CN105641696A - Gold-gadolinium composite nano material as well as preparation method and application of gold-gadolinium composite nano material - Google Patents
Gold-gadolinium composite nano material as well as preparation method and application of gold-gadolinium composite nano material Download PDFInfo
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- CN105641696A CN105641696A CN201511031874.4A CN201511031874A CN105641696A CN 105641696 A CN105641696 A CN 105641696A CN 201511031874 A CN201511031874 A CN 201511031874A CN 105641696 A CN105641696 A CN 105641696A
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- gadolinium
- silicon dioxide
- gold
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Abstract
The invention relates to a gold-gadolinium composite nano material as well as a preparation method and application of the gold-gadolinium composite nano material. The gold-gadolinium composite nano material provided by the invention comprises an inner core of a gold nano rod modified by silicon dioxide, and a gadolinium-containing silicon dioxide layer covering the outer side of the inner core. The gold-gadolinium composite nano material is high in gadolinium contain and each nano particle contains 1.5*10<6> Gd ions; the gold-gadolinium composite nano material is good in imaging effect and small in toxic side effect and can be used for loading a plurality of types of drugs and probe molecules, and target molecules can be adsorbed on the surface of the gold-gadolinium composite nano material, so that the drugs and the molecules can be efficiently transported to focus parts and multifunctional diagnosis and treatment can be realized. After the gold-gadolinium composite nano material is used as a carrier for loading the drugs, the gold-gadolinium composite nano material has the synergistic effect of thermal therapy and chemical therapy under laser irradiation in a treatment process of tumor-bearing mice, so that the growth of tumors is effectively inhibited; the gold-gadolinium composite nano material has multiple imaging functions including CT (Computed Tomography), MRI (Magnetic Resonance Imaging), photo-acoustic imaging and the like, and is suitable for being applied to complicated need tumor diagnosis and treatment.
Description
Technical field
The invention belongs to pharmaceutical carrier technical field, it relates to a kind of gold gadolinium composite nano materials, preparation method and its usage.
Background technology
In the past few decades, although the understanding of cancer has been achieved very big progress by people, but cancer is still one of main disease threatening human health. Chemotherapy is one of the most frequently used means of oncotherapy. But in clinical treatment, chemotherapy effect is not good. For the solid tumor of internal high pressure, weary oxygen, chemotherapeutics is considerably less to tumor tissues, and is difficult to penetrate into inside tumor, thus limits its result for the treatment of. In addition, chemotherapeutics lacks the identification to tumor tissues, normal tissue and cell is also had certain toxicity, therefore has obvious toxic side effect: such as doxorubicin hydrochloride has obvious cardiac toxic. In cancer therapy, thermotherapy and chemotherapy combined application have been proved to be able to optimize the effect of cancer therapy. The increase of the tumor vessel permeability that temperature rising causes and vascular endothelial cell gap become big, also can increase the accumulation of chemotherapeutics in tumour, it is to increase the curative effect of chemotherapy.
Existing document reports certain methods and is used for improving chemotherapeutics in the accumulation of inside tumor and infiltration. The nano-medicament carrier that journey seminar for army building in illinois university champagne branch school have studied different size is different with penetration degree to the accumulation of tumour. They have prepared the Drug-silica nano-complex of 20nm, 50nm and 200nm tri-kinds of different sizes, it has been found that the nano-complex of 50nm shows the longest residence time in tumor tissues, and the strongest in the perviousness of tumor tissues. Nano science center sill Xing Jie seminar of country reports can improve its perviousness in tumour after the novel short peptide molecule (iRGD) of nano-micelle finishing. In addition, outside energy stimulates, and such as new targeted approach, magnetic field, ultrasonic and near-infrared laser prove that be effective in living animal is tested. The research work in our early stage, devises the gold nanorods carrier of a kind of temperature sensitive high score attached bag quilt, under near-infrared laser irradiates, is enriched in tumor tissues (be not according to laser group 7.6 times according to laser group material percentage composition) more.Near-infrared laser etc. these by outside energy stimulate carry out neoplasm targeted therapy tactful prospect can the phase because the site of the stimulation in the external world, opportunity and intensity can control easily accurately.
The early diagnosis of tumour is significant for the treatment of tumour. Clearly determine that the position of tumour, size and blood vessel situation have guidance effect for the selection of methods for the treatment of, therefore select suitable imaging technique and method extremely important. Meanwhile, various imaging technique, it is possible to monitor therapy process, timely feedback treating situation. Design and apply the nano-medicament carrier of diagnosis and treatment integration, contribute to designing accurately treatment plan, be that the diagnosis and treatment of individuation provide and instruct and foundation. Up to the present, rarely have document and patent report multifunctional nano diagnosis and treatment carrier to be irradiated by near-infrared laser simultaneously and improve carrier and medicine in the enrichment of tumour and infiltration.
Containing gadolinium contrast medium in order to improve the contrast gradient of image, making abnormal structure or the affected part development of body parts, the Magnetic resonance imaging (MRI) being mainly used in head, backbone and whole body etc. checks. Free gadolinium has high toxicity, at distribution in vivo in bone and liver, and can cause rapidly hepatic necrosis. Use inner complex can change its distribution in body to guarantee image comparison intensity containing gadolinium contrast medium, and improve its toxic side effect. But, gadolinium chelate compound uses and human body still has very big toxicity, gadolinium is received with grafting or chemical bond-linking the surface of macromole, human body is still had very big toxic side effect by gadolinium element, and the charge capacity of gadolinium is few, being unfavorable for image checking, in the preparation method of the gold nano-material finishing gadolinium ion of current document report, normally each nano grain surface has an appointment 104Individual Gd ion (small, 2014,10,556 565; NatureMedicine, 2012,18,829-835), though gadolinium concentrations disclosed in prior art the highest be that each nano grain surface of one section of document report has the content of Gd ion also can only reach 5 �� 105Individual (Nanoscale, 2011,3,1990-1996), thus, it is necessary to develop a kind of high matrix material containing gadolinium amount and low toxic side effect and there is important meaning.
Summary of the invention
For problems of the prior art, it is an object of the invention to provide a kind of gold gadolinium composite nano materials, preparation method and its usage. Gadolinium concentrations height, the imaging effect of described gold gadolinium composite nano materials are good, and toxic side effect is little, it can carry high amount of drug as carrier bag, the medicinal composition being adsorbed with targeted molecular and medicine can also be made, under near-infrared laser irradiates, carrier and medicine can be realized in the significant effective enrichment of tumor locus, its perviousness in inside tumor can be increased. The conjunctive use of chemotherapy and thermotherapy two kinds of therapeutic modalities, can play the effect of synergy. And this gold gadolinium composite nano materials has multiple imaging function, gathered the multiple imaging functions such as light sound, CT scan (CT), nuclear magnetic resonance (MRI), can efficient diagnosis disease, monitoring therapeuticing effect.
For reaching this goal of the invention, the present invention by the following technical solutions:
First aspect, the present invention provides a kind of gold gadolinium composite nano materials, and described gold gadolinium composite nano materials comprises the kernel of silicon dioxide modified gold nanorods, and is coated on the gadolinium-containing silicon dioxide layer outside described kernel.
Preferably, described silicon dioxide modified gold nanorods kernel comprises gold nanorods and is coated on the mesoporous silicon oxide outside described gold nanorods.
The length of described gold nanorods is 5-100nm, such as, can be 5nm, 10nm, 15nm, 17nm, 20nm, 25nm, 30nm, 32nm, 35nm, 40nm, 45nm, 50nm, 60nm, 65nm, 70nm, 75nm, 80nm, 90nm, 95nm or 100nm etc.Consider from being conducive to reaching tumor tissues, it is more preferable to described gold nanorods length is 5-60nm.
The length-to-diameter ratio of described gold nanorods is preferably 1.5-20, can be such as 1.5,2,2.5,3,3.5,4,4.5,5,6,7,8,8.5,9,10,11,12,13.5,14,15,16,17,18,19 or 20 etc., it is preferably 2-8, from being conducive to reaching tumor tissues and be suitable for by near-infrared laser control is considered, the length-to-diameter ratio of further preferred described gold nanorods is 2.5-6, is further preferably 3.0-4.5.
The thickness of described mesoporous silicon oxide layer is preferably 3-50nm, can be such as 3nm, 5nm, 8nm, 10nm, 15nm, 20nm, 25nm, 30nm, 35nm, 40nm, 45nm, 50nm, it is preferably 5-45nm, from being easy to preparation and be conducive to arriving tumor tissues consider, it is more preferable to the thickness of described silicon dioxide layer is 10-30nm. More preferably 5-45nm, it is particularly preferred to be 10-30nm.
Preferably, described gadolinium-containing silicon dioxide layer is solid layer, its thickness is preferably 5-100nm, can be such as 5nm, 10nm, 15nm, 20nm, 30nm, 40nm, 45nm, 50nm, 55nm, 65nm, 70nm, 80nm, 90nm, 95nm or 100nm etc., from MRI imaging be conducive to arriving tumor tissues and consider, it is more preferable to the described thickness containing the silicon dioxide layer of gadolinium is 15-50nm. According to actual needs, in the preparation process of gold gadolinium composite nano materials, by regulating the add-on of reactant, regulate the ratio of Au and Gd, thus regulation and control are containing the thickness of gadolinium silicon layer.
Preferably, described gold gadolinium composite nano materials is electronegative.
Preferably, described gold gadolinium composite nano materials also comprises the adsorption layer that the band isoelectric substance of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer is formed.
Preferably, it is the material of positively charged and/or electronegative material with isoelectric substance, the combination of described band isoelectric substance preferably any one in targeted molecular, probe molecule, high molecular polymer or medicine or at least two kinds, described combination typical case but limiting examples has the combination of targeted molecular and high molecular polymer, the combination etc. of the combination of the combination of targeted molecular and medicine, targeted molecular and probe molecule, targeted molecular, high molecular polymer and medicine.
" band isoelectric substance is the material of positively charged and/or electronegative material " of the present invention refers to: band isoelectric substance can be the material of positively charged, it is also possible to be electronegative material, it is also possible to not only comprise the material of positively charged but also comprise electronegative material. It is noted that when not only comprising the material of positively charged but also comprise electronegative material, material and the electronegative material of positively charged alternately adsorb.
Preferably, described targeted molecular comprises hyaluronic acid (HA), hyaluronate sodium, Trastuzumab, Transferrins,iron complexes, the combination of any one or at least two kinds in folic acid or arginine-glycine-aspartic acid sequence (RGD), described targeted molecular combination typical case but limiting examples have: the combination of hyaluronic acid and hyaluronate sodium, the combination of hyaluronic acid and Trastuzumab, the combination of hyaluronate sodium and Transferrins,iron complexes, the combination of hyaluronate sodium and folic acid, hyaluronate sodium, Trastuzumab, Transferrins,iron complexes, the combination etc. of folic acid and arginine-glycine-aspartic acid sequence.
The molecular weight of described targeted molecular is preferably 1000-200,000, such as, can be 1000,5000,10,000,15,000,20,000,25,000,50,000,60,000,80,000,100,000,130,000,150,000,160,000,170,000,180,000 or 200,000 etc., more preferably 3000-30,000.
Preferably, described high molecular polymer is the high molecular polymer of positively charged, comprise diallyl dimethyl ammoniumchloride, the positively charged high molecular polymer that this areas such as polyetherimide (PEI) and chitosan are commonly used, those skilled in the art can experimentally demand select, one can be selected, the combination of at least two kinds can also be selected, described combination typical case but limiting examples have: the combination of diallyl dimethyl ammoniumchloride and polyetherimide, the combination of diallyl dimethyl ammoniumchloride and chitosan, diallyl dimethyl ammoniumchloride, the combination etc. of polyetherimide and chitosan.
The molecular weight of described high molecular polymer is 1000-200,000, such as, can be 1000,5000,10,000,15,000,20,000,25,000,30,000,50,000,60,000,80,000,100,000,120,000,150,000,180,000 or 200,000 etc., consider from stability of material, more preferably 10,000-100,000.
Preferably, described medicine comprises doxorubicin hydrochloride, along platinum, metal richness strangles alcohol, DNA, siRNA, protein drug, antibody, the combination of any one or at least two kinds in Indocyanine Green (ICG) or new Indocyanine Green (IR820), described combination typical case but limiting examples have: doxorubicin hydrochloride is with along the combination of platinum, doxorubicin hydrochloride and metal richness strangle the combination of alcohol, the combination of antibody and Indocyanine Green, along the combination of platinum and Indocyanine Green, doxorubicin hydrochloride, along platinum, metal richness strangles the combination etc. of alcohol and new Indocyanine Green, more preferably doxorubicin hydrochloride, the combination of any one or at least two kinds in Indocyanine Green or new Indocyanine Green.
The molecular weight of described medicine is preferably 100-30,000, such as can be 100,500,800,1000,5000,7000,10,000,15,000,18,000,20,000,25,000 or 30,000 etc., illustrate further, such as, doxorubicin hydrochloride molecular weight is 580, and the molecular weight along platinum is 300, and the molecular weight of Indocyanine Green is 775, the molecular weight of new Indocyanine Green is 849, the molecular weight of antibody and albumen is generally more than 10,000, and the molecular weight of metal richness Le alcohol is about the molecular weight of 800, DNA and RNA generally between 1 ten thousand to three ten thousand.
Preferably, the form electrostatic adhesion that described band isoelectric substance replaces with the material of positively charged and electronegative material is outside described gadolinium-containing silicon dioxide layer, form adsorption layer, and the material first adsorbing positively charged outside described gadolinium-containing silicon dioxide layer forms adsorption layer, then adsorption layer is formed at the material that the outside electrostatic adhesion of this layer of adsorption layer is electronegative, can also continue to form adsorption layer respectively by the material of electrostatic adhesion positively charged and electronegative material successively, it is possible to obtain the adsorption layer that multiple band isoelectric substance is formed.
Preferably, gold gadolinium composite nano materials by the kernel of silicon dioxide modified gold nanorods and is coated on the gadolinium-containing silicon dioxide layer outside described kernel and forms, its surface band negative electricity, thus during this gold gadolinium composite nano materials absorption band isoelectric substance, the material of preferential electrostatic adhesion positively charged.
The material of positively charged of the present invention can be such as but be not limited to following material: the medicine example hydrochloric acid Zorubicin of positively charged and suitable platinum; The high molecular polymer of positively charged is such as diallyl dimethyl ammoniumchloride, polyetherimide and chitosan etc.
Electronegative material of the present invention can be such as but be not limited to following material: electronegative medicine such as metal richness strangles alcohol, DNA, siRNA, protein drug, antibody, Indocyanine Green and new Indocyanine Green;Electronegative targeting substance is such as hyaluronic acid and hyaluronate sodium etc.
In the present invention, when the material of electrostatic adhesion comprises targeted molecular, then targeted molecular must at outermost layer, if because targeting substance be covered by internal layer can lose its target to effect.
Preferably, the quantity of the adsorption layer with isoelectric substance formation is 1-6 layer, can be such as 1 layer, 2 layers, 3 layers, 4 layers, 5 layers or 6 layers, it is preferably 4 layers, more preferably 2 layers, when adsorption layer is 2 layers, preferred the 1st layer of adsorption layer being the high molecular polymer of the medicine of positively charged or positively charged and being formed from inside to outside, the adsorption layer that the targeted molecular that 2nd layer is electronegative is formed such as hyaluronic acid and/or hyaluronate sodium, it is particularly preferably 1 layer, the adsorption layer of described band isoelectric substance refers to the material layer formed by the band isoelectric substance of electrostatic adhesion, the band isoelectric substance of absorption can be high molecular polymer, it can also be medicine, it can also be targeted molecular.
Preferably, described gold gadolinium composite nano materials comprises the kernel of silicon dioxide modified gold nanorods from inside to outside, is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the medicine of the one layer positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer.
Preferably, described gold gadolinium composite nano materials comprises the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the medicine of the one layer positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer, the electronegative targeted molecular of electrostatic adhesion outside the medicine of described positively charged.
Preferably, described gold gadolinium composite nano materials comprises the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the high molecular polymer of the positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer, with the electronegative targeted molecular of electrostatic adhesion outside the high molecular polymer of positively charged, described electronegative targeted molecular is hyaluronic acid and/or hyaluronate sodium.
" hyaluronic acid and/or hyaluronate sodium " of the present invention refers to: can be hyaluronic acid, it is also possible to be hyaluronate sodium, it is also possible to be the mixture of hyaluronic acid and hyaluronate sodium.
Preferably, the molecular weight of hyaluronic acid and hyaluronate sodium is preferably 1000-200,000 all independently, such as, can be 1000,5000,10,000,15,000,20,000,25,000,30,000,40,000,50,000,60,000,80,000,100,000,120,000,130,000,150,000,180,000 or 200,000 etc., it is preferable to 3000-30,000.
Second aspect, present invention also offers the preparation method of gold gadolinium composite nano materials as described in the first aspect of the invention, comprises the following steps:
(1) by the silicon dioxide modified gold nanorods dispersion liquid that is dispersed in alcohol with containing gadolinium aqueous solution, stir and after evenly, obtain gold gadolinium mixed solution, in gold gadolinium mixed solution, add alcoholic solution and the alkaline solution of silicon ester, carry out complex reaction, after centrifuge washing, obtain product. Products therefrom comprises the kernel of silicon dioxide modified gold nanorods from inside to outside, is coated on the gadolinium-containing silicon dioxide layer outside described kernel.
Silicon ester of the present invention is the mixture of a kind of in quanmethyl silicate, tetraethyl orthosilicate, silicic acid orthocarbonate or silicic acid four fourth ester or at least two kinds; Described mixture typical case but limiting examples have: the mixture of quanmethyl silicate and tetraethyl orthosilicate, the mixture of quanmethyl silicate and silicic acid orthocarbonate, the mixture of tetraethyl orthosilicate and silicic acid four fourth ester, the mixture etc. of quanmethyl silicate, tetraethyl orthosilicate and silicic acid orthocarbonate.
The alcoholic solution of described silicon ester can be such as the methanol solution etc. of the solution of the methanol solution of quanmethyl silicate, the ethanolic soln of quanmethyl silicate, the propanol solution of tetraethyl orthosilicate, the ethanolic soln of tetraethyl orthosilicate, the ethylene glycol solution of silicic acid orthocarbonate, the ethanolic soln of silicic acid orthocarbonate, the methyl alcohol of silicic acid four fourth ester and ethanol, quanmethyl silicate and tetraethyl orthosilicate, wherein, as long as the alcohol molecular weight used is liquid under being less than 200 and normal temperature and pressure, those skilled in the art can experimentally require to select.
Preferably, gold element and the mol ratio of gadolinium element in gold gadolinium mixed solution are 1:(0.1-10), can be such as 1:0.1,1:0.2,1:0.3,1:0.5,1:0.7,1:0.9,1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8 or 1:10 etc.
Preferably, the mol ratio of the gold element in gold gadolinium mixed solution and the element silicon in the alcoholic solution of silicon ester is 1:(1-100), can be such as 1:1,1:3,1:5,1:8,1:10,1:13,1:16,1:19,1:20,1:22,1:25,1:28,1:30,1:33,1:35,1:38,1:40,1:42,1:45,1:47,1:48,1:50,1:60,1:65,1:70,1:80,1:90 or 1:100 etc.
Preferably, silicon ester in the alcoholic solution of silicon ester is 1:(5-50 with the mol ratio of the alkali added), preferably, in step (4), the mol ratio of described silicon ester and alkali is 1:(5-50), can being such as 1:5,1:6,1:8,1:10,1:12,1:15,1:18,1:20,1:25,1:27,1:30,1:33,1:35,1:38,1:40,1:42,1:44,1:45,1:47 or 1:50 etc., the effect adding alkaline solution in gold gadolinium mixed solution be that silicon ester is hydrolyzed.
Preferably, the temperature of described complex reaction is 30-60 DEG C, such as, can be 30 DEG C, 35 DEG C, 40 DEG C, 50 DEG C, 55 DEG C or 60 DEG C etc.
Preferably, the time of complex reaction is preferably 6-72h, such as, can be 6h, 8h, 10h, 15h, 20h, 22h, 25h, 30h, 32h, 34h, 38h, 42h, 45h, 50h, 56h, 60h, 66h, 70h or 72h etc., more preferably 12-48h.
Centrifugal speed of the present invention is 9000-15000rpm, such as, can be 9000rpm, 10000rpm, 10500rpm, 11000rpm, 12000rpm, 13000rpm, 14000rpm or 15000rpm etc.; The centrifugal time is 5-30min, such as, can be 5min, 10min, 13min, 15min, 20min, 25min or 30min etc.
Washing of the present invention be to centrifugal remove supernatant liquor liquid after the throw out that obtains wash.
Preferably, remove supernatant liquor liquid by centrifugal for the mixture obtained after step (1) complex reaction, obtain throw out, with alcoholic solution to throw out washing repeatedly to wash the silicon ester not reacted and alkali etc., the more centrifugal supernatant liquor liquid that goes, wash with water once.
Preferably, the described gadolinium aqueous solution that contains is prepared by the following method: is added drop-wise to by sodium citrate aqueous solution in the Gadolinium trichloride aqueous solution, adds alkaline solution after mixed even, mixed even, obtains containing the gadolinium aqueous solution;
Preferably, the concentration of sodium citrate aqueous solution is 0.2-20mol/L, such as can be 0.2mol/L, 0.5mol/L, 1mol/L, 3mol/L, 5mol/L, 8mol/L, 10mol/L, 12mol/L, 14mol/L, 15mol/L, 18mol/L or 20mol/L etc., the concentration of the Gadolinium trichloride aqueous solution is 0.1-10mol/L, such as, can be 0.1mol/L, 0.5mol/L, 1mol/L, 2mol/L, 4mol/L, 6mol/L, 8mol/L or 10mol/L etc.
Preferably, the mol ratio of Trisodium Citrate and Gadolinium trichloride is 1:(0.1-1), can be such as 1:0.1,1:0.2,1:0.3,1:0.4,1:0.5,1:0.6,1:0.7,1:0.8,1:0.9 or 1:1 etc.
Preferably, the mol ratio of Trisodium Citrate and alkali is preferably 1:(0.1-1), can be such as 1:0.1,1:0.2,1:0.3,1:0.4,1:0.5,1:0.6,1:0.7,1:0.8 or 1:0.9 etc.
Alkali of the present invention is the basic cpd that this areas such as ammoniacal liquor, sodium hydroxide or potassium hydroxide are commonly used, and those skilled in the art can select as required.
The preparation method of gold nanorods dispersion liquid silicon dioxide modified described in the present invention is as follows:
Containing, in the gold nanorods aqueous solution of cetyl trimethylammonium bromide, when to add alkali adjust ph be 8.0-12.0, adding the alcoholic solution of silicon ester, reaction, obtains silicon dioxide modified gold nanorods;
Centrifugal remove supernatant liquor liquid, with alcoholic solution washing repeatedly to remove silicon ester and the alkali of cetyl trimethylammonium bromide and no reaction, finally it is dispersed in alcoholic solution.
Gold nanorods of the present invention can adopt the ordinary method of this area to prepare.
In the described gold nanorods aqueous solution containing cetyl trimethylammonium bromide, the length of gold nanorods is 5-100nm, such as, can be 5nm, 15nm, 25nm, 50nm, 60nm, 70nm, 80nm, 90nm or 100nm etc., it is preferable to 5-60nm; The length-to-diameter ratio of gold nanorods is 1.5-20, such as, can be 1.5,2.5,4,5,8,10,12,15 or 20 etc., it is preferable to 2-8, more preferably 2.5-6, is further preferably 3.0-4.5.
Preferably, in the described gold nanorods aqueous solution containing cetyl trimethylammonium bromide, in the gold nanorods aqueous solution containing cetyl trimethylammonium bromide, the concentration of gold element is 0.1-2mmol/L, can be such as 0.1mmol/L, 0.2mmol/L, 0.5mmol/L, 0.7mmol/L, 0.8mmol/L, 1mmol/L, 1.3mmol/L, 1.5mmol/L, 1.7mmol/L, 1.8mmol/L or 2mmol/L etc., it is preferable to 0.25-1.0mmol/L.
Preferably, in the gold nanorods aqueous solution containing cetyl trimethylammonium bromide, the concentration of cetyl trimethylammonium bromide is 0.1-10mmol/L, can be such as 0.1mmol/L, 0.3mmol/L, 0.5mmol/L, 1mmol/L, 2mmol/L, 3mmol/L, 3.5mmol/L, 4mmol/L, 5mmol/L, 6mmol/L, 6.5mmol/L, 7mmol/L, 8mmol/L, 9mmol/L or 10mmol/L etc., it is preferably 0.5-1.2mmol/L, when the concentration of CTAB in the gold nanorods solution prepared is higher than above-mentioned preferred concentration and 0.5-1.2mmol/L, the gold nanorods aqueous solution of required CTAB concentration can be obtained by centrifuge washing.
Preferably, pH is 8.0-12.0, such as, can be 8.0,8.2,8.5,9.0,9.3,9.5,10.0,11.0,11.5 or 12.0 etc., it is preferable that pH is 8.5-10.5.
Preferably, the gold element in the gold nanorods aqueous solution and the mol ratio of the element silicon in the alcoholic solution of silicon ester containing cetyl trimethylammonium bromide are 1:(1-50), such as 1:1,1:5,1:10,1:12,1:15,1:25,1:40 or 1:50 etc., it is preferable to 1:(2-10).
Preferably, add the alcoholic solution of silicon ester, can be disposable add or add several times, consider the homogeneity of the silicon dioxide layer obtained, preferably add several times, consider from operability and the homogeneity of silicon dioxide layer that obtains, it is preferable that point add for 2-4 time and often interval time between adjacent twice is 10-60min in the same manner, it is preferable to 30min.
Preferably, the temperature of described reaction is 20-60 DEG C, such as, can be 20 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 50 DEG C, 55 DEG C or 60 DEG C etc., it is preferable to 20-40 DEG C; The time of reaction is 0.04-3 days, can be such as 0.04 day, 0.06 day, 0.1 day, 0.2 day, 0.4 day, 0.5 day, 0.8 day, 1 day, 1.2 days, 1.5 days, 1.8 days, 2 days, 2.5 days, 2.6 days, 2.8 days or 3 days etc., it is preferably 1-3 days, more preferably 6-48h;
Alcohol of the present invention is that molecular weight is less than under 200 and normal temperature and pressure in the combination of any one in liquid alcohol or at least two kinds, it is preferable to methyl alcohol or ethanol. Typical but non-limiting molecular weight has in liquid alcohol under being less than 200 and normal temperature and pressure: methyl alcohol, ethanol, n-propyl alcohol, Virahol or ethylene glycol etc., alcohol can be selected by those skilled in the art as required.
Preferably, described method carries out step (2) after being also included in step (1): the product obtained by the aqueous dispersion step (1) of the material of positively charged, react under agitation condition, centrifugal, washing obtains product, described product is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the material of the positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer; The material of positively charged is preferably high molecular polymer and/or medicine, the concentration of the aqueous solution of the material of positively charged is 0.1-20mg/mL, such as, can be 0.1mg/mL, 0.5mg/mL, 1.5mg/mL, 3mg/mL, 5mg/mL, 8mg/mL, 10mg/mL, 13mg/mL, 15mg/mL, 18mg/mL or 20mg/mL etc.
Preferably, the temperature of step (2) described reaction is 10-40 DEG C, such as can be 10 DEG C, 15 DEG C, 18 DEG C, 20 DEG C, 22 DEG C, 24 DEG C, 26 DEG C, 28 DEG C, 30 DEG C, 32 DEG C, 34 DEG C, 35 DEG C, 37 DEG C, 39 DEG C or 40 DEG C etc., being preferably room temperature, room temperature of the present invention is 20-35 DEG C.
Preferably, the time of step (2) described reaction is 0.5-48h, such as, can be 0.5h, 1h, 3h, 5h, 6h, 8h, 10h, 12h, 13h, 15h, 16h, 18h, 19h, 20h, 22h, 24h, 26h, 30h, 32h, 35h, 40h, 45h or 48h etc.
Preferably, the mixture obtained after step (2) being reacted is centrifugal, then removes supernatant liquor, washes with water once.
Preferably, the high molecular polymer of described positively charged can be such as diallyl dimethyl ammoniumchloride, the positively charged high molecular polymer that this area such as polyetherimide or chitosan is commonly used, but it is not limited to this several material, those skilled in the art can select the positively charged high molecular polymer commonly used as required, the weight-average molecular weight of the high molecular polymer of described positively charged is 1000-200, 000, can be such as 1000, 2000, 3000, 5000, 10, 000, 20, 000, 30, 000, 50, 000, 60, 000, 80, 000, 100, 000, 120, 000, 150, 000, 180, 000 or 200, 000 etc., consider from stability of material, the molecular weight of described positively charged high molecular polymer is preferably 10, 000-100, 000.
Preferably, the medicine of described positively charged can be such as the medicine of the positively charged that this area such as doxorubicin hydrochloride and suitable platinum is commonly used, but it is not limited to this two kinds of materials, those skilled in the art can select the medicine of the positively charged commonly used as required, the molecular weight of the medicine of described positively charged is preferably 100-1000, such as, can be 100,300,500,800 or 1000 etc.
Preferably, the mixture obtained after step (2) being reacted is centrifugal, then removes supernatant liquor, washes with water once.
Preferably, described method carries out step (3) after being also included in step (2): have the golden gadolinium composite nano materials of positively charged material to disperse the surface adsorption that step (2) obtains with the aqueous solution of electronegative material, react under agitation condition, centrifugal, washing obtains product, described product is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the material of the positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer, and electrostatic adhesion is at the electronegative material in the outside of the material of described positively charged, electronegative material is preferably targeted molecular and/or electronegative medicine, more preferably electronegative targeted molecular, further it is preferably hyaluronic acid and/or hyaluronate sodium, the concentration of the aqueous solution of electronegative material is 0.1-20mg/mL, such as, can be 0.1mg/mL, 0.5mg/mL, 1mg/mL, 5mg/mL, 8mg/mL, 10mg/mL, 15mg/mL, 18mg/mL or 20mg/mL etc.
Preferably, the temperature of step (3) described reaction is 10-40 DEG C, such as can be 10 DEG C, 15 DEG C, 18 DEG C, 20 DEG C, 22 DEG C, 24 DEG C, 26 DEG C, 28 DEG C, 30 DEG C, 32 DEG C, 34 DEG C, 35 DEG C, 37 DEG C, 39 DEG C or 40 DEG C etc., being preferably room temperature, room temperature of the present invention is 20-35 DEG C.
Preferably, the time of step (3) described reaction is 0.5-48h, such as, can be 0.5h, 1h, 3h, 5h, 6h, 8h, 10h, 12h, 13h, 15h, 16h, 18h, 19h, 20h, 22h, 24h, 26h, 30h, 32h, 35h, 40h, 45h or 48h etc.
Preferably, the concentration of the aqueous solution of electronegative material is 0.1-20mg/mL, such as, can be 0.1mg/mL, 0.5mg/mL, 1mg/mL, 3mg/mL, 5mg/mL, 7mg/mL, 10mg/mL, 12mg/mL, 15mg/mL, 18mg/mL, 19mg/mL or 20mg/mL etc.
Preferably, the mixture obtained after step (3) being reacted is centrifugal, then removes supernatant liquor liquid, washes with water once.
Preferably, described electronegative targeted molecular comprises hyaluronic acid, hyaluronate sodium, Trastuzumab, Transferrins,iron complexes, the combination of any one or at least two kinds in folic acid or arginine-glycine-aspartic acid sequence, it is preferably hyaluronic acid or hyaluronate sodium, the molecular weight of described targeted molecular is preferably 1000-200, 000, can be such as 1000, 2000, 5000, 10000, 20000, 50000, 60000, 80000, 100000, 120000, 150000, 180000 or 200000 etc., consider to effect from stability of material and target, the molecular weight of described electronegative targeted molecular is preferably 3000-30, 000.
Medicine such as the metal richness that described electronegative medicine can be such as electronegative strangles alcohol, DNA, siRNA, protein drug, antibody, Indocyanine Green (ICG) and new Indocyanine Green (IR820), but it is not limited to this two kinds of materials, those skilled in the art can select the medicine of the positively charged commonly used as required, the molecular weight of described electronegative medicine is preferably 500-30, 000, such as can be 500, 800, 1000, 1500, 2500, 3500, 5000, 8000, 10, 000, 12, 000, 15, 000, 18, 000, 22, 000, 25, 000 or 30, 000 etc.
Preferably, can repeating step (2) and/or step (3).Repeating step of the present invention (2) and/or step (3) refer to: can repeating step (2) or separately repeating step (3) separately, or and then repeating step (3) after repeating step (2), or and then repeating step (2) after repeating step (3), but those skilled in the art should know, what occur due to step (2) described reaction and the described reaction of step (3) is the reaction of electrostatic adhesion, therefore the material of opposite-sign must be ensured to use between adjacent twice, the product that step (2) has obtained after having reacted is with positive electricity, therefore can only then repeating step (3) after step (2), step (3) has reacted after product with negative electricity, therefore can only then repeating step (2) after step (3).
It is noted that when the electronegative material selected is targeted molecular, the absorption of targeted molecular must carry out in final step, because targeting substance only just has targeting outermost time. If the position of targeting substance absorption is not outermost, then can lose its targeting and just simple a kind of electronegative material.
As from the foregoing, typical but non-limiting example is as follows:
When after completing steps (2) and step (3), repeating step (2), the product obtained is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the material of the positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer, electrostatic adhesion is at the electronegative material in the outside of the material of described positively charged, and electrostatic adhesion is at the material of the positively charged in the outside of electronegative material adjacent with it.
Preferably, described alcohol is that molecular weight is less than under 200 and normal temperature and pressure in the combination of any one in liquid alcohol or at least two kinds, it is preferable to methyl alcohol or ethanol.
Preferably, the preparation method of a kind of gold gadolinium composite nano materials, comprises the following steps:
(1) in the gold nanorods aqueous solution containing cetyl trimethylammonium bromide, the length of gold nanorods is 5-100nm, and length-to-diameter ratio is 1.5-10.0; Taking the gold nanorods concentration of gold element meter as 0.1-2mmol/L; The concentration of cetyl trimethylammonium bromide is 0.1-10mmol/L; Then sodium hydroxide or ammonia soln is added, pH value is made to be 8.0-12.0, divide the methyl alcohol or the ethanolic soln that add tetraethyl silicate for three times, often interval time between adjacent twice identical it is 10-60min, react on 20-60 DEG C to carry out 1-3 days, wherein, the element silicon mol ratio of the gold element in the described gold nanorods aqueous solution and described tetraethyl silicate is 1:(1-50); Obtain silicon dioxide modified gold nanorods;
(2) (centrifugal rotating speed is 9000-15000rpm the silicon dioxide modified gold nanorods solution centrifugal that step (1) obtains to be gone supernatant liquor, the centrifugal time is 5-30min), with centrifugal again after methyl alcohol or EtOH Sonicate dispersion, repetitive scrubbing to remove unnecessary cetyl trimethylammonium bromide and does not have silicon ester and the alkali of reaction 4-6 time, finally silicon dioxide modified gold nanorods is dispersed in methyl alcohol or ethanolic soln, obtains silicon dioxide modified gold nanorods dispersion liquid;
(3) sodium citrate aqueous solution is added drop-wise in the Gadolinium trichloride aqueous solution, the mol ratio of Trisodium Citrate and Gadolinium trichloride is 1:(0.1-1), finite concentration alkaline solution is added after mixed even, the mol ratio of described Trisodium Citrate and alkali is 1:(0.1-1), mixed even, obtain the aqueous solution containing gadolinium;
(4) under magnetic stirring, in the silicon dioxide modified gold nanorods dispersion liquid that step (2) obtains, add the gadolinium mixed solution that step (3) obtains successively, gold element in described silicon dioxide modified gold nanorods solution and in described gadolinium mixed solution the mol ratio of gadolinium element be 1:(0.1-10);Then adding methyl alcohol or the ethanolic soln of silicon ester, gold element and the element silicon mol ratio of described silicon ester in described silicon dioxide modified gold nanorods solution are 1:(1-100); Adding sodium hydroxide or ammonia soln after 2-10min, the mol ratio of described silicon ester and alkali is 1:(5-50), 30-60 DEG C is reacted 6-48 hour, obtains product.
In order to make gold gadolinium composite nano materials have better targeting, it is possible to make gold gadolinium composite nano materials surface be had polymkeric substance or the molecule of targeting by electrostatic interaction absorption. preferred preparation method carries out step (5) after step (4): with aqueous dispersion step (4) products therefrom of the high polymers of positively charged, 0.5-48h is reacted under 10-40 DEG C of agitation condition, centrifugal remove supernatant liquor liquid, with deionized water washing sediment, disperseed with hyaluronic acid or aqueous solution of sodium hyaluronate again, 0.5h-48h is reacted under 10-40 DEG C of agitation condition, obtain gold gadolinium composite nano materials, its composition is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the high molecular polymer of the alternately positively charged of absorption of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer, with the electronegative hyaluronic acid of electrostatic adhesion outside the high molecular polymer of positively charged and/or hyaluronate sodium.
The third aspect, the present invention provides a kind of medicinal composition, and it comprises the golden gadolinium composite nano materials described in first aspect present invention.
Preferably, described medicinal composition is the kernel of silicon dioxide modified gold nanorods from inside to outside, is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the medicine of the positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer.
Preferably, described medicinal composition is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the medicine of the alternately positively charged of absorption of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer and electronegative medicine, wherein, first adsorbing the medicine of positively charged outside described gadolinium-containing silicon dioxide layer, electronegative medicine is in the outermost of medicinal composition.
Preferably, described medicinal composition is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the high molecular polymer of the alternately positively charged of absorption of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer and electronegative targeted molecular, wherein, first adsorbing the high molecular polymer of positively charged outside described gadolinium-containing silicon dioxide layer, electronegative targeted molecular is in the outermost of medicinal composition.
Preferably, described medicinal composition is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the medicine of the alternately positively charged of absorption of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer and electronegative targeted molecular, wherein, first adsorbing the medicine of positively charged outside described gadolinium-containing silicon dioxide layer, electronegative targeted molecular is in the outermost of medicinal composition.
Preferably, described medicinal composition comprises the medicine thereon of gold gadolinium composite nano materials and load described in first aspect.
Preferably, the mode of loading of described medicine is electrostatic adhesion.
In the present invention, to the method for drug loading on above-mentioned carrier, there is no particular limitation, it is possible to adopts known various method. Such as, described can be contacted with described pharmaceutical carrier by drug solution by the method for drug loading on carrier. Contact Temperature is 20-40 DEG C, and duration of contact is 0.5h-3 days.Preferred described contact carries out under magnetic stirring.
Preferably, taking the quality of described carrier as benchmark, the carrying drug ratio of described pharmaceutical composition is 1-30wt%, such as, can be 1wt%, 2wt%, 5wt%, 8wt%, 10wt%, 15wt%, 18wt%, 22wt%, 25wt% or 30wt% etc., it is preferable to 10-20wt%;
Carrying drug ratio of the present invention is by formulae discovery below: the drug quality in carrying drug ratio (%)=pharmaceutical composition/(drug quality in carrier quality+pharmaceutical composition) * 100%.
Preferably, the combination of described medicine comprises doxorubicin hydrochloride, strangle in alcohol, DNA, siRNA, protein drug, antibody, Indocyanine Green ICG or new Indocyanine Green IR820 along platinum, metal richness any one or at least two kinds, it is preferable to the combination of any one or at least two kinds in doxorubicin hydrochloride, Indocyanine Green or new Indocyanine Green.
Fourth aspect, the present invention provides the purposes of a kind of gold gadolinium composite nano materials, and it can be used as carrier and carry out carrying medicament, it is possible to for the preparation of medicinal composition, and gained material all can be used for image-forming diagnose and treatment tumor disease.
Of the present invention for image-forming diagnose and treatment tumor disease, the kind of tumour is not particularly limited, it is only necessary to carrier, prepare corresponding pharmaceutical composition according to the medicine that the type load of tumour is applicable to. The tumour of the Diagnosis and Treat such as can applied comprises: mammary cancer, lung cancer, melanoma, liver cancer, skin carcinoma, cervical cancer, bladder cancer, carcinoma of the pancreas and cancer of the stomach etc.
In the present invention, gold gadolinium composite nano materials is as, after carrier carried medicine, in the tumor microenvironment and tumour cell lysosome of slightly acidic, enzyme existence, can effectively discharge drug molecule.
Under infrared laser irradiates, gold gadolinium composite nano materials can absorb infrared laser, and light energy conversion is become heat, may be used for thermotherapy on the one hand, the heat produced on the other hand can drives medication discharge, promote that medicine is in the infiltration of lesions position, it is achieved the multi-mode of disease such as cancer treated.
Preferably, the laser apparatus used in the present invention is 808nm CW laser. Actual application is not limited to this kind of laser apparatus. If there is the wavelength of near-infrared band and power enough make material be warmed up to the laser apparatus of more than 42 DEG C can.
In tumor-bearing mice therapeutic process, the effect of chemotherapy is not only embodied out using gold gadolinium composite nano materials as pharmaceutical composition prepared by carrier, the effect of thermotherapy and thermotherapy are also embodied to the synergism of chemotherapy, by the synergy of chemotherapy and thermotherapy, effectively inhibit the growth of tumour.
Compared with prior art, the useful effect of the present invention is as follows:
(1) the golden gadolinium composite nano materials that the present invention prepares, gadolinium is dispersed in solid silicon dioxide layer by electrostatic adsorption with the form of inner complex, gadolinium chelate compound is dispersed in solid silicon dioxide layer to reduce its toxic side effect in use, and the gadolinium concentrations height of this gold gadolinium composite nano materials, each nano particle has 1.5 �� 106Individual Gd ion, imaging effect is better.
(2) the golden gadolinium composite nano materials that prepared by the present invention, high amount of drug can be carried as carrier bag, carrying drug ratio can reach 30wt%, the medicinal composition being adsorbed with targeted molecular and medicine can also be made, under near-infrared laser irradiates, gold nanorods produces gentle heat, adds tumor vascular permeability, improve carrier and medicine in the accumulation of tumor locus and infiltration, for the treatment curative effect of follow-up raising tumour provides necessary condition;The conjunctive use of chemotherapy and thermotherapy two kinds of therapeutic modalities, can play the effect of synergy, also contributes to overcoming two kinds of therapeutic modalities shortcoming separately, obtains optimum result for the treatment of.
The medicinal composition being adsorbed with targeted molecular and medicine has active targeting, promote that cell is to multiple functions such as the endocytosis of pharmaceutical composition, thermotherapy and chemotherapy synergys.
(3) the present invention also has the function of multiple imaging using gold gadolinium composite nano materials and the golden gadolinium composite nano materials with targeting modification as two kinds of pharmaceutical compositions that carrier prepares, the multiple imaging functions such as light sound, CT scan, nuclear magnetic resonance are gathered, may be used for the position of diagnosing tumour and size, observation tumor neogenetic blood vessels situation, Real-Time Monitoring drug delivery and distribution situation, and monitoring therapeuticing effect.
(4) the present invention is by the combination of materials of multiple different in kind, prepare the mixture of nanoscale, and make its various composition coordinate to play a role, multiple function is united and applied in tumor diagnosis and therapy, open up the application space of Nano medication in oncotherapy further, it is particularly useful for having the tumor diagnosis and therapy of complicated needs.
Accompanying drawing explanation
Fig. 1 a-c is the transmission electron microscope picture of the golden gadolinium composite nano materials that embodiment 1-3 obtains; Wherein, Fig. 1 a represents to be the golden gadolinium composite nano materials of 27nm containing gadolinium silicon layer thickness, and Fig. 1 b represents to be the golden gadolinium composite nano materials of 15nm containing gadolinium silicon layer thickness, and Fig. 1 c represents to be the golden gadolinium composite nano materials of 45nm containing gadolinium silicon layer thickness;
Fig. 2 a-c is X-ray energy dispersion spectrum (EDS) figure of gold gadolinium composite nano materials, wherein Fig. 2 a is the EDS figure of the golden gadolinium composite nano materials of preparation in embodiment 1, Fig. 2 b is the EDS figure of the golden gadolinium composite nano materials of preparation in embodiment 2, Fig. 2 c is the EDS figure of the golden gadolinium composite nano materials of preparation in embodiment 3;
Fig. 3 be different concns golden gadolinium composite nano materials same laser power irradiate under heating curve;
Fig. 4 is gold gadolinium composite nano materials (AuSiO2) and medicine carrying material (AuSiO (Gd)2(Gd)-Dox-HA) abosrption spectrogram;
Fig. 5 is that gold gadolinium composite Nano medicine carrying material is at different pH with or without the drug release patterns under laser illumination;
Fig. 6 is that gold gadolinium composite Nano medicine carrying material is at 37 DEG C of different pH with or without the drug release patterns under Unidasa existence;
Fig. 7 is that gold gadolinium composite nano materials is on the impact of MDA-MB-231 cell viability;
Fig. 8 is that gold gadolinium composite Nano medicine carrying material and MDA-MB-231 Cytolysosome locate situation altogether; Wherein, Fig. 8 a-c represents the imaging results after hatching material 30min, 3h and 12h respectively;
Fig. 9 represents that the lysosome of gold gadolinium composite Nano medicine carrying material and MCF-7 cell locates situation altogether, and wherein, Fig. 9 a-c represents the imaging results after hatching material 30min, 3h and 12h respectively;
Figure 10 is the CT imaging results of gold gadolinium composite nano materials; Wherein, Figure 10 a represents the CT signal graph of the golden gadolinium composite nano materials of different concns, and Figure 10 b represents the linear relationship of CT strength of signal with gold gadolinium composite nano materials concentration;
Figure 11 is the MRI imaging results of gold gadolinium composite nano materials; Wherein, Figure 11 a represents the MRIT of the golden gadolinium composite nano materials of different concns1Image formation figure, Figure 11 b represent the linear relationship of MRI signal intensity with gold gadolinium composite nano materials concentration;
Figure 12 is the light sound three-dimensional imaging result of gold gadolinium composite nano materials; Wherein, Figure 12 a represents the photoacoustic imaging(PAI) figure before tumor-bearing mice administration, Figure 12 b represent tumor-bearing mice intravenous injection gold gadolinium composite nano materials and to the photoacoustic imaging(PAI) figure of its tumor locus according to after laser 6 hours;Figure 12 c represents the photoacoustic imaging(PAI) figure before tumor-bearing mice administration, and Figure 12 d represents the photoacoustic imaging(PAI) figure (tumor locus is not according to laser) of 6 hours after tumor-bearing mice intravenous injection gold gadolinium composite nano materials;
Figure 13 is the tumor suppression result of mouse vein administration; Wherein, Figure 13 a represents the result that treatment posterior tuberosity is heavy, and Figure 13 b represents the synergy of thermotherapy and chemotherapy;
Figure 14 is the tumor growth curve after mouse vein administration;
Figure 15 be in mouse therapeutic process body weight with the change of number of days.
Embodiment
Below in conjunction with accompanying drawing and the technical scheme of the present invention is described further by embodiment.
Reagent used by following examples or testing tool, if no special instructions, be and commercially available can obtain.
Embodiment 1
The present embodiment is for illustration of the preparation of gold gadolinium composite nano materials.
1) preparation of silicon dioxide modified gold nanorods
In the beaker of 20mL, being mixed with 250 �� L aqueous solution of chloraurate (concentration is 0.01mol/L) by the 7.5mL cetyl trimethylammonium bromide aqueous solution (concentration is 0.1mol/L), adding water to cumulative volume is 9.4mL; Then adding the cooled 0.6mL sodium borohydride aqueous solution of frozen water (concentration is 0.01mol/L), vigorous stirring 3min, is placed in 27 DEG C of thermostat container 2-5h, obtains gold nano grain seed solution.
In the beaker of 150mL, add 100mL cetyl trimethylammonium bromide (concentration is 0.1mol/L) respectively, 5mL aqueous solution of chloraurate (concentration is 0.01mol/L), 0.8mL silver nitrate aqueous solution (concentration is 0.01mol/L), 1mL aqueous sulfuric acid (concentration is 0.5mol/L), and 800 �� L aqueous ascorbic acids (concentration is 0.1mol/L); Then add 240 �� L gold nano grain seed solutions obtained above, it is placed in 30 DEG C of thermostat containers and reacts 12h, obtain gold nanorods solution. The length-to-diameter ratio of the gold nanorods that this step obtains is probably 4.
The gold nanorods solution centrifugal of above-mentioned for 20mL preparation is washed twice, all makes for twice residual volume be 1.8mL, and add water to 20mL and again disperse. In the gold nanorods aqueous solution finally obtained, cetyl trimethylammonium bromide concentration is 0.8mmol/L, and taking the gold nanorods concentration of gold element meter as 0.5mmol/L. Then the aqueous sodium hydroxide solution adjust ph under agitation adding 0.1mol/L is 10, then adds the tetraethoxy methanol solution (concentration is 20 volume %) of 40 �� L every 30min, altogether adds three times. Reaction carries out 24h in 26 DEG C under magnetic stirring, obtains silicon dioxide modified gold nanorods. The silicon dioxide modified gold nanorods that this step prepares, silicon dioxide layer is mesoporous silicon oxide, and its thickness is 25nm, and the aperture of mesoporous silicon oxide is 3-4nm.
2) preparation of gold gadolinium composite nano materials
Get the above-mentioned silicon dioxide coated gold nanorods aqueous solution of 20mL, centrifugal segregation supernatant liquor liquid, with 20mL methyl alcohol ultrasonic disperse, and then centrifugal, with methyl alcohol repetitive scrubbing material 4-5 time, finally use 6mL water-dispersion.
200 �� L sodium citrate aqueous solutions (concentration is 2mol/L) are added drop-wise in the 100 �� L Gadolinium trichloride aqueous solution (concentration is 1mol/L), vortex mix even after add 300 �� L ammoniacal liquor (concentration is 2.5%), then vortex mixes even namely obtaining containing the gadolinium aqueous solution.
Under magnetic stirring, above-mentioned 80 �� L are added containing the gadolinium aqueous solution in the silicon dioxide modified gold nanorods aqueous solution obtained above, and then add the ethanolic soln (40 �� L tetraethoxys are dissolved in 14mL ethanol) of tetraethoxy, after magnetic agitation 5min, add 0.56mL ammoniacal liquor (mass concentration is 25%), 40 DEG C are reacted 1-24 hour, namely obtain described golden gadolinium composite nano materials.
By centrifugal for above-mentioned reaction soln, remove after supernatant liquor with methanol wash once, wash with water more once, then with the aqueous dispersion of 3mg/mL diallyl dimethyl ammoniumchloride, under magnetic agitation, reaction is spent the night, and then centrifugal removes supernatant liquor, wash with water once, disperse with 3mg/mL hyaluronic acid or aqueous solution of sodium hyaluronate again, under magnetic agitation, react 1h, namely obtain that described what have targeting modification is that (Fig. 1 is a) for the golden gadolinium composite nano materials of 27nm containing gadolinium silicon layer thickness.
Fig. 2 a represents X-ray energy dispersion spectrum (EDS) figure of golden gadolinium composite Nano carrier prepared by embodiment 1, can determine in material main containing elements such as Au, Gd, Si, O, wherein the mass ratio of Au and Gd is about 1:1, and each nano particle has 1.5 �� 106Individual Gd ion.
Embodiment 2
Above-mentioned containing, except the gadolinium aqueous solution and 20 �� L tetraethoxys, other preparation methods are identical with embodiment 1 with condition except adding 40 �� L in the silicon dioxide modified gold nanorods aqueous solution.
The golden gadolinium composite nano materials that the present embodiment obtains containing gadolinium silicon layer thickness be 15nm (Fig. 1 b).
Fig. 2 b represents X-ray energy dispersion spectrum (EDS) figure of the golden gadolinium composite nano materials that the present embodiment obtains, can determine in material main containing elements such as Au, Gd, Si, O, wherein the mass ratio of Au and Gd is about 3:1, and each nano particle has 5 �� 105Individual Gd ion.
Embodiment 3
Above-mentioned containing, except the gadolinium aqueous solution and 80 �� L tetraethoxys, other preparation methods are identical with embodiment 1 with condition except adding 160 �� L in the silicon dioxide modified gold nanorods aqueous solution.
The golden gadolinium composite nano materials that the present embodiment obtains containing gadolinium layer thickness be 45nm (Fig. 1 c).
Fig. 2 c represents X-ray energy dispersion spectrum (EDS) figure of the golden gadolinium composite nano materials that the present embodiment obtains, can determine in material main containing elements such as Au, Gd, Si, O, wherein the mass ratio of Au and Gd is about 1:4, and each nano particle has 6 �� 106Individual Gd ion.
By embodiment 1-3, the amount containing the gadolinium aqueous solution and silicon ester added by regulating, can prepare the golden gadolinium composite nano materials of different gadolinium layer thickness, namely by control containing the amount of the gadolinium aqueous solution and silicon ester, gold and the content ratio of gadolinium can be regulated to golden gadolinium composite nano materials in different containing gadolinium layer thickness.
Embodiment 4
The present embodiment is for illustration of ramp case under laser illumination of the golden gadolinium composite nano materials of different concns.
By the golden gadolinium composite nano materials solution of preparation in embodiment 1, centrifugal washing is once, with the water-dispersion of 3 times of volumes, material concentration is 250 �� g/mL, dilute 2 times of (material concentration are 125 �� g/mL), 4 times (material concentration are 62.5 �� g/mL), 8 times (material concentration is 31.3 �� g/mL), 16 times (material concentration is 15.6 �� g/mL) more respectively, each taking-up 400 �� L are placed in the little centrifuge tube 808nm continuous wave laser irradiation of 1.5mL, and (power is 1W, spot diameter 5mm), by the top temperature in thermal imaging system record temperature-rise period. Fig. 3 is the curve that carrier concn is done by the top temperature of solution in temperature-rise period, it can be seen that reaching top temperature during the carrier soln 9min of different concns, then temperature keeps balance.
Embodiment 5
The present embodiment as carrier and carries the preparation process of medicine for illustration of gold gadolinium composite Nano.
Getting golden gadolinium composite Nano solid support material (0.75mg/mL) of preparation in 1mL embodiment 1, centrifugal, once, once, then with 1mL0.2mg/mL doxorubicin hydrochloride aqueous dispersion, room temperature lower magnetic force stirs 1.5h to methanol wash column in washing.Then centrifugal, washing once, merges supernatant liquor, measures the absorbance of supernatant liquor at 480nm place by microplate reader, substitutes into the content that typical curve calculates doxorubicin hydrochloride in supernatant liquor liquid. Carrying drug ratio and encapsulation rate are by formulae discovery below: carrying drug ratio (%)=pharmaceutical composition Chinese traditional medicine quality/(carrier quality+pharmaceutical composition Chinese traditional medicine quality) * 100%; Encapsulation rate (%)=carrier Chinese traditional medicine quality/input medicine total amount * 100%. As can be seen from Table 1, the carrying drug ratio of doxorubicin hydrochloride and encapsulation rate can reach 17.6% and 80% respectively. By improving the input amount of doxorubicin hydrochloride, it is possible to increase the carrying drug ratio of doxorubicin hydrochloride.
Table 1
Embodiment 6
The present embodiment is for illustration of the change of the absorption spectrum before and after gold gadolinium composite nano materials load medicine.
Respectively get in 200 �� L embodiments 1 medicine carrying material (it is 0.2mg/mL that doxorubicin hydrochloride drops into concentration) of preparation in the golden gadolinium composite nano materials and embodiment 5 prepared, washing is once, dilute 1 times, detect the absorption spectrum of solution under 400-1000nm wavelength by microplate reader. As shown in Figure 4, the maximum absorption band of gold gadolinium composite Nano carrier is at 805nm, and after carrying Zorubicin and modifying hyaluronic acid or hyaluronate sodium, maximum absorption band is 820nm, and obvious Zorubicin absorption peak occurs at 480nm place.
Embodiment 7
The present embodiment for illustration of gold gadolinium composite Nano medicine carrying material at different pH with or without the drug release behavior under laser illumination.
Get the medicine carrying material (it is 0.2mg/mL that doxorubicin hydrochloride drops into concentration) of preparation in 3 parts of 0.5mL embodiments 5, centrifugal remove supernatant liquor, disperseing with the phosphoric acid buffer (PBS) of pH=4.5, pH=6.0 and pH=7.4 respectively, then 37 DEG C of water-baths are hatched. Interval carries out centrifugal at regular intervals, takes supernatant liquor away and measures Zorubicin content in supernatant liquor by microplate reader, and the PBS of resistates same volume and pH disperses again, continues 37 DEG C and carries out release reaction. Laser illumination release experiment adopts similar step to carry out, and laser condition is 808nm wavelength, 0.8W power, 5mm spot diameter. Solution temperature is monitored by thermal imaging system, and 0.8W laser illumination solution outlet temperature is raised to 45 DEG C, and each time point first makes solution temperature be raised to 45 DEG C with laser illumination 5min, then continues 37 DEG C of water-baths and hatches. As shown in Figure 5, in acid condition than release under neutral condition faster and more (pH4.5 is faster than pH5.0 release, and pH5.0 is faster than pH7.4 release), and laser illumination causes intensification can promote drug release to Zorubicin.
Embodiment 8
The present embodiment for illustration of gold gadolinium composite Nano medicine carrying material 37 DEG C of water-baths, different pH, exist with or without Unidasa under drug release behavior.
Get the medicine carrying material (it is 0.2mg/mL that doxorubicin hydrochloride drops into concentration) of preparation in 3 parts of 0.5mL embodiments 5, centrifugal remove supernatant liquor, disperseing containing the PBS of 1mg/mL Unidasa containing 1mg/mL Unidasa, pH4.5 with pH7.4, pH6.0 respectively, then 37 DEG C of water-baths are hatched. Interval carries out centrifugal at regular intervals, takes supernatant liquor away and measures Zorubicin content in supernatant liquor by microplate reader, and the PBS of resistates same volume and pH disperses again, continues 37 DEG C and carries out release reaction. As shown in Figure 6, Zorubicin under existence that is acid and that have Unidasa than neutral condition under release faster and more.
Embodiment 9
The present embodiment for illustration of gold gadolinium composite nano materials itself on the impact of human breast carcinoma MDA-MB-231 cell viability.
1) cell cultures
By human breast carcinoma MDA-MB-231 cell cultures in containing in the DMEM of 10% foetal calf serum or 1640 liquid nutrient mediums, it is placed in 37 DEG C, the incubator of 5% carbonic acid gas cultivates.
2) cell viability measures
With 6000 cells/well density, cell is inoculated in 96 orifice plates. Pasting after wall 24h, adding is the DMEM of golden gadolinium composite nano materials (from embodiment 1) or 1640 liquid nutrient mediums (containing 10% foetal calf serum) of 0,10,50,100,200 �� g/mL containing concentration. Removing substratum after process 24h, every hole adds the cell culture fluid of 110 �� L containing 10% (volume ratio) CCK-8, after hatching 2h, measures 450nm place absorbance in microplate reader in incubator, and 600nm is as reference wavelength. After often organizing absorbance deduction blank solution absorbance, every hole respective value divided by the absorbance of control group as cell viability. Often group arranges 6 parallel holes. As shown in Figure 7, gold gadolinium composite Nano carrier of the present invention does not detect toxicity to cell viability measurement result within 200 �� g/mL concentration ranges.
Embodiment 10
The present embodiment is for illustration of the gold targeting of gadolinium composite Nano medicine carrying material and the location situation in tumour cell thereof.
1) cell cultures
Human breast carcinoma MDA-MB-231 and MCF-7 cell are inoculated in 35mm co-focusing imaging culture dish respectively, with containing the DMEM of 10% foetal calf serum or 1640 cultivate based on 37 DEG C, 24h cultivated by the incubator of 5% carbonic acid gas. Then wash twice with PBS, add the substratum of the golden gadolinium composite Nano medicine carrying material containing 5 ��m of ol/L equivalence Zorubicins containing preparation in 5 ��m of ol/L Zorubicins or embodiment 5, process cell 30min, 3h and 12h respectively.
2) mensuration of intracellular targeting
Abandon cell culture medium, with PBS washed cell three times, add serum-free without phenol red DMEM or 1640 substratum, with the fluorescence observing Zorubicin under laser confocal microscope. Fig. 8 and Fig. 9 shows after medicine carrying material hatches 30min, 3h and 12h respectively, with containing the cellular localization image after the serum-free DMEM or 1640 substratum, 37 DEG C of incubated cell 45min of the lysosome dyestuff (LysoTrackerGreen) of 100nmol/L. Fig. 8 a-c shows gold gadolinium composite Nano medicine carrying material in the absorption of MDA-MB-231 cell and location situation, and during 30min, part gold gadolinium composite Nano medicine carrying material is positioned on cytolemma, and a small amount of gold gadolinium composite Nano medicine carrying material enters in cell and lysosome is located altogether; During 3h, more gold gadolinium composite Nano medicine carrying material enters in cell and lysosome is located altogether; During 12h, part gold gadolinium composite Nano medicine carrying material is still located altogether with lysosome, and now existing a large amount of Zorubicin discharges from medicine carrying material and entered in nucleus. Fig. 9 a-c show gold gadolinium composite Nano medicine carrying material MCF-7 cell absorption and location situation, compare with Fig. 8 a-c, MCF-7 cell to gold gadolinium composite Nano medicine carrying material intake when 30min, 3h and 12h all than the MDA-MB-231 cell of corresponding time point, the intake of medicine carrying material is much lower. Due to the CD44 acceptor of hyaluronic acid or hyaluronate sodium energy target tumor cell surface, MDA-MB-231 cell surface high expression level CD44 acceptor, the low expression CD44 acceptor of MCF-7 cell surface, therefore MDA-MB-231 cell is much higher than MCF-7 cell to the intake of medicine carrying material, has embodied the targeting of medicine carrying material.
Embodiment 11
The present embodiment may be used for X ray computer tomoscan (CT) imaging for illustration of gold gadolinium composite nano materials.
By the golden gadolinium composite nano materials solution of preparation in embodiment 1, centrifugal methanol wash column is once, washing is once, concentrated 60 times, material concentration is 45mg/mL, Au concentration is 9mg/mL, dilute 2 times of (Au concentration are 4.5mg/mL), 4 times (Au concentration are 2.25mg/mL), 8 times (Au concentration is 1.13mg/mL), 16 times (Au concentration is 0.56mg/mL) and 32 times (Au concentration is 0.28mg/mL) more respectively, each 0.5mL that takes out is placed in the little centrifuge tube of 0.5mL, measures the CT signal of material.Figure 10 a shows the CT image of different concns material, and Figure 10 b is CT strength of signal and the graph of a relation of Au concentration, it can be seen that both show good linear relationship (R2=0.9954). Therefore, gold gadolinium composite nano materials can be used as a kind of well CT contrast medium, is used for carrying out bio-imaging.
Embodiment 12
The present embodiment may be used for nucleus magnetic resonance (MRI) imaging for illustration of gold gadolinium composite nano materials.
By the golden gadolinium composite nano materials solution of preparation in embodiment 1, centrifugal methanol wash column is once, washing is once, 4 times are diluted with water, material concentration is 62 �� g/mL, and Gd concentration is 0.072mM, then dilutes 2 times of (Gd concentration are 0.036mM), 4 times (Gd concentration are 0.018mM), 8 times (Gd concentration is 0.009mM) respectively, each 0.5mL that takes out is placed in the little centrifuge tube of 0.5mL, measures the MRI signal of material. Figure 11 a shows the MRIT of different concns material1Image, Figure 11 b is MRI signal intensity and the graph of a relation of Gd concentration, it can be seen that both show good linear relationship (R2=0.9949). Therefore, gold gadolinium composite Nano carrier can be used as a kind of well MRI contrast agent, is used for carrying out bio-imaging.
Embodiment 13
The present embodiment can increase gold gadolinium composite nano materials in the enrichment of tumor locus and infiltration for illustration of laser illumination.
By 1*107Individual human breast carcinoma MDA-MB-231 cell is inoculated in the back of the 4-6 week naked mouse of balb/c, waits gross tumor volume to grow to 150mm3Shi Jinhang tests. After mouse is anaesthetized, the golden gadolinium composite nano materials (embodiment 1a preparation) that intravenous injection 200 �� LPBS disperses, then at once irradiate 15min with 808nm continuous wave laser (1W, spot diameter 5mm), then observe material in the enrichment of tumour and infiltration by photoacoustic imaging(PAI). As shown in Figure 12 a-b, laser illumination can obviously increase gold gadolinium composite nano materials and permeate at the Cumulate Sum of tumor locus. Injection material not according to laser mouse in contrast (Figure 12 c-d).
Embodiment 14
The present embodiment is for illustration of the tumor suppression result after tumor-bearing mice intravenously administrable.
1) mouse inoculated tumour
By 1*107Individual human breast carcinoma MDA-MB-231 cell is inoculated in the right rear leg of the 4-6 week naked mouse of balb/c, and after 5 days, gross tumor volume reaches 100mm3Left and right, carries out laser therapy experiment.
2) inhibiting tumor assay
The golden gadolinium composite nano materials solution (3.2mg/mL of preparation in the embodiment 1 of 200 �� L, Au content is 650 �� g/mL), (Au content is 650 �� g/mL to golden gadolinium composite Nano medicine carrying material in embodiment 3, equivalence doxorubicin hydrochloride strengths is 0.8mg/mL), PBS and 0.8mg/mL doxorubicin hydrochloride solution through tail vein injection to the mouse in step 1, then at once with 808nm continuous wave laser (1W, spot diameter 5mm) irradiate tumour 15min, monitor temperature-rise period with thermal imaging system. Low temperature group (Au-Dox-Low) top temperature is finally warmed up to 45 DEG C, and high temperature group (Au-Dox-High) top temperature is finally warmed up to 50 DEG C. Tail vein injection medicine carrying material but not according to laser mouse (Au-Dox) in contrast. After laser illumination the 2nd day size of vernier caliper measurement tumour, backward every other day by the size of vernier caliper measurement tumour, monitors 21 days always. When 21 days, put to death mouse, take out tumour and weigh. Figure 13 a is the tumor suppression result represented with tumor weight, can find out that the tumour inhibiting rate of load medicine group (Au-Dox) and Zorubicin group (Dox) is similar, load medicine has compared significance difference (* P < 0.05 according to laser group (Au-Dox-Low with Au-Dox-High group) with load medicine group (Au-Dox), * P < 0.01), and obviously inhibit the growth of tumour.Carrier has been analyzed according to the tumour inhibiting rate of laser low temperature group by Figure 13 b according to laser group, load medicine group, load medicine, result display load medicine is higher according to the theoretical superposition value of laser low temperature group and the tumour inhibiting rate of load medicine group than carrier according to the tumour inhibiting rate of laser low temperature group, the thermotherapy and the chemotherapy that describe load medicine photograph laser group have synergy, namely gentle heat energy promotes that medicine carrying material is in the enrichment of tumor tissues and infiltration, thus improves result for the treatment of. Figure 14 is the growing state of tumour in the therapeutic process represented with gross tumor volume, and the tumor suppression result that its result represents with Figure 13 a weight is consistent.
Embodiment 15
The present embodiment is for illustration of the body weight change in tumor-bearing mice therapeutic process.
Every other day being weighed by each group of mouse in embodiment 12, mapped by number of days by body weight, such as Figure 15, the mouse body of Zorubicin group is reppeared existing one and is obviously reduced the process recovered gradually again over the course for the treatment of, shows obvious toxicity; And other body weight respectively organizing mouse change not quite over the course for the treatment of, illustrate that medicine carrying material can reduce the toxicity of chemotherapeutics Zorubicin.
Applicant states, the present invention illustrates the method detailed of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned method detailed, does not namely mean that the present invention must rely on above-mentioned method detailed and could implement. Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of ancillary component, the concrete way choice etc. of each raw material of product of the present invention, all drops within protection scope of the present invention and open scope.
Claims (10)
1. a golden gadolinium composite nano materials, it is characterised in that, comprise the kernel of silicon dioxide modified gold nanorods, and it is coated on the gadolinium-containing silicon dioxide layer outside described kernel.
2. material according to claim 1, it is characterised in that, described silicon dioxide modified gold nanorods kernel comprises gold nanorods and is coated on the mesoporous silicon oxide outside described gold nanorods;
Preferably, the length of described gold nanorods is 5-100nm, it is preferable to 5-60nm; The length-to-diameter ratio of described gold nanorods is preferably 1.5-20, more preferably 2-8, it is particularly preferred to be 2.5-6, it is most preferred that be 3.0-4.5; The thickness of described mesoporous silicon oxide layer is preferably 3-50nm, more preferably 5-45nm, it is particularly preferred to be 10-30nm;
Preferably, described gadolinium-containing silicon dioxide layer is solid layer, and its thickness is preferably 5-100nm, more preferably 15-50nm;
Preferably, described gold gadolinium composite nano materials is electronegative.
3. material according to claim 1 and 2, it is characterised in that, described gold gadolinium composite nano materials also comprises the adsorption layer that the band isoelectric substance of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer is formed;
Preferably, band isoelectric substance is the material of positively charged and/or electronegative material, the combination of described band isoelectric substance preferably any one in targeted molecular, probe molecule, high molecular polymer or medicine or at least two kinds;
Preferably, described targeted molecular comprises the combination of any one or at least two kinds in hyaluronic acid, hyaluronate sodium, Trastuzumab, Transferrins,iron complexes, folic acid or arginine-glycine-aspartic acid sequence RGD, the molecular weight of described targeted molecular is preferably 200-200,000, more preferably 1000-200,000, it is particularly preferred to be 3000-30,000;
Preferably, high molecular polymer is the high molecular polymer of positively charged, comprise the combination of any one or at least two kinds in diallyl dimethyl ammoniumchloride, polyetherimide PEI and chitosan, the molecular weight of described high molecular polymer is preferably 1000-200,000, more preferably 10,000-100,000;
Preferably, the combination of described medicine comprises doxorubicin hydrochloride, strangle in alcohol, DNA, siRNA, protein drug, antibody, Indocyanine Green ICG or new Indocyanine Green IR820 along platinum, metal richness any one or at least two kinds, the combination of any one or at least two kinds that are preferably in doxorubicin hydrochloride, Indocyanine Green or new Indocyanine Green, the molecular weight of described medicine is preferably 100-30,000;
Preferably, the form electrostatic adhesion that described band isoelectric substance replaces with the material of positively charged and electronegative material, outside described gadolinium-containing silicon dioxide layer, forms adsorption layer, and the material first adsorbing positively charged outside described gadolinium-containing silicon dioxide layer forms adsorption layer;
Preferably, when comprising targeted molecular in the material of electrostatic adhesion, then targeted molecular is at outermost layer;
Preferably, the quantity of the adsorption layer that described band isoelectric substance is formed is 1-6 layer, it is preferable to 4 layers, more preferably 2 layers, it is particularly preferred to be 1 layer;
Preferably, the adsorption layer that described band isoelectric substance is formed is 2 layers, and the 1st layer is the medicine of positively charged or the adsorption layer of high molecular polymer formation from inside to outside, the adsorption layer that the targeted molecular that the 2nd layer is electronegative is formed.
4. material according to the arbitrary item of claim 1-3, it is characterized in that, described gold gadolinium composite nano materials comprises the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the medicine of the one layer positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer;
Preferably, described gold gadolinium composite nano materials comprises the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the medicine of the one layer positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer, the electronegative targeted molecular of electrostatic adhesion outside the medicine of described positively charged;
Preferably, described gold gadolinium composite nano materials comprises the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the high molecular polymer of the positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer, and the electronegative targeted molecular of electrostatic adhesion outside the high molecular polymer of positively charged;
Preferably, the molecular weight of hyaluronic acid and hyaluronate sodium is preferably 1000-200,000 all independently, it is preferable to 3000-30,000.
5. the preparation method of a gold gadolinium composite nano materials as claimed in claim 1 or 2, it is characterised in that, described method comprises the following steps:
(1) by the silicon dioxide modified gold nanorods dispersion liquid that is dispersed in alcohol with containing gadolinium aqueous solution, stir and after evenly, obtain gold gadolinium mixed solution, in gold gadolinium mixed solution, add alcoholic solution and the alkaline solution of silicon ester, carry out complex reaction, after centrifuge washing, obtain product.
6. method according to claim 5, it is characterised in that, described silicon ester is the mixture of a kind of in quanmethyl silicate, tetraethyl orthosilicate, silicic acid orthocarbonate or silicic acid four fourth ester or at least two kinds;
Preferably, the mol ratio of the gold element in gold gadolinium mixed solution and gadolinium element is 1:(0.1-10);
Preferably, the mol ratio of the element silicon in the alcoholic solution of the gold element in gold gadolinium mixed solution and silicon ester is 1:(1-100);
Preferably, the silicon ester in the alcoholic solution of silicon ester is 1:(5-50 with the mol ratio of the alkali added);
Preferably, the temperature of described complex reaction is 30-60 DEG C, and the time of complex reaction is preferably 6-72h, more preferably 12-48h;
Preferably, centrifugal speed is 9000-15000rpm, and the centrifugal time is preferably 5-30min; Washing be preferably to centrifugal remove supernatant liquor liquid after the throw out that obtains wash;
Preferably, the described gadolinium aqueous solution that contains is prepared by the following method: is added drop-wise to by sodium citrate aqueous solution in the Gadolinium trichloride aqueous solution, adds alkaline solution after mixed even, mixed even, obtains containing the gadolinium aqueous solution;
Preferably, the concentration of sodium citrate aqueous solution is 0.2-20mol/L, and the concentration of the Gadolinium trichloride aqueous solution is 0.1-10mol/L;
Preferably, the mol ratio of Trisodium Citrate and Gadolinium trichloride is 1:(0.1-1), the mol ratio of Trisodium Citrate and alkali is preferably 1:(0.1-1).
7. method according to claim 5 or 6, it is characterized in that, described method carries out step (2) after being also included in step (1): the product obtained by the aqueous dispersion step (1) of the material of positively charged, 0.5-48h is reacted under agitation condition, centrifugal, washing obtains product, described product is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the material of the positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer; The material of positively charged is preferably high molecular polymer and/or medicine, and the concentration of the aqueous solution of the material of positively charged is 0.1-20mg/mL;
Preferably, positively charged high molecular polymer comprises the combination of any one or at least two kinds in diallyl dimethyl ammoniumchloride, polyetherimide or chitosan;
Preferably, the weight-average molecular weight of the high molecular polymer of positively charged is 1000-200,000, it is preferable to 10,000-100,000;
Preferably, the medicine of positively charged comprises doxorubicin hydrochloride and/or suitable platinum;
Preferably, the molecular weight of the medicine of positively charged is 100-1000.
8. method according to claim 7, it is characterized in that, described method carries out step (3) after being also included in step (2): have the golden gadolinium composite nano materials of positively charged material to disperse the surface adsorption that step (2) obtains with the aqueous solution of electronegative material, react under agitation condition, centrifugal, washing obtains product, described product is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the material of the positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer, and electrostatic adhesion is at the electronegative material in the outside of the material of described positively charged, electronegative material is preferably electronegative targeted molecular and/or medicine, more preferably electronegative targeted molecular, is further preferably hyaluronic acid and/or hyaluronate sodium, and the concentration of the aqueous solution of electronegative material is 0.1-20mg/mL,
Preferably, electronegative targeted molecular comprises the combination of any one or at least two kinds in hyaluronic acid, hyaluronate sodium, Trastuzumab, Transferrins,iron complexes, folic acid or arginine-glycine-aspartic acid sequence, it is preferable to hyaluronic acid and/or hyaluronate sodium;
Preferably, the molecular weight of electronegative targeted molecular is 1000-200,000, more preferably 3000-30,000;
Preferably, electronegative medicine comprises the combination of any one or at least two kinds that metal richness is strangled in alcohol, DNA, siRNA, protein drug, antibody, Indocyanine Green and new Indocyanine Green;
Preferably, the molecular weight of electronegative medicine is 500-30,000;
Can selection of land, repeating step (2) and/or step (3);
Preferably, described alcohol is that molecular weight is less than under 200 and normal temperature and pressure in the combination of any one in liquid alcohol or at least two kinds, it is preferable to methyl alcohol or ethanol.
9. a medicinal composition, it is characterised in that, described medicinal composition comprises gold gadolinium composite nano materials as described in item as arbitrary in claim 1-4;
Preferably, described medicinal composition is the kernel of silicon dioxide modified gold nanorods from inside to outside, is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the medicine of the positively charged of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer;
Preferably, described medicinal composition is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the drug molecule of the alternately positively charged of absorption of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer and electronegative drug molecule, wherein, first adsorbing the drug molecule of positively charged outside described gadolinium-containing silicon dioxide layer, electronegative medicine is in the outermost of medicinal composition;
Preferably, described medicinal composition is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the high molecular polymer of the alternately positively charged of absorption of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer and electronegative targeted molecular, wherein, first adsorbing the high molecular polymer of positively charged outside described gadolinium-containing silicon dioxide layer, electronegative targeted molecular is in the outermost of medicinal composition;
Preferably, described medicinal composition is the kernel of silicon dioxide modified gold nanorods from inside to outside, it is coated on the gadolinium-containing silicon dioxide layer outside described kernel, the medicine of the alternately positively charged of absorption of electrostatic adhesion outside described gadolinium-containing silicon dioxide layer and electronegative targeted molecular, wherein, first adsorbing the medicine of positively charged outside described gadolinium-containing silicon dioxide layer, electronegative targeted molecular is in the outermost of medicinal composition;
Preferably, described medicinal composition comprises the medicine thereon of gold gadolinium composite nano materials and load as described in item as arbitrary in claim 1-4;
Preferably, the mode of loading of described medicine is electrostatic adhesion; Taking the quality of described carrier as benchmark, the carrying drug ratio of described pharmaceutical composition is 1-30wt%, it is preferable to 10-20wt%;
Preferably, the combination of described medicine comprises doxorubicin hydrochloride, strangle in alcohol, DNA, siRNA, protein drug, antibody, Indocyanine Green ICG or new Indocyanine Green IR820 along platinum, metal richness any one or at least two kinds, it is preferable to the combination of any one or at least two kinds in doxorubicin hydrochloride, Indocyanine Green or new Indocyanine Green.
10. the purposes of a pharmaceutical composition as claimed in claim 9, it is characterised in that, described pharmaceutical composition can be used for imaging and treatment tumor disease.
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