 3, and the concentration of NaCl is 0.5mol/L;
Four, the 364mg10-hydroxy camptothecin is dissolved in the 150mLNaOH solution, regulating pH value is 11, add concentration be the HCl of 1mol/L to regulate pH value be 4.8, obtain the HCPT microemulsion, with 10mlFe 3O 4The magnetic nano-particle precursor joins in the 10mLHCPT microemulsion, stirring is also passed through the uv absorption monitoring reaction, when the characteristic absorption peak of 10-hydroxycamptothecine disappears, stopped reaction, the magnetic separation collecting precipitation, and be 4.8 HCl solution washing with pH value, then add in the 150mL deionized water, obtain the Fe of kayexalate/HCPT 3O 4The magnetic nano-particle aqueous solution;
Five, preparation Fe 3O 4-HCPT@SiO 2:
The 1mL ethyl orthosilicate is mixed with 30mL ethanol, obtain the alcoholic solution of ethyl orthosilicate, with 2.5mLNH 3H 2O, 38mLH 2The Fe of O, 38mL ethanol and 10mL kayexalate/HCPT 3O 4Then the magnetic nano-particle aqueous solution adds the alcoholic solution of ethyl orthosilicate, reacted 4 hours, and magnetic separation, collecting precipitation, and the mixed solution of water and ethanol washing 3 times, redispersion obtains Fe in the 100mL deionized water 3O 4-HCPT@SiO 2Aqueous solution;
Six, be centrifugal Fe under the condition of 10000rpm at rotating speed then 3O 4-HCPT@SiO 2Aqueous solution 30min removes supernatant, adds washing with alcohol, ultra-sonic dispersion 15-20min;
Seven, repeating step is six 3-4 time, and obtaining concentration is 7.5mg/mLFe 3O 4-HCPT@SiO 2Alcoholic solution;
Eight, with 10mLFe 3O 4-HCPT@SiO 2Alcoholic solution and 0.03ml aminopropyltriethoxywerene werene stirred 3 hours under 80 ℃ condition, then according at rotating speed being centrifugal 30min under the condition of 10000rpm, in precipitation, add ethanol, the order of ultra-sonic dispersion 15-20min, repeat 5 times, obtain the Fe that surface amination is modified 3O 4-HCPT@SiO 2Solution;
Nine, preparation golden nanometer particle:
Adding 0.01ml concentration in the 40mL distilled water is that 0.25mol/L aqueous solution of chloraurate, 0.2mL concentration are that 0.2mol/L wet chemical, 0.6mL concentration are the 0.5mol/L sodium borohydride aqueous solution, under the condition of 600rpm, stir 10min, add again the sodium borohydride aqueous solution that concentration is 0.5mol/L, until the bluish violet of solution becomes the orange red sodium borohydride aqueous solution that stops to add, restir 5min obtains solution of gold nanoparticles;
Ten, preparation strawberry shape gold nano compound particle:
Fe with the modification of 0.07ml surface amination 3O 4-HCPT@SiO 2Solution dilution is to 50ml, and then splashes in the solution of gold nanoparticles, then with the centrifugal 90min of the speed of 600rpm, obtains Au/SiO 2Solution;
11, preparation gold nanoshell:
The 25mg potassium carbonate is dissolved in the 100ml distilled water, and then the speed stirring 10min with 600rpm adds the aqueous solution of chloraurate that 1.5ml concentration is 0.25mol/L, continues to stir 30 minutes, gets mixed liquor, with 4ml mixed liquor and Au/SiO 2Solution mixes, and then with the centrifugal 30min of 5000rpm, and then is scattered in the 10mL water precipitation after centrifugal and ultrasonic 10min, obtains wrapping up the SiO of gold nanoshell 2The nanoparticle aqueous solution;
12, with 0.03g 1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 3～4ml oxolane join in the centrifuge tube, add the SiO that 1～5ml is wrapped up in gold nanoshell again 2Nanoparticle aqueous solution and 50mg Porphyrin-Based Sensitizer molecule reacted 72 hours, were under the condition of 6000rpm centrifugal 10 minutes at rotating speed after reaction finishes, collecting precipitation, and precipitation is dispersed in the methanol, obtain the Fe that concentration is 7.5mg/mL 3O 4-HCPT@SiO 2The methanol solution of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer;
13, with 50mg～100mg Fe 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours, then be that 14000rpm, temperature are centrifugal under 4 ℃ the condition at rotating speed, be dispersed in behind the collecting precipitation in the methanol, obtain the methanol solution of targeting composite nanoparticle;
Porphyrin-Based Sensitizer molecule described in the step 12 is 5-(4-chloroethene acyloxy phenyl)-10,15,20-three (4-carboxyl phenyl) porphyrin or tetrachloro acetoxyl group phenyl porphyrin;
Targeting biomolecule described in the step 13 is folic acid;
Antitumor drug described in the step 13 is monoclonal antibody Trastuzumab, paclitaxel, amycin, 5-fluorouracil or the cry of certain animals of first ammonia butterfly.
The specific embodiment two: present embodiment and the specific embodiment one are different be in the step 12 with 0.03g 1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 3.5ml oxolane join in the centrifuge tube.Other is identical with the specific embodiment one.
The specific embodiment three: what present embodiment and the specific embodiment one were different is with 60mg～90mgFe in the step 13 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.Other is identical with the specific embodiment one.
The specific embodiment four: what present embodiment and the specific embodiment one were different is with 70mg～80mgFe in the step 13 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.Other is identical with the specific embodiment one.
The specific embodiment five: what present embodiment and the specific embodiment one were different is with 75mgFe in the step 13 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.Other is identical with the specific embodiment one.
The specific embodiment six: the preparation method of present embodiment targeting composite nanoparticle is carried out according to following steps:
One, preparation magnetic nano-particle:
Be the FeCl of 1mol/L with 10mL concentration 3Aqueous solution, 2.5mLFeSO 47H 2The HCl solution of O joins the NH that 125mL concentration is 0.7mol/L 37H 2O continue to stir 30min, and centrifugalize is also collected product in the supernatant, and the product in the supernatant with deionized water wash 3 times, and then is dispersed in the 150mL deionized water, obtains Fe 3O 4Nano-particle solution;
Described FeSO 47H 2FeSO in the HCl solution of O 47H 2The concentration of O is that the concentration of 2mol/L, HCl is 2mol/L;
Two, preparation Fe 3O 4-HCPT nanoparticle:
With 10mlFe 3O 4Nano-particle solution is distributed in the NaCl aqueous solution of the poly-hydrogen chloropropene amine of 10ml, ultrasonic reaction 30min, and then magnetic separation is the NaCl solution washing of 0.51mol/L with concentration, is dispersed in water at last, obtaining concentration is the Fe of the PAH-parcel of 7.5mg/ml 3O 4Nano-particle solution;
Poly-hydrogen chloropropene amine concentration is 1mg/ml in the NaCl aqueous solution of the poly-hydrogen chloropropene amine described in the step 2, and the concentration of NaCl is 0.5mol/L;
Three, the Fe that 10mLPAH-is wrapped up 3O 4Nano-particle solution is distributed to ultrasonic reaction 30min in the NaCl aqueous solution of 10mL kayexalate, obtains Fe 3O 4The magnetic nano-particle precursor;
The concentration of kayexalate is 1mg/ml in the NaCl aqueous solution of the kayexalate described in the step 3, and the concentration of NaCl is 0.5mol/L;
Four, the 364mg10-hydroxy camptothecin is dissolved in the 150mLNaOH solution, regulating pH value is 11, add concentration be the HCl of 1mol/L to regulate pH value be 4.8, obtain the HCPT microemulsion, with 10mLFe 3O 4The magnetic nano-particle precursor joins in the 10mLHCPT microemulsion, and stirring is also passed through the uv absorption monitoring reaction, when the characteristic absorption peak of 10-hydroxycamptothecine disappears, stopped reaction, magnetic separation, and be 4.8 HCl solution washing with pH value, the Fe of kayexalate/HCPT obtained 3O 4Magnetic nano-particle;
Five, with the Fe of kayexalate/HCPT 3O 4Magnetic nano-particle is distributed in the 150ml deionized water, obtains the Fe of kayexalate/HCPT 3O 4The magnetic nano-particle dispersion liquid is with the Fe of 10mL kayexalate/HCPT 3O 4The magnetic nano-particle dispersion liquid is distributed to ultrasonic reaction 30min in the NaCl aqueous solution of 10mL kayexalate, Fe 3O 4Magnetic nano-particle precursor a;
The 364mg10-hydroxy camptothecin is dissolved in the 150mLNaOH solution, and regulating pH value is 11, add concentration be the HCl of 1mol/L to regulate pH value be 4.8, obtain the HCPT microemulsion, with 10mLFe 3O 4Magnetic nano-particle precursor a joins in the 10mLHCPT microemulsion, and stirring is also passed through the uv absorption monitoring reaction, when the characteristic absorption peak of 10-hydroxycamptothecine disappears, stopped reaction, magnetic separation, and be 4.8 HCl solution washing with pH value, the Fe of 2 strata Sodium styrene sulfonate/HCPT obtained 3O 4Magnetic nano-particle;
The concentration of kayexalate is 1mg/ml in the NaCl aqueous solution of described kayexalate, and the concentration of NaCl is 0.5mol/L;
Six, repeating step five, then add in the 150mL deionized water, obtain the Fe of n+2 strata Sodium styrene sulfonate/HCPT 3O 4The magnetic nano-particle aqueous solution, wherein n is positive integer;
Seven, preparation Fe 3O 4-HCPT@SiO 2:
The 1mL ethyl orthosilicate is mixed with 30mL ethanol, obtain the alcoholic solution of ethyl orthosilicate, with 2.5mLNH 3H 2O, 38mLH 2The Fe of O, 38mL ethanol and 10mLn+2 strata Sodium styrene sulfonate/HCPT 3O 4Then the magnetic nano-particle aqueous solution adds the alcoholic solution of ethyl orthosilicate, reacted 4 hours, and magnetic separation, collecting precipitation, and the mixed solution of water and ethanol washing 3 times, redispersion obtains Fe in the 100mL deionized water 3O 4-HCPT@SiO 2Aqueous solution;
Eight, be centrifugal Fe under the condition of 10000rpm at rotating speed then 3O 4-HCPT@SiO 2Aqueous solution 30min removes supernatant, adds an amount of washing with alcohol, ultra-sonic dispersion 15-20min;
Nine, repeating step is eight 3-4 time, and obtaining concentration is 7.5mg/mLFe 3O 4-HCPT@SiO 2Alcoholic solution;
Ten, with 10mLFe 3O 4-HCPT@SiO 2Alcoholic solution and 0.03ml aminopropyltriethoxywerene werene stirred 3 hours under 80 ℃ condition, then according at rotating speed being centrifugal 30min under the condition of 10000rpm, in precipitation, add ethanol, the order of ultra-sonic dispersion 15-20min, repeat 5 times, obtain the Fe that surface amination is modified 3O 4-HCPT@SiO 2Solution;
11, preparation golden nanometer particle:
Adding 0.01ml concentration in the 40mL distilled water is that 0.25mol/L aqueous solution of chloraurate, 0.2mL concentration are that 0.2mol/L wet chemical, 0.6mL concentration are the 0.5mol/L sodium borohydride aqueous solution, 600rpm stirs 10min, add again the sodium borohydride aqueous solution that concentration is 0.5mol/L, until the bluish violet of solution becomes the orange red sodium borohydride aqueous solution that stops to add, restir 5min obtains solution of gold nanoparticles;
12, preparation strawberry shape gold nano compound particle:
Fe with the modification of 0.07ml surface amination 3O 4-HCPT@SiO 2Solution dilution is to 50ml, and then splashes in the solution of gold nanoparticles, then with the centrifugal 90min of the speed of 600rpm, obtains Au/SiO 2Solution;
13, preparation gold nanoshell:
The 25mg potassium carbonate is dissolved in the 100ml distilled water, and then the speed stirring 10min with 600rpm adds the aqueous solution of chloraurate that 1.5ml concentration is 0.25mol/L, continues to stir 30 minutes, gets mixed liquor, with 4ml mixed liquor and Au/SiO 2Solution mixes, and then with the centrifugal 30min of 5000rpm, and then is scattered in the 10mL water precipitation after centrifugal and ultrasonic 10min, obtains wrapping up the SiO of gold nanoshell 2The nanoparticle aqueous solution;
14, with 0.03g 1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 3～4ml oxolane join in the centrifuge tube, add the SiO that 1～5ml is wrapped up in gold nanoshell again 2Nanoparticle aqueous solution and 50mg Porphyrin-Based Sensitizer molecule reacted 72 hours, were under the condition of 6000rpm centrifugal 10 minutes at rotating speed after reaction finishes, collecting precipitation, and precipitation is dispersed in the methanol, obtain the Fe that concentration is 7.5mg/mL 3O 4-HCPT@SiO 2The Integral rice corpuscles of coupling Porphyrin-Based Sensitizer;
15, with 50mg～100mg Fe 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours, then be that 14000rpm, temperature are centrifugal under 4 ℃ the condition at rotating speed, be dispersed in behind the collecting precipitation in the methanol, obtain the methanol solution of targeting composite nanoparticle;
Porphyrin-Based Sensitizer molecule described in the step 13 is 5-(4-chloroethene acyloxy phenyl)-10,15,20-three (4-carboxyl phenyl) porphyrin or tetrachloro acetoxyl group phenyl porphyrin;
Targeting biomolecule described in the step 14 is folic acid;
Antitumor drug described in the step 14 is monoclonal antibody Trastuzumab, paclitaxel, amycin, 5-fluorouracil or the cry of certain animals of first ammonia butterfly.
The specific embodiment seven: present embodiment and the specific embodiment six are different be in the step 14 with 0.03g 1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 3.5ml oxolane join in the centrifuge tube.Other is identical with the specific embodiment six.
The specific embodiment eight: what present embodiment and the specific embodiment six were different is with 60mg～90mgFe in the step 15 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.Other is identical with the specific embodiment six.
The specific embodiment nine: what present embodiment and the specific embodiment six were different is with 70mg～80mgFe in the step 15 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.Other is identical with the specific embodiment six.
The specific embodiment ten: what present embodiment and the specific embodiment six were different is with 75mgFe in the step 15 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.Other is identical with the specific embodiment six.
Adopt following experimental verification effect of the present invention:
Experiment one:
The preparation method of targeting composite nanoparticle is carried out according to following steps:
One, preparation magnetic nano-particle:
Be the FeCl of 1mol/L with 10mL concentration 3Aqueous solution, 2.5mLFeSO 47H 2The HCl solution of O joins the NH that 125mL concentration is 0.7mol/L 37H 2O continue to stir 30min, and centrifugalize is also collected product in the supernatant, and the product in the supernatant with deionized water wash 3 times, and then is dispersed in the 150mL deionized water, obtains Fe 3O 4Nano-particle solution;
Described FeSO 47H 2FeSO in the HCl solution of O 47H 2The concentration of O is that the concentration of 2mol/L, HCl is 2mol/L;
Two, preparation Fe 3O 4-HCPT nanoparticle:
With 10mLFe 3O 4Nano-particle solution is distributed in the NaCl aqueous solution of the poly-hydrogen chloropropene amine of 10ml, ultrasonic reaction 30min, and then magnetic separation is the NaCl solution washing of 0.51mol/L with concentration, is dispersed in water at last, obtaining concentration is the Fe of the PAH-parcel of 7.5mg/ml 3O 4Nano-particle solution;
Poly-hydrogen chloropropene amine concentration is 1mg/ml in the NaCl aqueous solution of the poly-hydrogen chloropropene amine described in the step 2, and the concentration of NaCl is 0.5mol/L;
Three, the Fe that 10mLPAH-is wrapped up 3O 4Nano-particle solution is distributed to ultrasonic reaction 30min in the NaCl aqueous solution of 10ml polystyrolsulfon acid acid sodium, obtains Fe 3O 4The magnetic nano-particle precursor;
The concentration of kayexalate is 1mg/ml in the NaCl aqueous solution of the polystyrolsulfon acid acid sodium described in the step 3, and the concentration of NaCl is 0.5mol/L;
Four, the 364mg10-hydroxy camptothecin is dissolved in the 150mLNaOH solution, regulating pH value is 11, add concentration be the HCl of 1mol/L to regulate pH value be 4.8, obtain the HCPT microemulsion, with 10mlFe 3O 4The magnetic nano-particle precursor joins in the 10mLHCPT microemulsion, stirring is also passed through the uv absorption monitoring reaction, when the characteristic absorption peak of 10-hydroxycamptothecine disappears, stopped reaction, the magnetic separation collecting precipitation, and be 4.8 HCl solution washing with pH value, then add in the 150mL deionized water, obtain the Fe of kayexalate/HCPT 3O 4The magnetic nano-particle aqueous solution;
Five, preparation Fe 3O 4-HCPT@SiO 2:
The 1mL ethyl orthosilicate is mixed with 30mL ethanol, obtain the alcoholic solution of ethyl orthosilicate, with 2.5mLNH 3H 2O, 38mLH 2The Fe of O, 38mL ethanol and 10mL kayexalate/HCPT 3O 4Then the magnetic nano-particle aqueous solution adds the alcoholic solution of ethyl orthosilicate, reacted 4 hours, and magnetic separation, collecting precipitation, and the mixed solution of water and ethanol washing 3 times, redispersion obtains Fe in the 100mL deionized water 3O 4-HCPT@SiO 2Aqueous solution;
Six, be centrifugal Fe under the condition of 10000rpm at rotating speed then 3O 4-HCPT@SiO 2Aqueous solution 30min removes supernatant, adds washing with alcohol, ultra-sonic dispersion 20min;
Seven, repeating step is 63 times, and obtaining concentration is 7.5mg/mLFe 3O 4-HCPT@SiO 2Alcoholic solution;
Eight, with 10mLFe 3O 4-HCPT@SiO 2Alcoholic solution and 0.03ml aminopropyltriethoxywerene werene stirred 3 hours under 80 ℃ condition, then according at rotating speed being centrifugal 30min under the condition of 10000rpm, in precipitation, add ethanol, the order of ultra-sonic dispersion 15-20min, repeat 5 times, obtain the Fe that surface amination is modified 3O 4-HCPT@SiO 2Solution;
Nine, preparation golden nanometer particle:
Adding 0.01ml concentration in the 40mL distilled water is that 0.25mol/L aqueous solution of chloraurate, 0.2mL concentration are that 0.2mol/L wet chemical, 0.6mL concentration are the 0.5mol/L sodium borohydride aqueous solution, under the condition of 600rpm, stir 10min, add again the sodium borohydride aqueous solution that concentration is 0.5mol/L, until the bluish violet of solution becomes the orange red sodium borohydride aqueous solution that stops to add, restir 5min obtains solution of gold nanoparticles;
Ten, preparation strawberry shape gold nano compound particle:
Fe with the modification of 0.07ml surface amination 3O 4-HCPT@SiO 2Solution dilution is to 50ml, and then splashes in the solution of gold nanoparticles, then with the centrifugal 90min of the speed of 600rpm, obtains Au/SiO 2Solution;
11, preparation gold nanoshell:
The 25mg potassium carbonate is dissolved in the 100ml distilled water, and then the speed stirring 10min with 600rpm adds the aqueous solution of chloraurate that 1.5ml concentration is 0.25mol/L, continues to stir 30 minutes, gets mixed liquor, with 4ml mixed liquor and Au/SiO 2Solution mixes, and then with the centrifugal 30min of 5000rpm, and then is scattered in the 10mL water precipitation after centrifugal and ultrasonic 10min, obtains wrapping up the SiO of gold nanoshell 2The nanoparticle aqueous solution;
12, with 0.03g 1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 4ml oxolane join in the centrifuge tube, add the SiO that 5ml is wrapped up in gold nanoshell again 2Nanoparticle aqueous solution and 50mg Porphyrin-Based Sensitizer molecule reacted 72 hours, were under the condition of 6000rpm centrifugal 10 minutes at rotating speed after reaction finishes, collecting precipitation, and precipitation is dispersed in the methanol, obtain the Fe that concentration is 7.5mg/mL 3O 4-HCPT@SiO 2The methanol solution of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer;
13, with 50mg Fe 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule were stirring at room reaction 2 hours, then be that 14000rpm, temperature are centrifugal under 4 ℃ the condition at rotating speed, be dispersed in behind the collecting precipitation in the methanol, obtain the methanol solution of targeting composite nanoparticle;
Porphyrin-Based Sensitizer molecule described in the step 12 is 5-(4-chloroethene acyloxy phenyl)-10,15,20-three (4-carboxyl phenyl) porphyrin;
Targeting biomolecule described in the step 13 is folic acid.
Experiment two:
The preparation method of targeting composite nanoparticle is carried out according to following steps:
One, preparation magnetic nano-particle:
Be the FeCl of 1mol/L with 10mL concentration 3Aqueous solution, 2.5mLFeSO 47H 2The HCl solution of O joins the NH that 125mL concentration is 0.7mol/L 37H 2O continue to stir 30min, and centrifugalize is also collected product in the supernatant, and the product in the supernatant with deionized water wash 3 times, and then is dispersed in the 150mL deionized water, obtains Fe 3O 4Nano-particle solution;
Described FeSO 47H 2FeSO in the HCl solution of O 47H 2The concentration of O is that the concentration of 2mol/L, HCl is 2mol/L;
Two, preparation Fe 3O 4-HCPT nanoparticle:
With 10mlFe 3O 4Nano-particle solution is distributed in the NaCl aqueous solution of the poly-hydrogen chloropropene amine of 10ml, ultrasonic reaction 30min, and then magnetic separation is the NaCl solution washing of 0.51mol/L with concentration, is dispersed in water at last, obtaining concentration is the Fe of the PAH-parcel of 7.5mg/ml 3O 4Nano-particle solution;
Poly-hydrogen chloropropene amine concentration is 1mg/ml in the NaCl aqueous solution of the poly-hydrogen chloropropene amine described in the step 2, and the concentration of NaCl is 0.5mol/L;
Three, the Fe that 10mLPAH-is wrapped up 3O 4Nano-particle solution is distributed to ultrasonic reaction 30min in the NaCl aqueous solution of 10mL kayexalate, obtains Fe 3O 4The magnetic nano-particle precursor;
The concentration of kayexalate is 1mg/ml in the NaCl aqueous solution of the kayexalate described in the step 3, and the concentration of NaCl is 0.5mol/L;
Four, the 364mg10-hydroxy camptothecin is dissolved in the 150mLNaOH solution, regulating pH value is 11, add concentration be the HCl of 1mol/L to regulate pH value be 4.8, obtain the HCPT microemulsion, with 10mLFe 3O 4The magnetic nano-particle precursor joins in the 10mLHCPT microemulsion, and stirring is also passed through the uv absorption monitoring reaction, when the characteristic absorption peak of 10-hydroxycamptothecine disappears, stopped reaction, magnetic separation, and be 4.8 HCl solution washing with pH value, the Fe of kayexalate/HCPT obtained 3O 4Magnetic nano-particle;
Five, with the Fe of kayexalate/HCPT 3O 4Magnetic nano-particle is distributed in the 150ml deionized water, obtains the Fe of kayexalate/HCPT 3O 4The magnetic nano-particle dispersion liquid is with the Fe of 10mL kayexalate/HCPT 3O 4The magnetic nano-particle dispersion liquid is distributed to ultrasonic reaction 30min in the NaCl aqueous solution of 10mL kayexalate, Fe 3O 4Magnetic nano-particle precursor a;
The 364mg10-hydroxy camptothecin is dissolved in the 150mLNaOH solution, and regulating pH value is 11, add concentration be the HCl of 1mol/L to regulate pH value be 4.8, obtain the HCPT microemulsion, with 10mLFe 3O 4Magnetic nano-particle precursor a joins in the 10mLHCPT microemulsion, and stirring is also passed through the uv absorption monitoring reaction, when the characteristic absorption peak of 10-hydroxycamptothecine disappears, stopped reaction, magnetic separation, and be 4.8 HCl solution washing with pH value, the Fe of 2 strata Sodium styrene sulfonate/HCPT obtained 3O 4Magnetic nano-particle;
The concentration of kayexalate is 1mg/ml in the NaCl aqueous solution of described kayexalate, and the concentration of NaCl is 0.5mol/L;
Six, repeating step five, then add in the 150mL deionized water, obtain the Fe of n+2 strata Sodium styrene sulfonate/HCPT 3O 4The magnetic nano-particle aqueous solution, wherein n is positive integer;
Seven, preparation Fe 3O 4-HCPT@SiO 2:
The 1mL ethyl orthosilicate is mixed with 30mL ethanol, obtain the alcoholic solution of ethyl orthosilicate, with 2.5mLNH 3H 2O, 38mLH 2The Fe of O, 38mL ethanol and 10mLn+2 strata Sodium styrene sulfonate/HCPT 3O 4Then the magnetic nano-particle aqueous solution adds the alcoholic solution of ethyl orthosilicate, reacted 4 hours, and magnetic separation, collecting precipitation, and the mixed solution of water and ethanol washing 3 times, redispersion obtains Fe in the 100mL deionized water 3O 4-HCPT@SiO 2Aqueous solution;
Eight, be centrifugal Fe under the condition of 10000rpm at rotating speed then 3O 4-HCPT@SiO 2Aqueous solution 30min removes supernatant, adds an amount of washing with alcohol, ultra-sonic dispersion 15-20min;
Nine, repeating step is 84 times, and obtaining concentration is 7.5mg/mLFe 3O 4-HCPT@SiO 2Alcoholic solution;
Ten, with 10mLFe 3O 4-HCPT@SiO 2Alcoholic solution and 0.03ml aminopropyltriethoxywerene werene stirred 3 hours under 80 ℃ condition, then according at rotating speed being centrifugal 30min under the condition of 10000rpm, in precipitation, add ethanol, the order of ultra-sonic dispersion 15-20min, repeat 5 times, obtain the Fe that surface amination is modified 3O 4-HCPT@SiO 2Solution;
11, preparation golden nanometer particle:
Adding 0.01ml concentration in the 40mL distilled water is that 0.25mol/L aqueous solution of chloraurate, 0.2mL concentration are that 0.2mol/L wet chemical, 0.6mL concentration are the 0.5mol/L sodium borohydride aqueous solution, 600rpm stirs 10min, add again the sodium borohydride aqueous solution that concentration is 0.5mol/L, until the bluish violet of solution becomes the orange red sodium borohydride aqueous solution that stops to add, restir 5min obtains solution of gold nanoparticles;
12, preparation strawberry shape gold nano compound particle:
Fe with the modification of 0.07ml surface amination 3O 4-HCPT@SiO 2Solution dilution is to 50ml, and then splashes in the solution of gold nanoparticles, then with the centrifugal 90min of the speed of 600rpm, obtains Au/SiO 2Solution;
13, preparation gold nanoshell:
The 25mg potassium carbonate is dissolved in the 100ml distilled water, and then the speed stirring 10min with 600rpm adds the aqueous solution of chloraurate that 1.5ml concentration is 0.25mol/L, continues to stir 30 minutes, gets mixed liquor, with 4ml mixed liquor and Au/SiO 2Solution mixes, and then with the centrifugal 30min of 5000rpm, and then is scattered in the 10mL water precipitation after centrifugal and ultrasonic 10min, obtains wrapping up the SiO of gold nanoshell 2The nanoparticle aqueous solution;
14, with 0.03g 1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 3ml oxolane join in the centrifuge tube, add the SiO that 4ml is wrapped up in gold nanoshell again 2Nanoparticle aqueous solution and 50mg Porphyrin-Based Sensitizer molecule reacted 72 hours, were under the condition of 6000rpm centrifugal 10 minutes at rotating speed after reaction finishes, collecting precipitation, and precipitation is dispersed in the methanol, obtain the Fe that concentration is 7.5mg/mL 3O 4-HCPT@SiO 2The Integral rice corpuscles of coupling Porphyrin-Based Sensitizer;
15, with 80mgFe 3O 4-HCPT@SiO 2Methanol solution, the 10mLN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg antitumor drug were stirring at room reaction 2 hours, then be that 14000rpm, temperature are centrifugal under 4 ℃ the condition at rotating speed, be dispersed in behind the collecting precipitation in the methanol, obtain the methanol solution of targeting composite nanoparticle;
Porphyrin-Based Sensitizer molecule described in the step 13 is tetrachloro acetoxyl group phenyl porphyrin;
Antitumor drug described in the step 14 is the monoclonal antibody Trastuzumab.

Claims (10)

1. the preparation method of targeting composite nanoparticle is characterized in that the preparation method of targeting composite nanoparticle is carried out according to following steps:
One, preparation magnetic nano-particle:
Be the FeCl of 1mol/L with 10ml concentration 3Aqueous solution, 2.5ml FeSO 47H 2The HCl solution of O joins the NH that 125ml concentration is 0.7mol/L 37H 2O continue to stir 30min, and centrifugalize is also collected product in the supernatant, and the product in the supernatant with deionized water wash 3 times, and then is dispersed in the 150ml deionized water, obtains Fe 3O 4Nano-particle solution;
Described FeSO 47H 2FeSO in the HCl solution of O 47H 2The concentration of O is that the concentration of 2mol/L, HCl is 2mol/L;
Two, preparation Fe 3O 4-HCPT nanoparticle:
With 10ml Fe 3O 4Nano-particle solution is distributed in the NaCl aqueous solution of the poly-hydrogen chloropropene amine of 10ml, ultrasonic reaction 30min, and then magnetic separation is the NaCl solution washing of 0.51mol/L with concentration, is dispersed in water at last, obtaining concentration is the Fe of the PAH-parcel of 7.5mg/ml 3O 4Nano-particle solution;
Poly-hydrogen chloropropene amine concentration is 1mg/ml in the NaCl aqueous solution of the poly-hydrogen chloropropene amine described in the step 2, and the concentration of NaCl is 0.5mol/L;
Three, the Fe that 10ml PAH-is wrapped up 3O 4Nano-particle solution is distributed to ultrasonic reaction 30min in the NaCl aqueous solution of 10ml polystyrolsulfon acid acid sodium, obtains Fe 3O 4The magnetic nano-particle precursor;
The concentration of kayexalate is 1mg/ml in the NaCl aqueous solution of the polystyrolsulfon acid acid sodium described in the step 3, and the concentration of NaCl is 0.5mol/L;
Four, the 364mg10-hydroxy camptothecin is dissolved in the 150ml NaOH solution, regulating pH value is 11, add concentration be the HCl of 1mol/L to regulate pH value be 4.8, obtain the HCPT microemulsion, with 10mlFe 3O 4The magnetic nano-particle precursor joins in the 10ml HCPT microemulsion, stirring is also passed through the uv absorption monitoring reaction, when the characteristic absorption peak of 10-hydroxycamptothecine disappears, stopped reaction, the magnetic separation collecting precipitation, and be 4.8 HCl solution washing with pH value, then add in the 150mL deionized water, obtain the Fe of kayexalate/HCPT 3O 4The magnetic nano-particle aqueous solution;
Five, preparation Fe 3O 4-HCPT@SiO 2:
The 1ml ethyl orthosilicate is mixed with 30ml ethanol, obtain the alcoholic solution of ethyl orthosilicate, with 2.5mLNH 3H 2O, 38mL H 2The Fe of O, 38mL ethanol and 10mL kayexalate/HCPT 3O 4Then the magnetic nano-particle aqueous solution adds the alcoholic solution of ethyl orthosilicate, reacted 4 hours, and magnetic separation, collecting precipitation, and the mixed solution of water and ethanol washing 3 times, redispersion obtains Fe in the 100ml deionized water 3O 4-HCPT@SiO 2Aqueous solution;
Six, be centrifugal Fe under the condition of 10000rpm at rotating speed then 3O 4-HCPT@SiO 2Aqueous solution 30min removes supernatant, adds washing with alcohol, ultra-sonic dispersion 15-20min;
Seven, repeating step is six 3-4 time, and obtaining concentration is 7.5mg/mLFe 3O 4-HCPT@SiO 2Alcoholic solution;
Eight, with 10ml Fe 3O 4-HCPT@SiO 2Alcoholic solution and 0.03ml aminopropyltriethoxywerene werene stirred 3 hours under 80 ℃ condition, then according at rotating speed being centrifugal 30min under the condition of 10000rpm, in precipitation, add ethanol, the order of ultra-sonic dispersion 15-20min, repeat 5 times, obtain the Fe that surface amination is modified 3O 4-HCPT@SiO 2Solution;
Nine, preparation golden nanometer particle:
Adding 0.01ml concentration in the 40ml distilled water is that 0.25mol/L aqueous solution of chloraurate, 0.2ml concentration are that 0.2mol/L wet chemical, 0.6ml concentration are the 0.5mol/L sodium borohydride aqueous solution, under the condition of 600rpm, stir 10min, add again the sodium borohydride aqueous solution that concentration is 0.5mol/L, until the bluish violet of solution becomes the orange red sodium borohydride aqueous solution that stops to add, restir 5min obtains solution of gold nanoparticles;
Ten, preparation strawberry shape gold nano compound particle:
Fe with the modification of 0.07ml surface amination 3O 4-HCPT@SiO 2Solution dilution is to 50ml, and then splashes in the solution of gold nanoparticles, then with the centrifugal 90min of the speed of 600rpm, obtains Au/SiO 2Solution;
11, preparation gold nanoshell:
The 25mg potassium carbonate is dissolved in the 100ml distilled water, and then the speed stirring 10min with 600rpm adds the aqueous solution of chloraurate that 1.5ml concentration is 0.25mol/L, continues to stir 30 minutes, gets mixed liquor, with 4ml mixed liquor and Au/SiO 2Solution mixes, and then with the centrifugal 30min of 5000rpm, and then is scattered in the 10ml water precipitation after centrifugal and ultrasonic 10min, obtains wrapping up the SiO of gold nanoshell 2The nanoparticle aqueous solution;
12, with 0.03g 1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 3～4ml oxolane join in the centrifuge tube, add the SiO that 1～5ml is wrapped up in gold nanoshell again 2Nanoparticle aqueous solution and 50mg Porphyrin-Based Sensitizer molecule reacted 72 hours, were under the condition of 6000rpm centrifugal 10 minutes at rotating speed after reaction finishes, collecting precipitation, and precipitation is dispersed in the methanol, obtain the Fe that concentration is 7.5mg/mL 3O 4-HCPT@SiO 2The methanol solution of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer;
13, with 50mg～100mg Fe 3O 4-HCPT@SiO 2The methanol solution of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, 10ml N, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours, then be that 14000rpm, temperature are centrifugal under 4 ℃ the condition at rotating speed, be dispersed in behind the collecting precipitation in the methanol, obtain the methanol solution of targeting composite nanoparticle;
Porphyrin-Based Sensitizer molecule described in the step 12 is 5-(4-chloroethene acyloxy phenyl)-10,15,20-three (4-carboxyl phenyl) porphyrin or tetrachloro acetoxyl group phenyl porphyrin;
Targeting biomolecule described in the step 13 is folic acid;
Antitumor drug described in the step 13 is monoclonal antibody Trastuzumab, paclitaxel, amycin, 5-fluorouracil or the cry of certain animals of first ammonia butterfly.
2. the preparation method of described targeting composite nanoparticle according to claim 1 is characterized in that in the step 12 that with 0.03g1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 3.5ml oxolane join in the centrifuge tube.
3. the preparation method of described targeting composite nanoparticle according to claim 1 is characterized in that in the step 13 60mg～90mg Fe 3O 4-HCPT@SiO 2Methanol solution, the 10mlN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.
4. the preparation method of described targeting composite nanoparticle according to claim 1 is characterized in that in the step 13 70mg～80mg Fe 3O 4-HCPT@SiO 2Methanol solution, the 10mlN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.
5. the preparation method of described targeting composite nanoparticle according to claim 1 is characterized in that in the step 13 75mgFe 3O 4-HCPT@SiO 2The methanol solution of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, 10ml DMF and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.
6. the preparation method of targeting composite nanoparticle is characterized in that the preparation method of targeting composite nanoparticle is carried out according to following steps:
One, preparation magnetic nano-particle:
Be the FeCl of 1mol/L with 10ml concentration 3Aqueous solution, 2.5ml FeSO 47H 2The HCl solution of O joins the NH that 125ml concentration is 0.7mol/L 37H 2O continue to stir 30min, and centrifugalize is also collected product in the supernatant, and the product in the supernatant with deionized water wash 3 times, and then is dispersed in the 150ml deionized water, obtains Fe 3O 4Nano-particle solution;
Described FeSO 47H 2FeSO in the HCl solution of O 47H 2The concentration of O is that the concentration of 2mol/L, HCl is 2mol/L;
Two, preparation Fe 3O 4-HCPT nanoparticle:
With 10mlFe 3O 4Nano-particle solution is distributed in the NaCl aqueous solution of the poly-hydrogen chloropropene amine of 10ml, ultrasonic reaction 30min, and then magnetic separation is the NaCl solution washing of 0.51mol/L with concentration, is dispersed in water at last, obtaining concentration is the Fe of the PAH-parcel of 7.5mg/ml 3O 4Nano-particle solution;
Poly-hydrogen chloropropene amine concentration is 1mg/ml in the NaCl aqueous solution of the poly-hydrogen chloropropene amine described in the step 2, and the concentration of NaCl is 0.5mol/L;
Three, the Fe that 10ml PAH-is wrapped up 3O 4Nano-particle solution is distributed to ultrasonic reaction 30min in the NaCl aqueous solution of 10ml kayexalate, obtains Fe 3O 4The magnetic nano-particle precursor;
The concentration of kayexalate is 1mg/ml in the NaCl aqueous solution of the kayexalate described in the step 3, and the concentration of NaCl is 0.5mol/L;
Four, the 364mg10-hydroxy camptothecin is dissolved in the 150ml NaOH solution, regulating pH value is 11, add concentration be the HCl of 1mol/L to regulate pH value be 4.8, obtain the HCPT microemulsion, with 10ml Fe 3O 4The magnetic nano-particle precursor joins in the 10ml HCPT microemulsion, and stirring is also passed through the uv absorption monitoring reaction, when the characteristic absorption peak of 10-hydroxycamptothecine disappears, stopped reaction, magnetic separation, and be 4.8 HCl solution washing with pH value, the Fe of kayexalate/HCPT obtained 3O 4Magnetic nano-particle;
Five, with the Fe of kayexalate/HCPT 3O 4Magnetic nano-particle is distributed in the 150ml deionized water, obtains the Fe of kayexalate/HCPT 3O 4The magnetic nano-particle dispersion liquid is with the Fe of 10ml kayexalate/HCPT 3O 4The magnetic nano-particle dispersion liquid is distributed to ultrasonic reaction 30min in the NaCl aqueous solution of 10ml kayexalate, Fe 3O 4Magnetic nano-particle precursor a;
The 364mg10-hydroxy camptothecin is dissolved in the 150ml NaOH solution, and regulating pH value is 11, add concentration be the HCl of 1mol/L to regulate pH value be 4.8, obtain the HCPT microemulsion, with 10ml Fe 3O 4Magnetic nano-particle precursor a joins in the 10ml HCPT microemulsion, and stirring is also passed through the uv absorption monitoring reaction, when the characteristic absorption peak of 10-hydroxycamptothecine disappears, stopped reaction, magnetic separation, and be 4.8 HCl solution washing with pH value, the Fe of 2 strata Sodium styrene sulfonate/HCPT obtained 3O 4Magnetic nano-particle;
The concentration of kayexalate is 1mg/ml in the NaCl aqueous solution of described kayexalate, and the concentration of NaCl is 0.5mol/L;
Six, repeating step five, then add in the 150mL deionized water, obtain the Fe of n+2 strata Sodium styrene sulfonate/HCPT 3O 4The magnetic nano-particle aqueous solution, wherein n is positive integer;
Seven, preparation Fe 3O 4-HCPT@SiO 2:
The 1ml ethyl orthosilicate is mixed with 30ml ethanol, obtain the alcoholic solution of ethyl orthosilicate, with 2.5mLNH 3H 2O, 38mL H 2The Fe of O, 38mL ethanol and 10mL n+2 strata Sodium styrene sulfonate/HCPT 3O 4Then the magnetic nano-particle aqueous solution adds the alcoholic solution of ethyl orthosilicate, reacted 4 hours, and magnetic separation, collecting precipitation, and the mixed solution of water and ethanol washing 3 times, redispersion obtains Fe in the 100ml deionized water 3O 4-HCPT@SiO 2Aqueous solution;
Eight, be centrifugal Fe under the condition of 10000rpm at rotating speed then 3O 4-HCPT@SiO 2Aqueous solution 30min removes supernatant, adds an amount of washing with alcohol, ultra-sonic dispersion 15-20min;
Nine, repeating step is eight 3-4 time, and obtaining concentration is 7.5mg/mL Fe 3O 4-HCPT@SiO 2Alcoholic solution;
Ten, with 10ml Fe 3O 4-HCPT@SiO 2Alcoholic solution and 0.03ml aminopropyltriethoxywerene werene stirred 3 hours under 80 ℃ condition, then according at rotating speed being centrifugal 30min under the condition of 10000rpm, in precipitation, add ethanol, the order of ultra-sonic dispersion 15-20min, repeat 5 times, obtain the Fe that surface amination is modified 3O 4-HCPT@SiO 2Solution;
11, preparation golden nanometer particle:
Adding 0.01ml concentration in the 40ml distilled water is that 0.25mol/L aqueous solution of chloraurate, 0.2ml concentration are that 0.2mol/L wet chemical, 0.6ml concentration are the 0.5mol/L sodium borohydride aqueous solution, 600rpm stirs 10min, add again the sodium borohydride aqueous solution that concentration is 0.5mol/L, until the bluish violet of solution becomes the orange red sodium borohydride aqueous solution that stops to add, restir 5min obtains solution of gold nanoparticles;
12, preparation strawberry shape gold nano compound particle:
Fe with the modification of 0.07ml surface amination 3O 4-HCPT@SiO 2Solution dilution is to 50ml, and then splashes in the solution of gold nanoparticles, then with the centrifugal 90min of the speed of 600rpm, obtains Au/SiO 2Solution;
13, preparation gold nanoshell:
The 25mg potassium carbonate is dissolved in the 100ml distilled water, and then the speed stirring 10min with 600rpm adds the aqueous solution of chloraurate that 1.5ml concentration is 0.25mol/L, continues to stir 30 minutes, gets mixed liquor, with 4ml mixed liquor and Au/SiO 2Solution mixes, and then with the centrifugal 30min of 5000rpm, and then is scattered in the 10ml water precipitation after centrifugal and ultrasonic 10min, obtains wrapping up the SiO of gold nanoshell 2The nanoparticle aqueous solution;
14, with 0.03g 1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 3～4ml oxolane join in the centrifuge tube, add the SiO that 1～5ml is wrapped up in gold nanoshell again 2Nanoparticle aqueous solution and 50mg Porphyrin-Based Sensitizer molecule, reacted 72 hours, it is under the condition of 6000rpm centrifugal 10 minutes at rotating speed after reaction finishes, collecting precipitation, and precipitation is dispersed in the methanol, obtaining concentration is the Integral rice corpuscles of the Fe3O4-HCPT@SiO2 coupling Porphyrin-Based Sensitizer of 7.5mg/mL;
15, with 50mg～100mg Fe 3O 4-HCPT@SiO 2The methanol solution of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, 10ml N, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours, then be that 14000rpm, temperature are centrifugal under 4 ℃ the condition at rotating speed, be dispersed in behind the collecting precipitation in the methanol, obtain the methanol solution of targeting composite nanoparticle;
Porphyrin-Based Sensitizer molecule described in the step 13 is 5-(4-chloroethene acyloxy phenyl)-10,15,20-three (4-carboxyl phenyl) porphyrin or tetrachloro acetoxyl group phenyl porphyrin;
Targeting biomolecule described in the step 14 is folic acid;
Antitumor drug described in the step 14 is monoclonal antibody Trastuzumab, paclitaxel, amycin, 5-fluorouracil or the cry of certain animals of first ammonia butterfly.
7. the preparation method of described targeting composite nanoparticle according to claim 6 is characterized in that in the step 14 that with 0.03g1,2-dimercapto-3-cyclohexyl Polyethylene Glycol and 3.5ml oxolane join in the centrifuge tube.
8. the preparation method of described targeting composite nanoparticle according to claim 6 is characterized in that in the step 15 60mg～90mg Fe 3O 4-HCPT@SiO 2Methanol solution, the 10mlN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.
9. the preparation method of described targeting composite nanoparticle according to claim 6 is characterized in that in the step 15 70mg～80mg Fe 3O 4-HCPT@SiO 2Methanol solution, the 10mlN of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, dinethylformamide and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.
10. the preparation method of described targeting composite nanoparticle according to claim 6 is characterized in that in the step 15 75mgFe 3O 4-HCPT@SiO 2The methanol solution of the Integral rice corpuscles of coupling Porphyrin-Based Sensitizer, 10ml DMF and 50mg targeting biomolecule or antitumor drug were stirring at room reaction 2 hours.
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