CN102172410B - Construction method of targeted nano particle transmission system for cancer diagnosis and treatment - Google Patents
Construction method of targeted nano particle transmission system for cancer diagnosis and treatment Download PDFInfo
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Abstract
本发明公开了用于癌症诊断与治疗的靶向纳米粒传输系统的构建方法。以单链抗体为介导构建载超顺磁性四氧化三铁和抗肿瘤药物的纳米粒传输系统，靶向给药，向全身传递抗肿瘤药物至靶部位来治疗癌症，利用抗体-抗原高特异性结合作用识别靶点，可使药物在体内传输具有主动靶向性，既可提高药效，又可减少药物对正常组织的毒副作用；同时该系统还可作为核磁共振成像技术造影剂以提高实时监测靶部位肿瘤变化情况的准确性。The invention discloses a construction method of a targeted nanoparticle delivery system for cancer diagnosis and treatment. A nanoparticle delivery system loaded with superparamagnetic ferroferric oxide and anti-tumor drugs is mediated by a single-chain antibody, targeted drug delivery, and anti-tumor drugs are delivered to the target site throughout the body to treat cancer, using antibody-antigen high specificity Target recognition through sexual binding can make the drug delivery in the body have active targeting, which can not only improve the efficacy of the drug, but also reduce the side effects of the drug on normal tissues; at the same time, the system can also be used as a contrast agent for MRI technology to improve The accuracy of real-time monitoring of tumor changes at the target site.
Description
Technical field
The NMR (Nuclear Magnetic Resonance)-imaging that the invention belongs to antitumor drug transmission, cancer (is called for short: MRI) Clinics and Practices and molecular targeted field.Relate to the construction method for the targeted nano granule transmission system of cancer diagnosis and treatment, relate to the construction method that the single-chain antibody targeting carries the nanoparticle transmission system of superparamagnetism ferroso-ferric oxide and antitumor drug particularly.
Background technology
Nanoparticle pharmaceutical preparation has the dissolubility that improves insoluble medicine, prolong drug action time, improve bioavailability, change and improve the advantages such as kinetic property of medicine, become one of important directions of medicine and pharmacology area research in recent years.Generally speaking, the nano-particle of surface modification does not enter blood circulation, most of by the macrophage phagocytic in the monokaryon macrophage system, medicine is enriched in the organs such as liver, spleen and lung, particle diameter then easily enters bone marrow less than the nanoparticle of 50nm, these organs and tissue are the natural target organs of drug-carrying nanometer particle, can utilize the phagocytosis of macrophage to reach the purpose of passive target administration.But, for other tissue or organ, owing to only have the small part nano-particle to enter through the big blood vessel of permeability, this medicament-carried nano granule life period in blood circulation is short in addition, the medication amount that infiltrates through tissue is few, is difficult to the effective treatment concentration that reaches required.Therefore, the specificity effect of development and use antibody, surface of cell membrane receptor or specific gene fragment, ligand is combined on the carrier, carrying out specificity with the antigenicity evaluator on target cell surface under the effect of promoter is combined, medicine can accurately be delivered in the target cell, realize that initiatively targeted therapy is one of trend of modern targeting preparation development.
Imaging diagnosis has consequence in the early diagnosis and therapy monitoring of cancer.Wherein, MRI is with respect to the pneumoradiography technology, and is radiationless; With respect to the supersonic sounding technology, its imaging is more clear, the resolution height; Therefore follow up a case by regular visits to for the formulation of assessment, operation plan before cancer patient's the art and postoperative and have great importance.The chelate that is extensive use of gadolinium at present clinically strengthens contrast agent as MRI, but, such contrast agent is not high to the sensitivity of infantile tumour and micrometastasis diagnosis, can not accurately distinguish the boundary of tumor and normal structure, and can increase the Fibrotic risk of kidney systematicness, therefore develop new MRI and strengthen contrast agent to improve MRI significant for the diagnostic accuracy of early-stage cancer and micrometastasis thereof.Along with the development of modern medicine, the targeting spike becomes the new technique of effective diagnosis infantile tumour in the body.Utilize magnetic nanometer particles surface combination affinity molecules such as monoclonal antibody, can provide targeting for tumor cell.Therefore making up for the cancer diagnosis of targeting spike in the body and the targeted nano granule transmission system for the treatment of is one of recent tendency of modern cancer diagnosis treatment.
Summary of the invention
The construction method that the purpose of this invention is to provide a kind of targeted nano granule transmission system of cancer MRI Clinics and Practices.Utilize and make up the nanoparticle transmission system that a kind of single-chain antibody targeting carries superparamagnetism ferroso-ferric oxide and antitumor drug, be used for transmitting in the body antitumor drug to target site and treat cancer, and the accuracy that improves real-time monitoring tumor situation of change as MRI technology contrast agent.
Purpose of the present invention is achieved through the following technical solutions:
Be used for the construction method of the targeted nano granule transmission system of cancer diagnosis and treatment, may further comprise the steps:
(1) utilizes the double-stranded antibody of mercaptoethylmaine cracking, obtain to have the single-chain antibody of free sulfhydryl groups;
(2) preparation of the polyethyleneglycol modified single-chain antibody of alpha-amido: above-mentioned single-chain antibody with free sulfhydryl groups is mixed the back hatch 12h with the PBS buffer that contains alpha-amido-ω-maleimide Polyethylene Glycol and EDTA at 4 ℃, obtain the polyethyleneglycol modified single-chain antibody of alpha-amido behind the desalting column purification;
(3) preparation of the nanoparticle of carrying anti-tumor medicine and super-paramagnetic ferriferrous oxide: take by weighing 5～15mg antitumor drug and 20mg super-paramagnetic ferriferrous oxide, be dissolved in the dichloromethane, mixing 1h; Poly-(lactic-co-glycolic acid) copolymer of the end carboxyl of 100mg is dissolved in wherein, under ultrasound condition, adds in the polyvinyl alcohol water solution of mass fraction 2%; Fling to organic solvent, centrifugal, ultrafiltration is washed 3～5 times, and lyophilization gets the nanoparticle of carrying anti-tumor medicine and super-paramagnetic ferriferrous oxide;
(4) preparation of targeted nano granule transmission system: the nanoparticle that step (3) is made is dispersed in the water, adds N-hydroxy-succinamide and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, hatches 2h; Add the polyethyleneglycol modified single-chain antibody of alpha-amido that step (2) makes, hatch 12h for 4 ℃; It is centrifugal., obtain the targeted nano granule transmission system for cancer diagnosis and treatment behind the desalting column purification.
The double-stranded antibody of mercaptoethylmaine cracking that utilizes of the present invention may further comprise the steps: the double-stranded antibody of 10 μ g is joined in the EDTA solution of 10 μ L0.5mol/L; The 60mg mercaptoethylmaine is dissolved in 0.5mL contains in the PBS buffer of 10 μ L 0.5mol/L EDTA, hatch 15min for 4 ℃, obtain mercaptoethylmaine solution; Above-mentioned mercaptoethylmaine solution is joined in the solution that step (1) obtains, hatch 1.5h for 37 ℃; The desalting column purification is removed excessive mercaptoethylmaine.
In the step of the present invention (1), described double-stranded antibody is anti-epidermal growth factor receptor antibody, immunoglobulin g antibody, vascular endothelial growth factor receptor antibody or cell surface antigen antibody.
In the step of the present invention (3), described centrifugal rotation speed is 2500rpm, and the rotating speed of ultrafiltration is 6000rpm.
In the step of the present invention (3), described antitumor drug is paclitaxel or Docetaxel.
In the step of the present invention (3), described super-paramagnetic ferriferrous oxide is the nano ferriferrous oxide granule of oleic acid or oleyl amine modification, and particle diameter is 6～12nm, and the magnetic saturation intensity value is 50～90emu/g under the 300K.
Super-paramagnetic ferriferrous oxide of the present invention is the nano ferriferrous oxide granule of oleic acid or oleyl amine modification, and particle diameter is 6～12nm, and the magnetic saturation intensity value is 50～90emu/g under the 300K.
The preparation of the nano ferriferrous oxide granule of oleic acid of the present invention or oleyl amine modification is with reference to following document: Sun S, Zeng H, Robinson DB, Raoux S, Rice PM, Wang SX, Li G., Monodisperse MFe
2O
4(M=Fe, Co, Mn) Nanoparticles, Journal of the American Chemical Society, 2004,126:273-279.Specifically may further comprise the steps:
(1) with 2mmol ferric acetyl acetonade, 10mmol 1,2-hexadecane glycol, 6mmol oleic acid and 6mmol oleyl amine add in three mouthfuls of reaction bulbs, after the dissolving of adding 20ml benzyl ether, are heated to 200 ℃ of stirring 2h that reflux in sand-bath under the nitrogen protection;
(2) be heated to 300 ℃ of backflow 1h, reaction system is removed thermal source, natural cooling after becoming black by kermesinus;
(3) above-mentioned reactant is deposited in the 80ml ethanol, under the 10000rpm rotating speed centrifugal 5 minutes, discard the supernatant, lower sediment is dissolved in the 35ml normal hexane that is added with 0.5ml oleic acid and oleyl amine respectively; Under the 10000rpm rotating speed centrifugal 10 minutes, remove and do not dissolve part, the solution redeposition is in 100ml ethanol; Under the 10000rpm rotating speed centrifugal 10 minutes, get lower sediment and be nano ferriferrous oxide, place 4 ℃ to preserve standby down.
The present invention compared with prior art has following beneficial effect:
1. utilize macromolecules such as functional poly (lactic-co-glycolic acid) copolymer, polyvinyl alcohol derivative as carrier material, have excellent biological compatibility, the gentle release rerum natura energy of degradability;
2. with single-chain antibody decorated nanometer grain, can will wrap the nanoparticle specificity target goal target spot of carrying anti-tumor medicine and magnetic-particle, thereby improve the targeting of nanoparticulate carriers, increase bioavailability of medicament, reduce the whole body toxic and side effects;
3. nanoparticle carries the superparamagnetism ferroferric oxide nano granules and can be used as MRI technology contrast agent, improves the imaging and real-time monitoring accuracy of tumor locus.
Description of drawings
Fig. 1 is the antitumor drug release profiles of embodiment 1 prepared nanoparticle transmission system.
Fig. 2 is that the cell of embodiment 2 prepared nanoparticle transmission systems absorbs back MRI imaging T2 weighted graph, and a, b are respectively cell and absorb after the nanoparticle transmission system and the weighted signal of the T2 of blank cell.
Fig. 3 is the laser co-focusing photo after the tumor cell of embodiment 2 prepared nanoparticle transmission systems absorbs, and nanoparticle transmission system bag carries green fluorescence dyestuff coumarin as spike, and tumor cell is examined the position with the blue fluorescent dyes transfect cell.
Fig. 4 is the laser co-focusing photo after the tumor cell of common nanoparticle absorbs, and nanoparticle transmission system bag carries green fluorescence dyestuff coumarin as spike, and tumor cell is examined the position with the blue fluorescent dyes transfect cell.
The specific embodiment
Below in conjunction with accompanying drawing the specific embodiment of the present invention is described further, but embodiments of the present invention are not limited thereto.
Embodiment 1
(1) double-stranded antibody cracking prepares single-chain antibody: (be called for short: monoclonal antibody ICAM-1) (is called for short: Ab with adhesion molecule-1 between the capillary endothelial cell superficial cell of 20 μ L
ICAM-1, 0.5mg/ml, molecular weight: 95kDa) join in the EDTA solution of 10 μ L 0.5mol/L; The 60mg mercaptoethylmaine is dissolved in 0.5mL contains in the PBS buffer of 10 μ L 0.5mol/L EDTA, 4 ℃ of pre-coolings are hatched and are handled 15min; Mercaptoethylmaine solution is joined Ab
ICAM-1In the solution, hatch 1.5h for 37 ℃; (model: PD-10 Desalting Columns, GE Healthcare MWCO=5000Da) removes excessive mercaptoethylmaine with desalting column.
(2) preparation of the polyethyleneglycol modified single-chain antibody of alpha-amido: will contain alpha-amido-ω-maleimide Polyethylene Glycol and (be called for short: mal-PEG-NH
2) and the PBS buffer of 10 μ L 0.5mol/L EDTA pre-cooling 15 minutes to 4 ℃ in refrigerator earlier, to wherein adding single-chain antibody that step (1) obtains and mixed, hatch 12h at 4 ℃; Getting adhesion molecule-1 strand monoclonal antibody between the polyethyleneglycol modified capillary endothelial cell superficial cell of alpha-amido with the desalting column purification (is called for short: NH
2-PEG-scAb
ICAM-1).
(3) preparation of the PLGA nanoparticle of carrying anti-tumor medicine and super-paramagnetic ferriferrous oxide: the antitumor drug paclitaxel that accurately takes by weighing 10mg (is called for short: PTX) (be called for short: USPIO) with the 20mg super-paramagnetic ferriferrous oxide, be dissolved in the 4ml dichloromethane, mixing is hatched 1h; Taking by weighing poly-(lactic-co-glycolic acid) copolymer of 100mg end carboxyl (is called for short: PLGA-COOH, LA: GA=50: 50) be dissolved in wherein, under ultrasound condition, splash in the polyvinyl alcohol water solution of 100ml mass fraction 2%; Fling to organic solvent, with the centrifugal removal large granular impurity of 2500rpm, with the centrifugal removal polyvinyl alcohol of the ultrafiltration of 6000rpm molecular cut off 3500, wash 3～5 times, lyophilization, the nanoparticle that must carry paclitaxel and ferroso-ferric oxide (is called for short: USPIO-PTX-PLGA-COOH).
(4) preparation of targeted nano granule transmission system: take by weighing the nanoparticle that 10mg above-mentioned steps (3) makes and be dispersed in the water, add 10 μ g N-hydroxy-succinamides and 10 μ g 1-ethyls-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, incubated at room 2h; Add the NH that step (2) makes
2-PEG-scAb
ICAM-1, hatch 12h for 4 ℃, centrifugal removal impurity gets the nanoparticle transmission system (abbreviation: USPIO-PTX-PLGA-PEG-scAb that the single-chain antibody targeting carries superparamagnetism ferroso-ferric oxide and antitumor drug behind the desalting column purification
ICAM-1).
Fig. 1 shows that the nanoparticle transmission system that makes up by the present invention has the excellent drug slow release effect, does not have that obvious initial stage medicine is prominent to be released, and slow-release time reaches 800h.
Embodiment 2
(1) double-stranded antibody cracking prepares single-chain antibody: the carcinoma of prostate stem cell antigen of 50 μ L (is called for short: (the abbreviation: Ab of monoclonal antibody PSCA)
PSCA, 0.2mg/ml, molecular weight: 29kDa) join in the EDTA solution of 10 μ L 0.5mol/L; The 60mg mercaptoethylmaine is dissolved in 0.5mL contains in the PBS buffer of 10 μ L 0.5mol/L EDTA, 4 ℃ of pre-coolings are hatched and are handled 15min; Mercaptoethylmaine solution is joined Ab
PSCAIn the solution, hatch 1.5h for 37 ℃; (model: PD-10 Desalting Columns, GE Healthcare MWCO=5000Da) removes excessive mercaptoethylmaine with desalting column.
(2) preparation of the polyethyleneglycol modified single-chain antibody of alpha-amido: will contain alpha-amido-ω-maleimide Polyethylene Glycol and (be called for short: mal-PEG-NH
2) and the PBS buffer of 10 μ L 0.5mol/L EDTA pre-cooling 15 minutes to 4 ℃ in refrigerator earlier, to wherein adding single-chain antibody that step (1) obtains and mixed, hatch 12h at 4 ℃; Getting the polyethyleneglycol modified carcinoma of prostate stem cell antigen strand monoclonal antibody of alpha-amido with the desalting column purification (is called for short: NH
2-PEG-scAb
PSCA).
(3) preparation of the PLGA nanoparticle of carrying anti-tumor medicine and super-paramagnetic ferriferrous oxide: the antitumor drug Docetaxel that accurately takes by weighing 10mg (is called for short: DTX) (be called for short: USPIO) with the 20mg super-paramagnetic ferriferrous oxide, be dissolved in the 4ml dichloromethane, mixing is hatched 1h; Taking by weighing poly-(lactic-co-glycolic acid) copolymer of 100mg end carboxyl (is called for short: PLGA-COOH, LA: GA=50: 50) be dissolved in wherein, under ultrasound condition, splash in the polyvinyl alcohol water solution of 100ml mass fraction 2%; Fling to organic solvent, with the centrifugal removal large granular impurity of 2500rpm, with the centrifugal removal polyvinyl alcohol of the ultrafiltration of 6000rpm molecular cut off 3500, wash 3～5 times, lyophilization, the nanoparticle that must carry paclitaxel and ferroso-ferric oxide (is called for short: USPIO-DTX-PLGA-COOH).
(4) preparation of targeted nano granule transmission system: take by weighing the nanoparticle that 10mg above-mentioned steps (3) makes and be dispersed in the water, add 10 μ g N-hydroxy-succinamides and 10 μ g 1-ethyls-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, incubated at room 2h; Add the NH that step (2) makes
2-PEG-scAb
PSCA, hatch 12h for 4 ℃, centrifugal removal impurity gets the nanoparticle transmission system (abbreviation: USPIO-DTX-PLGA-PEG-scAb that the single-chain antibody targeting carries superparamagnetism ferroso-ferric oxide and antitumor drug behind the desalting column purification
PSCA).
Fig. 2 shows, MRI imaging T2 weighted signal intensity obviously weakened after cell absorbed the nanoparticle transmission system, it is more black that image becomes, signal contrast significantly strengthens, and as seen the nanoparticle transmission system that makes up by the present invention can improve the imaging and real-time monitoring accuracy of tumor locus as the MRI contrast agent.
Fig. 3 and Fig. 4 show, compare with common nanoparticle, and the nanoparticle transmission system that makes up by the present invention has higher targeting.
Embodiment 3
(1) double-stranded antibody cracking prepares single-chain antibody: the bevacizumab of 10 μ L (is called for short: (the abbreviation: Ab of monoclonal antibody Avastin)
Avastin, 1mg/ml, molecular weight: 149kDa) join in the EDTA solution of 10 μ L 0.5mol/L; The 60mg mercaptoethylmaine is dissolved in 0.5mL contains in the PBS buffer of 10 μ L 0.5mol/L EDTA, 4 ℃ of pre-coolings are hatched and are handled 15min; Mercaptoethylmaine solution is joined Ab
AvastinIn the solution, hatch 1.5h for 37 ℃; (model: PD-10Desalting Columns, GE Healthcare MWCO=5000Da) removes excessive mercaptoethylmaine with desalting column.
(2) preparation of the polyethyleneglycol modified single-chain antibody of alpha-amido: will contain alpha-amido-ω-maleimide Polyethylene Glycol and (be called for short: mal-PEG-NH
2) and the PBS buffer of 10 μ L 0.5mol/L EDTA pre-cooling 15 minutes to 4 ℃ in refrigerator earlier, to wherein adding single-chain antibody that step (1) obtains and mixed, hatch 12h at 4 ℃; Getting the polyethyleneglycol modified carcinoma of prostate stem cell antigen strand monoclonal antibody of alpha-amido with the desalting column purification (is called for short: NH
2-PEG-scAb
Avastin).
(3) preparation of the PLGA nanoparticle of carrying anti-tumor medicine and super-paramagnetic ferriferrous oxide: the antitumor drug Docetaxel that accurately takes by weighing 15mg (is called for short: DTX) (be called for short: USPIO) with the 20mg super-paramagnetic ferriferrous oxide, be dissolved in the 4ml dichloromethane, mixing is hatched 1h; Taking by weighing poly-(lactic-co-glycolic acid) copolymer of 100mg end carboxyl (is called for short: PLGA-COOH, LA: GA=50: 50) be dissolved in wherein, under ultrasound condition, splash in the polyvinyl alcohol water solution of 100ml mass fraction 2%; Fling to organic solvent, with the centrifugal removal large granular impurity of 2500rpm, with the centrifugal removal polyvinyl alcohol of the ultrafiltration of 6000rpm molecular cut off 3500, wash 3～5 times, lyophilization, the nanoparticle that must carry paclitaxel and ferroso-ferric oxide (is called for short: USPIO-DTX-PLGA-COOH).
(4) preparation of targeted nano granule transmission system: take by weighing the nanoparticle that 10mg above-mentioned steps (3) makes and be dispersed in the water, add 10 μ g N-hydroxy-succinamides and 10 μ g 1-ethyls-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, incubated at room 2h; Add the NH that step (2) makes
2-PEG-scAb
Avastin, hatch 12h for 4 ℃, centrifugal removal impurity gets the nanoparticle transmission system (abbreviation: USPIO-DTX-PLGA-PEG-scAb that the single-chain antibody targeting carries superparamagnetism ferroso-ferric oxide and antitumor drug behind the desalting column purification
Avastin).
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| CN103520728B (en) * | 2013-10-25 | 2015-10-07 | 扬州大学 | The preparation method of arsenic trioxide invisible immunity targeting anti-tumor preparation |
| EP3373921B1 (en) | 2015-11-13 | 2019-08-28 | The University of Massachusetts | Bifunctional molecules containing peg for use in inhibiting cataracts and presbyopia |
| CN105727320B (en) * | 2016-01-30 | 2018-10-19 | 山西大学 | Detect the Targeted nanobubble and its preparation method and application of Small Cell Lung Cancer |
| CN108732151B (en) * | 2018-05-31 | 2021-01-19 | 华南理工大学 | Preparation of luminescent gold nanoparticles with high-sensitivity optical response to volatile amine and rapid analysis and detection method thereof |
| CN109364270B (en) * | 2018-10-25 | 2021-10-08 | 中国科学院过程工程研究所 | A kind of nuclear magnetic contrast agent with oligomer specificity and its preparation method and application |
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| WO2010120385A1 (en) * | 2009-04-18 | 2010-10-21 | Massachusetts Institute Of Technology | pH SENSITIVE BIODEGRADABLE POLYMERIC PARTICLES FOR DRUG DELIVERY |
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