CN103845743A - Gold particle-loaded silica multi-mode contrast agent and high intensity focused ultrasound (HIFU) synergist - Google Patents
Gold particle-loaded silica multi-mode contrast agent and high intensity focused ultrasound (HIFU) synergist Download PDFInfo
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- CN103845743A CN103845743A CN201210518109.5A CN201210518109A CN103845743A CN 103845743 A CN103845743 A CN 103845743A CN 201210518109 A CN201210518109 A CN 201210518109A CN 103845743 A CN103845743 A CN 103845743A
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Abstract
The invention relates to a gold particle-loaded mesoporous silica nanocapsule multi-mode contrast agent, which can be used for strengthening drug release, and used as an ultrasonic contrast agent and a high intensity focused ultrasound (HIFU) synergist and an HIFU synergist and a preparation method of the contrast agent. The multi-mode contrast agent and the HIFU synergist comprise mesoporous silica nanoparticle capsules which modified by polyethylene glycol on surfaces and beneficiated by gold nanoparticles, and guest molecules loaded to the mesoporous silica nanoparticle capsules for HIFU synergism.
Description
Technical field
The present invention relates to technical field of nano material, be particularly related to medical nano technical field of biological materials, be specifically related to a kind of mesoporous silicon dioxide nano capsule base hybrid material that is also used as the golden nanometer particle load that strengthens drug release, acoustic contrast agent and HIFU synergist and preparation method thereof.
Background technology
Tumor is the major disease of serious threat people's life health, and its M & M is lasting ascendant trend, within 2008, accounts for the more than 27.12% of the lethal total number of persons of disease (China Statistical Yearbook, 2009).In the past, played huge effect in the now struggle of the mankind and tumor, but toxic and side effects also can not be ignored for operation, radiation and chemotherapy.Although it is traumatic that the part malignant tumor such as image-guided lower radio frequency, microwave ablation of liver cancer have reduced, still need percutaneous to insert active antenna or electrode.Development energy specificity, targeting are killed tumor, and normal tissue and body impact are very little, and even noninvasive tumor therapeuticing method is the important directions of medical development.Wherein the non-invasive therapy method that provides can vernier focusing treatment tumor but there is no skin incision is provided for high intensity focused ultrasound (HIFU), and supersonic melting treatment tumor, side effect will significantly decline (" natural news " (" Nature News "), 2004, February 17).
The features such as focused ultrasound therapy is radiationless because having, noinvasive (retain organ and limbs), Partial tumors can outpatient operations, equipment Market and medical market have a extensive future, cause that in the world the medical apparatus and instruments giants such as many national government, colleges and universities, scientific research institution and GE, Siemens (Siemens), Philip (Philips) pay close attention to, and continued to increase scientific research and drop into.The U.S. set up the project specially and encouraged to carry out " comparative study that Noninvasive focus supersonic technology and other have wound, minimally-invasive treatment technology " in March, 2009.At the end of the nineties in last century, China takes the lead in focus supersonic, for clinical treatment hepatocarcinoma, breast carcinoma, renal carcinoma, bone tumor, showing good effectiveness and safety (" natural cancer summary " (" Nature ReviewsCancer "), 2005,5,321).Focus supersonic has formed vigorous growth trend aspect oncotherapy.
But, effectively strengthen the contrast agent of guiding imaging and the synergist that potentiation is melted owing to lacking, it is still lower to the space/temporal resolution of imaging of tissue, can not meet the diagnosis of some early stage diseases, and tumour ablation efficiency is lower, its application is still subject to larger restriction.
The contrast agent of research mainly concentrates on the microvesicle that adopts polymer or alicyclic organic plastid etc. to wrap up temperature sensitive type fluorocarbons both at home and abroad at present, it is due to the short combination that affects targeting substance and receptor of poor stability retention time in blood vessel, and particle diameter is large (mostly being micron order), and the granule that the blood vessel endothelium gap of tumor locus allows diameter to be less than 700nm at the most passes (" American Academy of Sciences's progress " (" Proc.Natl.Acad Sci USA "), 1998, 95, 4607), therefore microbubble contrast agent can not penetration rate of blood endothelial tube gap, belong to blood pool imaging, them are limited to blood vessel Clinics and Practices (" ultrasonics " (" Ultrasonics ") of disease outward, 2004, 42, 343), the synergist melting for HIFU is especially due to the emerging and scarcity of HIFU equipment, and its research only limits to adopt organic microbubble contrast agent (Sono Vue etc.) of current commercialization to reduce HIFU to melt the time, strengthens and melt efficiency to improve treatment safety.Therefore, find stable, efficient, nanometer HIFU and become the important research direction in molecular imaging field with the shared contrast agent/synergist of HIFU coupling (CT, MRI, ultrasonic), also become clinical diagnosis and disease treatment in the urgent need to.
Nanometer biotechnology is forward position and the study hotspot problem in International Biotechnology field, has great using value and industrialization prospect at human health, pharmaceutical sanitary field.Particle diameter causes that to regulating and controlling nano-contrast agent in hundreds of nanometer range people pay close attention to (" German applied chemistry magazine " (" Angew.Chem.Int.Ed. ") greatly tens in recent years, 2003,42,3218), it can pass through blood vessel endothelium gap, and the limitation of ultrasonoscopy in blood pond only can occur microvesicle class contrast agent/synergist, thereby greatly improve the early diagnosis ability to the outer pathological tissues of blood vessel.Wherein of paramount importance is meso-porous nano material, such as mesoporous silicon oxide hollow nano-material have huge cavity nanostructured, high-specific surface area, large pore volume, can load guest molecule and can be used for the association areas such as adsorbent, catalyst carrier and pharmaceutical carrier.
Mesopore silicon dioxide nano material is rarely had to report (" advanced material " (" Adv.Mater. "), 2009,21,3949) in the application in ultrasonic image-guided lower HIFU potentiation treatment field both at home and abroad at present.Inventor has studied the mesoporous nano silicon dioxide capsule material of this particle diameter 300nm thin-walled with meso-hole structure for ultrasonic response, result shows that itself just has certain ultrasonic potentiation (" materials chemistry magazine " (" J.Mater.Chem. ") for ultrasonic, 2012,22,12553).The bigger serface simultaneously having in conjunction with itself, high pore capacities, good modifiability, excellent chemistry and heat stability, large kernel cavity volume and shell mesopore orbit, the good advantage such as biocompatibility and degradability (" nanometer wall bulletin " (" Nano Lett. "), 2003,3,609; " biomaterial " (" Biomaterials "), 2010,31,1085), load temperature sensitive fluorocarbons (perflexane), under ultrasonic effect, temperature sensitive fluorocarbons is vaporized into a large amount of bubbles, strengthen the ablation (" German applied chemistry magazine " of ultra sonic imaging and potentiation HIFU, 2011,50,12505; " advanced material ", 2012,6,785).
This research still belongs to the starting stage, relevant inorganic SiO
2the biological effect of nanometer acoustic contrast agent and and ultrasonic between interaction mechanism also do not relate to.Ultra sonic imaging be multi-functional a, Noninvasive, low-risk, at a low price, portable Real Time Imaging Technology, be one of most widely used imaging technique in the world at present.But owing to lacking effective contrast agent, it is still lower to the space/temporal resolution of imaging of tissue, can not meet the diagnosis of some early stage diseases, its application is still subject to larger restriction.Simultaneously because nanoscale material own is smaller for ultrasonic response, radiography weak effect, therefore loads the SiO of fluorocarbons
2the ultra sonic imaging performance of composite Nano capsule material needs further to improve, and under multi-modal imaging guiding, more efficient HIFU potentiation treatment research have not been reported, and more can seek without Patents, needs further research.
Summary of the invention
In the face of the problems referred to above of prior art existence, the inventor is through research with keen determination, on the basis of the compound acoustic contrast agent of novel organic-inorganic and the development of HIFU synergist, modify grafting function nano particle by chemical bonding method, improve ultra sonic imaging performance and realize the potentiation HIFU ablation under multi-modal imaging guiding, effectively improve safety and effectiveness in HIFU therapeutic process.
The inventor recognizes and can carry out surface modification to mesoporous silicon dioxide nano capsule material, make its surface with sulfydryl isoreactivity functional group, then one-step method reduction gold seeds, by sulfur-aurification abundant nanogold particle (2-4nm) on Nano capsule surface graft.
Simultaneously, can also carry out amino isoreactivity functional group modification to mesoporous silicon dioxide nano capsule material, prepare carboxy-modified gold nano grain (10nm) by citrate reducing process, then by amide reactive chemistry abundant nanogold particle on Nano capsule surface graft.
In addition, the inventor also recognizes that meso-porous nano material is owing to having large cavity structure (hollow ball), can load a large amount of guest molecule (fluorocarbons, close hydrophobic anticancer drug), is expected to the Synergistic treatment pattern for HIFU potentiation treatment and chemotherapy.
Finally, the capsule surface of nanometer gold load being carried out to finishing (poly-diethanol, hyaluronic acid and lipoid molecule) connection can increase its dispersibility and then can increase its ultra sonic imaging effect.
At this, the invention provides a kind of silicon-dioxide-substrate multi-mode contrast agent and HIFU synergist of golden nanometer particle load, it comprises:
Finishing has the mesoporous silicon dioxide nano capsule of Polyethylene Glycol, golden nanometer particle potentiation; And
Be loaded in the guest molecule for radiography and HIFU potentiation in described mesoporous silicon dioxide nano capsule.
In one embodiment of the present invention, described mesoporous silicon dioxide nano capsule grain diameter is 100～1000nm, and aperture is 2.5～5nm, and pore volume is 0.2～1.4cm
3/ g.
In one embodiment of the present invention, described golden nanometer particle is 1～10% of described mesoporous silicon dioxide nano capsule quality, and described guest molecule is 1.7～8.5% of described mesoporous silicon dioxide nano capsule quality.
In one embodiment of the present invention, described guest molecule comprises perflexane, perfluoro bromide octane and object drug molecule, dye molecule.
In one embodiment of the present invention, described mesoporous silicon dioxide nano loading of capsules has fluorescent marker.
In one embodiment of the present invention, described mesoporous silicon dioxide nano loading of capsules has antitumor drug.
On the other hand, the invention provides a kind of method of silicon-dioxide-substrate multi-mode contrast agent and the HIFU synergist of preparing described golden nanometer particle load, described method comprises:
Mesoporous silicon dioxide nano capsule is carried out to surface modification, so that the surface of described mesoporous silicon dioxide nano capsule is with amino, carboxyl or sulfydryl;
Make the gold nano grain of described mesoporous silicon dioxide nano capsule surface load different-grain diameter and content; And
Make the guest molecule of described mesoporous silicon dioxide nano loading of capsules for radiography or HIFU potentiation; And
Utilize chemical grafting to carry out finishing so that the finishing of described mesoporous silicon dioxide nano capsule has Polyethylene Glycol to described mesoporous silicon dioxide nano capsule.
In one embodiment of the present invention, flood or priming by vacuum makes the mesoporous silicon dioxide nano loading of capsules of described golden nanometer particle load for the guest molecule of HIFU potentiation by volatilization.
In one embodiment of the present invention, described mesoporous silicon dioxide nano capsule is synthetic by selective etch method, comprising:
Adopt deionized water and ethanol to make solid silica nanosphere as silicon source and employing silane coupler as structure directing agent as basifier, ethyl orthosilicate as solvent, ammonia; And
Adopt aqueous sodium carbonate as solid silica nanosphere described in etchant etching.
In one embodiment of the present invention, described silane coupler comprises octadecyl trimethyl silane, cetyl trimethyl ammonium bromide and perfluor heptadecane trimethyl oxosilane.
Specifically, the silicon-dioxide-substrate acoustic contrast agent that golden function nano particle of the present invention is modified and HIFU synergist comprise surface graft different-grain diameter golden nanometer particle, be modified with the mesoporous silicon dioxide nano capsule of Polyethylene Glycol and be loaded in the guest molecule for HIFU potentiation in described mesoporous silicon dioxide nano capsule.
Adopt the present invention, well in conjunction with the golden function nano particle that can increase ultrasonic scattering performance, HIFU heat effect, the advantage of inorganic mesoporous Nano particles of silicon dioxide and organic fluorocarbon compounds, the compound enhancing ultrasonic contrast of nanometer organic-inorganic, CT imaging, the lower efficient HIFU synergist material of photoacoustic imaging guiding can be provided, more stablized, biocompatibility better, more good, the obvious diagnosis and treatment agent of HIFU potentiation of multi-modal imaging performance.And select the good mesoporous silicon dioxide nano capsule of biocompatibility to can further improve clinical practice of the present invention as matrix material.
Preferably, the particle diameter of described mesoporous silicon oxide hollow Nano capsule can be 100～1000nm, and aperture can be 2.5～5nm.This bigger serface and wide-aperture hollow carrier structure can be loaded guest molecule more efficiently for HIFU potentiation.The golden nanometer particle size supporting is 2-10nm, and loading is 1-10%
Guest molecule for HIFU potentiation can be organic fluorocarbon compounds or organic fluorocarbon gas, comprises perflexane (PFH) and perfluoro bromide octane (PFOB).
In the present invention, described mesoporous silicon dioxide nano capsule also can be mounted with fluorescent marker.Tracking test and diagnosis and treatment like this, more easily.
Silicon-dioxide-substrate acoustic contrast agent of the present invention and HIFU synergist also can comprise the antitumor drug being loaded in described mesoporous nano-grain.Cavity structure and pore passage structure can be given the performance that this nano material medicine is coated and transmit, and make chemotherapy and the integrated possibility that becomes of HIFU treatment.Described antitumor drug includes but not limited to one or more the mixture in amycin, paclitaxel, Docetaxel, vincristine, fluorouracil, methotrexate, mitoxantrone, adenosine cyclophosphate, cyclophosphamide, peplomycin, nitre card Jie, solaziquonum, aclarubicin, carmustine, temozolomide, lomustine, carmofur, ftorafur, actinomycin D, mitomycin, amsacrine, peace phosphorus spit of fland, cisplatin, alarelin, An Lu meter Te, chlormethine.
On the other hand, the invention provides a kind of multi-modal contrast agent of silicon-dioxide-substrate of above-mentioned gold nano functional particles load and method of HIFU synergist prepared, described method comprise to mesoporous silicon dioxide nano capsule carry out surface modification so that the surface of described mesoporous silicon dioxide nano capsule with amino, carboxyl or sulfydryl, the golden nanometer particle of load different-grain diameter and content; Make the guest molecule of described mesoporous silicon dioxide nano loading of capsules for HIFU potentiation; And utilize chemical grafting to carry out finishing so that the finishing of described mesoporous silicon dioxide nano capsule has Polyethylene Glycol to described mesoporous silicon dioxide nano capsule.
Method of the present invention is by carrying out surface modification and finishing grafting function golden nanometer particle to mesopore silicon dioxide nano material, the guest molecule that loads HIFU potentiation forms organic inorganic compounding multifunctional material, can increase ultrasonic scattered signal and the thermal efficiency melting, the potentiation HIFU that improves ultra sonic imaging performance and realize under CT/ photoacoustic imaging multi-mode guiding imaging melts, and finally realizes the safety of HIFU treatment and the raising of effectiveness.Method of the present invention, synthesis technique is simple, pollution-free, cost is low.
In the present invention, described mesoporous silicon dioxide nano capsule can be synthetic by traditional selective etch method, comprising: adopt deionized water and ethanol to make solid silica nanosphere as silicon source and employing silane coupler as structure directing agent as basifier, ethyl orthosilicate TEOS as solvent, ammonia; And adopt aqueous sodium carbonate as solid silica nanosphere described in etchant etching.
In the present invention, mesoporous silicon dioxide nano capsule material is carried out to surface modification, make its surface with sulfydryl, amino isoreactivity functional group, by sulfur-aurification, amide reactive chemistry abundant different-grain diameter nanogold particle on Nano capsule surface graft, realize multi-modal imaging and potentiation HIFU heat effect ablation.
Adopt the method, can be adjustable at Nano capsule area load particle diameter, gold nano grain that content is adjustable, after synthesizing inorganic organic composite silica nano material, be easy to carry out surface modification and finishing, preparation technology is simple, Yi Hang.
Again on the one hand, the present invention also provides a kind of method of silicon-dioxide-substrate acoustic contrast agent and the HIFU synergist of preparing above-mentioned golden nanometer particle potentiation, comprise and adopt traditional selective etch method synthesizing mesoporous silicon dioxide Nano capsule 100mg, dispersed with stirring in ethanol, add at 70 DEG C of 100 μ l-500 μ l mercaptosilane coupling agents and reflux 4～12 hours, obtain the hollow Nano capsule of sulfydryl modification.Get the chlorauric acid solution of 0.01-0.1M, between the NaOH adjusting pH=8-10 with 0.01M, add above-mentioned sulfydryl hollow Nano capsule, add afterwards golden reducing agent sodium borohydride reduction gold grain, by sulfur-Jin chemical grafting gold grain; To mesoporous silicon dioxide nano loading of capsules fluorocarbons and the guest molecule of described gold nano grain grafting; And utilize chemical grafting to carry out finishing so that the finishing of described mesoporous silicon dioxide nano capsule has Polyethylene Glycol to the mesoporous silicon dioxide nano capsule of described gold grain load.
Again on the one hand, the present invention also provides the another kind of preparation silicon-dioxide-substrate acoustic contrast agent of above-mentioned golden nanometer particle potentiation and the method for HIFU synergist, comprise and adopt traditional selective etch method synthesizing mesoporous silicon dioxide Nano capsule 100mg, dispersed with stirring in ethanol, add at 70 DEG C of 100 μ l-500 μ l amino silicane coupling agents and reflux 4～12 hours, obtain amido modified hollow Nano capsule.Get the chlorauric acid solution of 0.01-0.1M, add sodium citrate solution reduction gold grain, finally adopt amide reactive chemistry abundant nanogold particle on Nano capsule surface graft; To mesoporous silicon dioxide nano loading of capsules fluorocarbons and the guest molecule of described gold nano grain grafting; And utilize chemical grafting to carry out finishing so that the finishing of described mesoporous silicon dioxide nano capsule has Polyethylene Glycol to the mesoporous silicon dioxide nano capsule of described gold grain load.
The present invention's golden reducing agent used comprises sodium borohydride, sodium citrate.Regulate kind and addition and the pH value of reducing agent, be conducive to obtain the Nano capsule composite of appropriate particle size size and the load of content gold.
Can flood or priming by vacuum makes the guest molecule of described mesoporous silicon dioxide nano loading of capsules for HIFU potentiation by volatilization.The present invention's loading is easy for the mode of the guest molecule of HIFU potentiation, Yi Hang.
Synthesis technique of the present invention is simple, without any pollution (non-pollutant discharge), output is high, cost is low, efficiency is high, easy suitability for industrialized production; The silicon-dioxide-substrate multi-mode contrast agent of the golden nanometer particle load making and HIFU synergist can develop to tumor tissues effectively, and can significantly improve the effect of HIFU treatment, therefore demonstrate wide application prospect.In addition, this contrast agent/synergist specific surface area is high, pore volume is large, pore-size distribution homogeneous, is conducive to medicine efficiently supporting therein, is conducive to realize the integrated of chemotherapy and HIFU non-invasive therapy.
Brief description of the drawings
Fig. 1 is the schematic flow diagram of preparation gold grain load silicon-dioxide-substrate multi-mode contrast agent of the present invention and HIFU synergist.
Fig. 2 is the mesoporous SiO making as structure directing agent using surfactant C18TMS
2the transmission electron microscope photo of the Nano capsule of Nano capsule and load 2-4nm gold grain.
Fig. 3 is the loaded mesoporous SiO of golden nanometer particle
2the nitrogen adsorption curve of Nano capsule and grading curve (a), mean diameter (b), Infrared Characterization (c) and ultraviolet characterize (d).
Fig. 4 is golden nanometer particle load silicon-dioxide-substrate acoustic contrast agent of the present invention and HIFU synergist (1MHz, 2W/cm under ultrasonication
2, 50% working cycle (duty cycle), 30s, d=25mm) and the burnt photo of copolymerization of temperature sensitive phenomenon.
Fig. 5 be the golden nanometer particle load silicon-dioxide-substrate acoustic contrast agent of loading model dyestuff pyrene of the present invention and HIFU synergist under ultrasonication, strengthen the burnt photo of the cytophagic copolymerization of L929.
Fig. 6 is different synergist material of the present invention temperature rising curve under ultrasonication.
Fig. 7 is the extinction situation of the cell under ultrasonication after the silicon-dioxide-substrate acoustic contrast agent of gold grain load of the present invention and HIFU synergist and co-culture of cells.
Fig. 8 is the ultrasonoscopy result of the silicon-dioxide-substrate synergist material of in-vitro evaluation gold grain load of the present invention.
Fig. 9 is the CT video picture result of the silicon-dioxide-substrate synergist material of in-vitro evaluation gold grain load of the present invention.
Figure 10 is the ultrasonoscopy result of the silicon-dioxide-substrate synergist material of tumor rabbit interior evaluating gold grain load of the present invention.
Figure 11 adopts lotus to have silicon-dioxide-substrate acoustic contrast agent and the potentiation result of HIFU synergist in HIFU treatment of the rabbit model evaluation golden nanometer particle potentiation of the present invention of tumor.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail.It should be noted that content of the present invention is not limited to these concrete embodiments.Do not deviating under the prerequisite of background of the present invention and spirit, those skilled in the art can carry out substitutions and modifications of equal value on the basis of reading content of the present invention, and its content is also included within the scope of protection of present invention.
Referring to Fig. 1, it illustrates the example preparation flow of the silicon-dioxide-substrate multi-mode contrast agent of model dye load of the present invention, golden nanometer particle grafting and two kinds of methods of HIFU synergist.
First, can adopt different preparation technology's preparations to there is the mesoporous SiO of different pore passage structures and surface characteristic
2nano-carrier.For example adopt traditional alkali condition selective etch method, by the solid SiO of etching
2nanosphere makes mesoporous SiO
2nano-carrier.Also can pass through Protection Code, the synthesising mesoporous SiO of acid condition selective etch method
2nano-carrier.
Selective etch method is synthesized different mesoporous SiO
2nano capsule carrier: preparation process can deionized water and ethanol as solvent, ammonia is as base catalyst, (for example can adopt different silane couplers, octadecyl trimethyl silane (C18TMS), cetyl trimethyl ammonium bromide (CTAB), perfluor heptadecane trimethyl oxosilane (PDES) etc.) as structure directing agent, add ethyl orthosilicate (TEOS) react at a certain temperature the regular hour and process as silicon source, obtain mesoporous SiO
2nano carrier material.
Prepare the method for silicon-dioxide-substrate acoustic contrast agent and the HIFU synergist of above-mentioned golden nanometer particle potentiation: will adopt traditional selective etch method synthesizing mesoporous silicon dioxide Nano capsule 100mg, dispersed with stirring in ethanol, add at 70 DEG C of 100 μ l-500 μ l mercaptosilane coupling agents and reflux 4～12 hours, obtain the hollow Nano capsule of sulfydryl modification.Get the chlorauric acid solution of 0.01-0.1M, between the NaOH adjusting pH=8-10 with 0.01M, add above-mentioned sulfydryl hollow Nano capsule, add afterwards sodium borohydride reduction gold grain, by sulfur-Jin chemical grafting gold grain; To mesoporous silicon dioxide nano loading of capsules fluorocarbons and the guest molecule of described gold nano grain grafting; And utilize chemical grafting to carry out finishing so that the finishing of described mesoporous silicon dioxide nano capsule has Polyethylene Glycol to the mesoporous silicon dioxide nano capsule of described gold grain load.
Prepare the another kind of method of silicon-dioxide-substrate acoustic contrast agent and the HIFU synergist of above-mentioned golden nanometer particle potentiation: adopt traditional selective etch method synthesizing mesoporous silicon dioxide Nano capsule 100mg, dispersed with stirring in ethanol, add at 70 DEG C of 100 μ l-500 μ l amino silicane coupling agents and reflux 4～12 hours, obtain amido modified hollow Nano capsule.Get the chlorauric acid solution of 0.01-0.1M, add sodium citrate solution reduction gold grain, finally adopt amide reactive chemistry abundant nanogold particle on Nano capsule surface graft; To mesoporous silicon dioxide nano loading of capsules fluorocarbons and the guest molecule of described gold nano grain grafting; And utilize chemical grafting to carry out finishing so that the finishing of described mesoporous silicon dioxide nano capsule has Polyethylene Glycol to the mesoporous silicon dioxide nano capsule of described gold grain load.
Above-mentioned preparation method adopts ethyl orthosilicate (TEOS) as silicon source, but should be understood that the silicon source that also can adopt other non-functional.Method of the present invention can be by adopting the preparation of different surfaces activating agent to have the mesoporous SiO of different surfaces characteristic
2nano material, for example, adopt novel surfactant PDES, due to its ability with stronger combination organic fluorocarbon compounds, can increase the ability of the nano material load organic fluorocarbon compounds making, and then improve the potentiation of HIFU.By different preparation technologies (for example, the synthetic Capsules of selective corrosion, one-step method), adopt different surfactant material C18TMS, CTAB and PDES as structure directing agent, can prepare different-shape (Capsules, hybridization mesoporous material), size (100～1000nm), meso-hole structure (in order/unordered, aperture 2.3～5nm, pore volume 0.2～1.4cm
3/ g).
Then, the mesoporous SiO to the golden nanometer particle load making
2the sonic oscillation that nano material is carried out dye molecule or object drug molecule loads, and ethanol or aqueous solution clean repeatedly, removes after the guest molecule of capsule outer surface absorption dry.
Meanwhile, adopt different loading technique (for example, volatilization infusion process, priming by vacuum method) to load for the guest molecule (organic fluorocarbon compounds or fluorocarbon gas) of HIFU potentiation and obtain inorganic organic composite nano material.The roughly process of loading can be as follows: the object drug molecule that different condition is prepared loads, the loaded mesoporous SiO of golden nanometer particle
2nano capsule powder through certain preprocessing process (for example, dissolve, degassed), add the organic fluorocarbon compounds (PFH, PFOB) of a certain amount of (for example 1～10 μ L/mg hollow Nano capsule material (MSNCs)) or be fed into fluorocarbon gases, the stirring of process certain hour or ultrasonic, obtain compound nanometer diagnosis and treatment agent (MSNC-PFH, PMSNC-PFH).
To loading that the capsule surface of guest molecule is carried out finishing so that its surface with amino, carboxyl or sulfydryl isoreactivity functional group.The operation of surface modification can adopt common method well known to those skilled in the art.The selected face finish material of the present invention is to generally acknowledge the biomacromolecule Polyethylene Glycol with good biocompatibility.The common method that the method for modifying of Polyethylene Glycol can adopt those skilled in the art to know, for example, adopt the Polyethylene Glycol being activated by amide groups, or suitable condensing agent or the bridging agent of auxiliary employing.After certain surface is modified, nano material dispersibles in the solution of phosphate buffer (PBS), is mixed with the solution of variable concentrations, seals up for safekeeping.
The invention provides a kind of simple, eco-friendly method prepare there is good dispersion, good biocompatibility, particle diameter is controlled and aperture is controlled, ultrasonic contrast and CT function admirable, the obvious multifunctional nano material of HIFU potentiation.
In addition, the present invention can also integrate other functional module, and such as fluorescence imaging, PET imaging, photoacoustic imaging, CT imaging and ultra sonic imaging etc., obtain more intelligentized Nano medication/location of contrast agent delivery system.Importantly, utilize mesoporous SiO
2the controllable hole structure of nano based carrier and surperficial modifiability, before supporting organic fluorocarbon compounds, can also realize supporting of parent/dewatering medicament, realize several functions compound of material diagnosis, HIFU treatment, medicine chemotherapy, medicament slow release and targeting, therefore can realize the integrated of HIFU non-invasive therapy and chemotherapy, for the treatment of tumor provides better, more effective therapeutic scheme.
Fig. 2 illustrates the mesoporous SiO making as structure directing agent using surfactant C18TMS, CTAB, PDES
2the mesoporous SiO that nano material and one-step method make
2the transmission electron microscope photo (TEM photo) of nano material.Result shows that carrier material prepared by distinct methods all has good dispersibility, controlled aperture and cavity volume.In Fig. 2, (a1-a3) is the projection photo of different amplification hollow Nano capsule material (MSNCs).In Fig. 2, (b1-b3) is the projection photo of the gold-supported granule Nano capsule material (MSNC@Au) of different amplification.Figure under it is its scanning projection photo, elemental line scan dough-making powder scanned photograph.
In Fig. 3, (a) N of MSNCs and MSNC@Au
2adsorption/desorption curve and pore size distribution curve; (b) novel load gold grain meso-porous nano capsule base synergist material (MSNC@Au-PFH-PEG, MAPP) dynamic light scattering particle size distribution in aqueous solution; (c) the ultraviolet-visible absorption spectroscopy UV-vi s of the golden nanometer particle loaded with nano capsule material (pyr-MSNC@Au) of MSNC@Au and loading model dyestuff pyrene (pyr) and (d) infrared spectrum FTIR.
Fig. 4 illustrates silicon-dioxide-substrate multi-mode contrast agent and HIFU synergist (1MHz, 2W/cm under ultrasonication of novel golden nanometer particle potentiation of the present invention
2, 50% working cycle, 30 seconds (s), d=25mm) and the burnt photo of copolymerization of acoustic cavitation; As can be seen from the figure at room temperature (a), perflexane (PFH) stable existence of loading is in MSNC Au, and after carrying out a ultrasonic irradiation, ultrasonic sensitive/temperature sensitive PFH undergoes phase transition and produces bubble (b), can play ultrasonically enhanced effect; Can observe the bubble cavitation effect (c1-c4) such as grow up after secondary irradiation.
Fig. 5 illustrates after the silicon-dioxide-substrate multi-mode contrast agent of the loading model dyestuff pyrene with fluorescent marker (FITC) of the present invention, golden nanometer particle load and HIFU synergist are by L929 cytophagy the burnt microphotograph of copolymerization of 2 hours; The model dyestuff pyrene loading presents blue spot.MAPP is presented green speckle by FITC labelling.From picture, can find out, before ultrasonication, a small amount of green fluorescence appears in endochylema, and green and blue coincidence, proves that MAPP nanoparticle can be on a small quantity by cytophagy, and medicine does not substantially discharge (a1-d1) in carrier; After ultrasonication, a large amount of bluenesss appears in cell, show medicine enhancing discharge and by cell capture (a2-d2), the ultrasonic obvious release of medicine in cell that strengthened.
Fig. 6 illustrates the different medium (3mL, 6mg/mL) relating in the present invention (1MHz, 2W/cm under ultrasonication
2) ascending curve of different time temperature.As can be seen from the figure, Nano capsule material (MSNC@Au) after gold-supported granule temperature under ultrasonication raises obviously faster than simple Nano capsule material (MSNCs), and loading fluorocarbons golden nanometer particle loaded with nano capsule base synergist material (MSNC@Au-PFH-PEG, MAPP) afterwards has the fastest ultrasonic effect temperature increase rate.
Fig. 7 illustrates that MAPP material and L929 cultivate after 18 hours mortality rate under ultrasonication condition altogether.As can be seen from the figure,, although only act on 30 second time, owing to having added MAPP synergist material, the mortality rate of cell all more than 40%, embodies the ability that ultrasonic potentiation that MAPP material is good is melted.
Fig. 8 illustrates PBS matched group, polyethyleneglycol modified golden nanometer particle loaded with nano capsule material (MSNC@Au-PEG, MAP) and MAPP material bodies outer ultrasonic video picture photo and corresponding gray value icon thereof.Same, MAPP material presents the best ultrasonoscopy result, and this may be because material after load gold nano particle be for the enhancing of ultrasonic scattered signal.
Fig. 9 illustrates the CT imaging effect of variable concentrations MAPP material.As can be seen from the figure, along with the rising of MAPP concentration, the value of CT also constantly raises, and this is the rising due to the content of supported gold granule.This also shows, MAPP material not only can strengthen ultrasonic imaging, simultaneously can also enhanced CT imaging, realize the efficient HIFU treatment of multi-mode guiding.
Figure 10 illustrates rabbit VX2 tumor ultrasonoscopy photo under different mode in injection MAPP material forebody-afterbody.As can be seen from the figure, after injection MAPP material, the gray value of tumor all has obvious variation, especially remarkable in the lower effect of imaging pattern (contrast (Contrast)).
Figure 11 illustrates the rabbit model evaluation golden nanometer particle load of the present invention silicon-dioxide-substrate multi-mode contrast agent and the potentiation result of HIFU synergist (MAPP) in HIFU treatment that adopt lotus to have tumor.The B ultrasonic figure of the ultra sonic imaging after injecting by the tumor rabbit ear vein of plantation VX2 tumor by MAPP material after HIFU ablated tumor can find out the position of tumor, the gray value that melts rear tumor locus by HIFU obviously strengthens, and demonstrates HIFU and melts the variation that produces acoustic environment.Before and after tumour ablation, digital pictures has illustrated that MAPP can effectively realize the ability of HIFU ablated tumor.
The experimental result of in vitro and in vivo shows that the diagnosis and treatment agent material of this multifunctional nanoparticle potentiation provided by the invention can be effectively (ultrasonic as multi-mode, CT etc.) contrast agent, be accurately HIFU treatment positioning tumor position, and effectively improve the therapeutic effect of HIFU.Importantly, this novel multifunctional material can also carry out supporting and transmitting of cancer therapy drug, therefore HIFU treatment and chemotherapy can be carried out to mutual auxiliary treatment, thereby improve the therapeutic effect of tumor.
The present invention further for example following examples so that the present invention to be described better.Should be understood that equally following examples are for the present invention is described better, and unrestricted the present invention.
Synthesising mesoporous SiO
2nano capsule: 35.7mL ethanol, 5mL deionized water and 1.57mL ammonia stir 30 minutes in 30 DEG C of waters.Add rapidly 3mL ethyl orthosilicate (TEOS) to stir 1 hour.Afterwards, then add 2.5mL TEOS and 1mL octadecyl trimethyl silane (C18TMS) to continue to stir 1 hour, the white precipitate obtaining is centrifugal.The Na of preparation 0.6M
2cO
3aqueous solution, adds 80 DEG C of above-mentioned white precipitates to stir etching 0.5 hour.The precipitation washing obtaining 3 times, dry rear 550 DEG C of calcinings 6 hours.
The order mesoporous SiO of synthetic load fluorescence
2nano capsule: 35.7mL ethanol, 5mL deionized water and 1.57mL ammonia stir 30 minutes in 30 DEG C of waters.Add rapidly 3mL ethyl orthosilicate (TEOS) to stir 1 hour.React rear Centrifugal dispersion in 14mL water afterwards, then after adding 2mL TEOS; Get above-mentioned solution 2mL, 75mg CTAB, deionized water 15mL, ethanol 15mL and ammonia 0.275mL stir 0.5 hour.Finally add 0.125mL TEOS and 150uL FITC-APTES at 30 DEG C, to stir 2 hours.In 10mL water, add 212mg Na
2cO
3, add centrifugal product, 50 DEG C are reacted 10 hours, in methanol, reflux and remove Surfactant CTAB, obtain the order mesoporous hollow ball carrier of load fluorescence.
The 2-4 nanogold particle of load 5% content on Nano capsule: the method that repeats embodiment 1, obtaining hollow Nano capsule 100mg is dispersed in ethanol, dispersed with stirring in ethanol, adds at 70 DEG C of 100 μ l mercaptosilane coupling agents and refluxes 8 hours, obtains the hollow Nano capsule of sulfydryl modification.Get the chlorauric acid solution of 0.01M, regulating pH with the NaOH of 0.01M is 9, adds above-mentioned sulfydryl hollow Nano capsule, adds afterwards sodium borohydride reduction gold grain, by sulfur-Jin chemical grafting gold grain.
Embodiment 4
Repeat the method for embodiment 3, regulating pH with the NaOH of 0.01M is 11, obtains the 2-4 nanogold particle Nano capsule of load 10% content.
Embodiment 5
10 nanogold particles of load 5% content on Nano capsule: the method that repeats embodiment 1, obtaining hollow Nano capsule 100mg is dispersed in ethanol, dispersed with stirring in ethanol, adds at 70 DEG C of 100 μ l amino silicane coupling agents and refluxes 8 hours, obtains amido modified hollow Nano capsule.Get the chlorauric acid solution of 0.025M, add 30 minutes reduction gold grains of sodium citrate solution (5ml, 1 % by weight) reaction, finally adopt amide reactive chemistry abundant nanogold particle on Nano capsule surface graft
Repeat the method for embodiment 3, after the golden loaded with nano capsule ethanol obtaining is cleaned and is dried, put in the tetrahydrofuran solution of model dyestuff pyrene (6mg/mL) sonic oscillation 1 hour, afterwards Centrifugal dispersion, cleaning, the dry golden loaded with nano capsule that obtains loading pyrene dye molecule.
Repeat the method for embodiment 6, after product is dry, be encapsulated in the bottle with serum cap, will after evacuation in bottle, add a certain amount of perflexane (PFH) 10 μ L/mg MSNC@Au with syringe.
The method that repeats embodiment 7, product is dispersed in MES buffer solution, adds the mercapto-polyglycol (SH-PEG) of 1:1, and stirring at room temperature is put into the PBS solution of preparation and is dialysed 24 hours after 8 hours, be mixed with the solution of respective concentration.
Embodiment 9
Carry out cytophagy observation by Laser Scanning Confocal Microscope: first the good Pyr-MAPP of FITC labelling is distributed to (200 μ g/mL) in cell culture medium.Seed cells into again in Laser Scanning Confocal Microscope special culture dish, in the time that cell density grows to 60%-70%, remove culture medium, add the cell culture medium that contains Pyr-MAPP nanoparticle to cultivate altogether again.Remove culture medium, wash not by cytophagic nanoparticle with PBS solution as far as possible, transfer under Laser Scanning Confocal Microscope and observe.Fig. 5 illustrates after the silicon-dioxide-substrate multi-mode contrast agent of the loading model dyestuff pyrene with fluorescent marker (FITC) of the present invention, golden nanometer particle load and HIFU synergist are by L929 cytophagy the burnt microphotograph of copolymerization of 2 hours; The model dyestuff pyrene loading presents blueness.MAPP is presented green by FITC labelling.From picture, can find out, before ultrasonication, a small amount of green fluorescence appears in endochylema, and green and blue coincidence, proves that MAPP nanoparticle can be on a small quantity by cytophagy, and medicine does not substantially discharge (a1-d1) in carrier; After ultrasonication, a large amount of bluenesss appears in cell, show medicine enhancing discharge and by cell capture (a2-d2), the ultrasonic obvious release of medicine in cell that strengthened.
The PBS solution 0.3mL that supports the MAPP after PFH is encapsulated at the bottom of glass in culture dish, after ultrasonication, produces bubble and occur that bubble merges growth process; By in material injected plastic pipe, imbed in conducting resinl, under ultrasonication, after different time, measure the temperature rising data in solution, with PBS or not the Nano capsule material of supported gold nano-particle compare, MAPP has good thermal effect of ultrasound (referring to Fig. 6).
Embodiment 11
Material is injected to rubber membrane, put into de aerated water, (MI=1.1) external imaging under different mode ultrasonication, compares with the result of the ultra sonic imaging of PBS, and MAPP has a good ultra sonic imaging effect (referring to Fig. 8).
Embodiment 12
The PBS solution of MAPP is injected in tumor rabbit body by the ear vein of tumor rabbit, through the circulation of 30 minutes, adopt ultrasonic scanning tumor Hepar Leporis seu Oryctolagi portion, after positioning tumor, adopt HIFU ablated tumor, the different gray values before and after record melts also calculate the lesion volume after melting.Referring to Figure 11, from figure, can find out significantly at tumor locus, after melting through HIFU, the gray value of tumor locus obviously strengthens, and demonstrates HIFU and melts generation damage.Before and after tumour ablation, digital pictures has illustrated that MAPP can effectively realize the ability of HIFU ablated tumor.
Industrial applicability
The invention provides a kind of silicon-dioxide-substrate multi-mode contrast agent of preparing the golden nanometer particle potentiation with good biocompatibility and HIFU synergist and preparation method thereof.It is of the present invention that preparation is simple, without any pollution, output is high, cost is low, efficiency is high, the synergist material obtaining can be effectively develops to tumor tissues, and significantly improves the effect of HIFU treatment, therefore demonstrates wide application prospect.In addition, this many kinetic energy material specific surface area is high, pore volume is large, pore-size distribution homogeneous is adjustable, is conducive to medicine efficiently supporting therein, is conducive to realize the integrated of chemotherapy and HIFU non-invasive therapy.
Claims (10)
1. the silicon-dioxide-substrate multi-mode contrast agent of golden nanometer particle load and a HIFU synergist, it comprises:
Finishing has the mesoporous silicon dioxide nano capsule of Polyethylene Glycol, golden nanometer particle potentiation; And
Be loaded in the guest molecule for radiography and HIFU potentiation in described mesoporous silicon dioxide nano capsule.
2. the silicon-dioxide-substrate multi-mode contrast agent of golden nanometer particle load according to claim 1 and HIFU synergist, is characterized in that, described mesoporous silicon dioxide nano capsule grain diameter is 100～1000nm, and aperture is 2.5～5nm, and pore volume is 0.2～1.4cm
3/ g.
3. the silicon-dioxide-substrate multi-mode contrast agent of golden nanometer particle load according to claim 1 and HIFU synergist, it is characterized in that, described golden nanometer particle is 1～10% of described mesoporous silicon dioxide nano capsule quality, and described guest molecule is 1.7～8.5% of described mesoporous silicon dioxide nano capsule quality.
4. the silicon-dioxide-substrate multi-mode contrast agent of golden nanometer particle load according to claim 1 and HIFU synergist, is characterized in that, described guest molecule comprises perflexane, perfluoro bromide octane and object drug molecule, dye molecule.
5. the silicon-dioxide-substrate multi-mode contrast agent of golden nanometer particle load according to claim 1 and HIFU synergist, is characterized in that, described mesoporous silicon dioxide nano loading of capsules has fluorescent marker.
6. according to the silicon-dioxide-substrate multi-mode contrast agent of the golden nanometer particle load described in any one in claim 1～5 and HIFU synergist, it is characterized in that, described mesoporous silicon dioxide nano loading of capsules has antitumor drug.
7. prepare in claim 1～6 the silicon-dioxide-substrate multi-mode contrast agent of golden nanometer particle load and a method for HIFU synergist described in any one, described method comprises:
Mesoporous silicon dioxide nano capsule is carried out to surface modification, so that the surface of described mesoporous silicon dioxide nano capsule is with amino, carboxyl or sulfydryl;
Make the gold nano grain of described mesoporous silicon dioxide nano capsule surface load different-grain diameter and content; And
Make the guest molecule of described mesoporous silicon dioxide nano loading of capsules for radiography and HIFU potentiation; And
Utilize chemical grafting to carry out finishing so that the finishing of described mesoporous silicon dioxide nano capsule has Polyethylene Glycol to described mesoporous silicon dioxide nano capsule.
8. method according to claim 7, is characterized in that, floods or priming by vacuum makes the mesoporous silicon dioxide nano loading of capsules of described golden nanometer particle load for the guest molecule of HIFU potentiation by volatilization.
9. method according to claim 7, is characterized in that, described mesoporous silicon dioxide nano capsule is synthetic by selective etch method, and described selective etch method comprises:
Adopt deionized water and ethanol to make solid silica nanosphere as silicon source and employing silane coupler as structure directing agent as basifier, ethyl orthosilicate as solvent, ammonia; And
Adopt aqueous sodium carbonate as solid silica nanosphere described in etchant etching.
10. method according to claim 9, is characterized in that, described silane coupler comprises octadecyl trimethyl silane, cetyl trimethyl ammonium bromide and perfluor heptadecane trimethyl oxosilane.
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Cited By (5)
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| CN104162665A (en) * | 2014-08-29 | 2014-11-26 | 华东理工大学 | Gold-organic silicon-gold multilayer core-shell nano-structure and preparing method and application thereof |
| CN109675034A (en) * | 2019-02-22 | 2019-04-26 | 重庆医科大学 | A kind of multi-modal contrast agent and application thereof |
| CN110257054A (en) * | 2019-07-09 | 2019-09-20 | 长春工业大学 | The preparation of gold nanoclusters base fluorescence composite material and its application in ion detection |
| CN114887056A (en) * | 2022-04-25 | 2022-08-12 | 天津医科大学 | Preparation method and application of multifunctional bionic nanoparticles based on oxygen supply and ultra-small Cu-Se-Au |
| WO2022179307A1 (en) * | 2021-02-24 | 2022-09-01 | 上海纳米技术及应用国家工程研究中心有限公司 | Method for preparing multifunctional intestinal diagnosis and treatment formulation, and product thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104162665A (en) * | 2014-08-29 | 2014-11-26 | 华东理工大学 | Gold-organic silicon-gold multilayer core-shell nano-structure and preparing method and application thereof |
| CN104162665B (en) * | 2014-08-29 | 2017-01-11 | 华东理工大学 | Gold-organic silicon-gold multilayer core-shell nano-structure and preparing method and application thereof |
| CN109675034A (en) * | 2019-02-22 | 2019-04-26 | 重庆医科大学 | A kind of multi-modal contrast agent and application thereof |
| CN109675034B (en) * | 2019-02-22 | 2021-04-30 | 重庆医科大学 | Multi-modal contrast agent and application thereof |
| CN110257054A (en) * | 2019-07-09 | 2019-09-20 | 长春工业大学 | The preparation of gold nanoclusters base fluorescence composite material and its application in ion detection |
| WO2022179307A1 (en) * | 2021-02-24 | 2022-09-01 | 上海纳米技术及应用国家工程研究中心有限公司 | Method for preparing multifunctional intestinal diagnosis and treatment formulation, and product thereof |
| CN114887056A (en) * | 2022-04-25 | 2022-08-12 | 天津医科大学 | Preparation method and application of multifunctional bionic nanoparticles based on oxygen supply and ultra-small Cu-Se-Au |
| CN114887056B (en) * | 2022-04-25 | 2024-01-26 | 天津医科大学 | Preparation method and application of multifunctional bionic nano particles based on oxygen supply and ultra-small Cu-Se-Au |
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