CN112316143A - Asymmetric nano composite material of titanium dioxide-gold nanorod, preparation method and application thereof - Google Patents
Asymmetric nano composite material of titanium dioxide-gold nanorod, preparation method and application thereof Download PDFInfo
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- CN112316143A CN112316143A CN202011397346.1A CN202011397346A CN112316143A CN 112316143 A CN112316143 A CN 112316143A CN 202011397346 A CN202011397346 A CN 202011397346A CN 112316143 A CN112316143 A CN 112316143A
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- titanium dioxide
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- 239000002114 nanocomposite Substances 0.000 title claims abstract description 21
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- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- B22F9/00—Making metallic powder or suspensions thereof
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- B22F9/24—Making metallic powder or suspensions thereof using chemical processes with reduction of metal compounds starting from liquid metal compounds, e.g. solutions
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- B—PERFORMING OPERATIONS; TRANSPORTING
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Abstract
The invention discloses an asymmetric nano composite material of titanium dioxide-gold nanorods, a preparation method and application thereof, wherein one end of the gold nanorods is used as a growth point of the titanium dioxide nano, so that the titanium dioxide is directly contacted with one end of the gold nanorods and has an asymmetric structure, the length-diameter ratio of the gold nanorods is about 2.5-3.5, the thickness of the directly contacted titanium dioxide is 7-20 nm, the nano composite particles have better tumor permeability due to small size, are absorbed in a near infrared light region 650-shaped and 900 nm with stronger penetrability, and are subjected to surface modification by PEG and fluorescent molecule-PEG to increase biocompatibility. Can be used for near-infrared illumination of hypoxic tumors, and is suitable for photo-thermal and better photodynamic cooperative treatment; the synthesis method of the nano composite particles has the advantages of convenient operation, cheap raw materials, simple separation and the like.
Description
Technical Field
The invention relates to the technical field of nano materials, in particular to an asymmetric nano composite material of titanium dioxide-gold nanorods, a preparation method thereof and application thereof in the photo-thermal and photodynamic cooperative treatment of hypoxic tumors.
Background
In recent years, near-infrared-based phototherapy techniques, mainly including photothermal therapy and photodynamic therapy, have been widely developed because they exhibit advantages such as high accuracy, high efficiency, deep tissue permeability, minimal invasive surgery, and low side effects in tumor therapy. The photothermal therapy is to use a photothermal agent (such as gold nanoparticles, polyaniline nanoparticles, carbon nanotubes, polypyrrole nanoparticles, and the like) to realize irradiation heating on the tumor by near infrared light transmission so as to realize rapid ablation. However, locally excessive temperatures can cause a heat shock response and damage normal tissue surrounding the tumor. In addition, photodynamic, i.e., local generation of reactive oxygen species by photosensitizers under light, has also attracted considerable attention for the precise and effective treatment of tumors. However, considering that hypoxia is a common feature of tumors, the photodynamic effect of most photosensitizers diminishes as oxygen consumption at the tumor increases. In addition, small molecule photosensitizers have also limited the development of photodynamic activity due to rapid metabolism, photobleaching and autoxidation. Therefore, the method for treating various cancers such as photothermal therapy, photodynamic therapy and the like has the advantages due to the synergistic effect, and is the best choice for controllable and accurate treatment of tumors.
Compared with small molecules, the nano system is a promising tumor treatment strategy and has the advantages of long circulation, good stability, good passive targeting effect and the like in a living body. Titanium dioxide nano is an interesting and important photocatalyst, and has been researched and applied to the fields of catalysis and environment due to the advantages of low toxicity, good stability, high efficiency, low cost and the like. Under illumination, the process of generating active oxygen without depending on oxygen can well solve the problem of poor photodynamic effect of a plurality of photosensitizers in hypoxic tumors at present, thereby arousing wide attention. However, the application of the compound in the biological field is still faced with great challenge due to the large band gap requiring high-energy ultraviolet excitation and fast recombination of electron holes. Therefore, how to reduce the electron-hole recombination rate of titanium dioxide and adjust the excitation wavelength directly or indirectly to the near infrared range has important practical value in biological applications.
Currently, gold, silver, palladium nanoparticles with surface plasmon resonance and electron donating molecules have been applied to facilitate electron generation and enhance absorption of long wavelength light. But still has the problems that the penetration force at the tumor is influenced by overlarge composite nanometer size, a single photodynamic therapy mode is adopted, the electron transmission efficiency is low, and more absorbed light is in a visible region. Therefore, a representation of photothermal materials: gold nanorods (less than 15nm in diameter), flexible and adjustable SPR absorption, high photothermal conversion efficiency, low toxicity and good electron donor can be used for adjusting titanium dioxide nanometer. However, because the growth conditions of the gold nanorods are severe, the titanium dioxide nano can only be regenerated as a seed on the gold nanorods. However, under uncontrolled conditions, the synthesis of well-defined spatially separated titanium dioxide on single-ended small gold nanorods by a wet chemical method is still a technical problem to be solved.
Disclosure of Invention
The invention aims to provide a fluorescence-modified gold nanorod and titanium dioxide asymmetric nano composite particle, wherein the composite material is a composite nano particle for the photothermal and photodynamic synergistic treatment of hypoxic tumors; the nano composite particle has better tumor permeability due to small size, absorbs 650-900 nm in a near infrared region with stronger permeability, and is modified on the surface by PEG and fluorescent molecule-PEG to increase biocompatibility. Can be used for near-infrared illumination of hypoxic tumors, and is suitable for photo-thermal and better photodynamic cooperative treatment; the synthesis method of the nano composite particles has the advantages of convenient operation, cheap raw materials, simple separation and the like.
One of the objectives of the present invention is to provide an asymmetric nanocomposite of titanium dioxide-gold nanorods, wherein one end of the gold nanorod is used as a growth point of the titanium dioxide nanometer, so that the titanium dioxide directly contacts with the end of the gold nanorod and has an asymmetric structure, wherein the length-diameter ratio of the gold nanorod is about 2.5-3.5, the thickness of the directly contacting titanium dioxide is 7-20 nanometers, preferably 13-20 nanometers, the composite nanoparticle can transfer thermal electrons on the gold nanorod to a conduction band of the titanium dioxide through a schottky barrier under the irradiation of near-infrared light, and can simultaneously perform photothermal therapy and photodynamic therapy on a tumor part, and the structure of the composite nanoparticle is shown in fig. 1:
preferably, in the above technical solution, the surface of the asymmetric nanocomposite of titanium dioxide-gold nanorods is further modified by a fluorescent molecule emitting at 650-900 nm through an azo bond.
Preferably, for the technical solutions described above, the fluorescent molecule comprises: cyanine dyes, hemicyanine dyes, nile blue, methylene blue, rhodamine-based dyes. Further preferred are fluorescent molecules emitting at 810 nm.
The second aspect of the application is a method for synthesizing composite nanoparticles for the photothermal and photodynamic synergistic treatment of hypoxic tumors, which specifically comprises the following steps:
(1)C16mixing TAB with chloroauric acid solution, and then adding NaBH4Injecting the solution, standing and aging to obtain a gold seed solution;
(2) c is to be16After dissolving the TAB, adding silver nitrate, chloroauric acid, concentrated hydrochloric acid and ascorbic acid one by one, and uniformly stirring to obtain a gold nanorod growth solution;
(3) injecting the gold seed solution into the growth solution of the gold nanorods, mixing overnight and separating to obtain the gold nanorods with the length-width ratio of about 2.5-3.5 and the diameter of 10-20 nanometers;
(4) NaHCO is added3Dropwise addition of diluted TiCl3Obtaining Ti solution in the solution, and then adding gold nanorods and C16Adding the mixture of TAB into the Ti solution to react to obtain the final product, wherein the final product is an asymmetric structure formed by directly contacting and growing the titanium dioxide at one end of the gold nanorod, the length-diameter ratio of the gold nanorod is about 2.5-3.5, the thickness of the directly contacted titanium dioxide is 7-20 nanometers, preferably 13-20 nanometers, and finally storing the titanium dioxide in a C storage tank16TAB solution.
Preferably, in the above technical solution, the step of preparing the gold seed solution in step (1) of the method comprises: mixing 5-20 volumes of C with concentration of 0.1-0.5M16Mixing the TAB solution with a 10-50mM concentration of 0.1-3 volumes of chloroauric acid solution, and rapidly adding 0.6-1.2 volumes of NaBH while stirring4And standing and aging the solution to obtain the gold seed solution.
Preferably, in the above technical solution, the step of preparing the gold nanorod growth solution in step (2) in the method comprises: a certain amount of C16Dissolving TAB in 50-1000 volume of deionized water, cooling, and adding 2-10 volume of 1-10mM silver nitrate; stirring the mixture, and adding 5-20 volumes of chloroauric acid solution with the concentration of 0.5-2 mM; then the mixture turns colorless, and after stirring, 0-2 volumes of concentrated hydrochloric acid are added to adjust the pH value of the mixture; slowly stirring, adding 0.2-0.8 volume of ascorbic acid with concentration of 40-100mM, and stirring vigorously.
Preferably, in the above technical solution, the step of preparing gold nanorods in step (3) of the method comprises: injecting 0.2-0.5 volume of the gold seed solution prepared in the step (1) into the gold nanorod growth solution prepared in the step (2); after vigorous stirring for a short time, the resulting mixture was allowed to stand overnight to obtain a stock solution of gold nanorods; and (5) carrying out centrifugal separation to obtain the gold nanorods.
Preferably, for the technical scheme mentioned above, the step of preparing the final product in step (4) of the method comprises: diluting 0-0.5 ml of 10-30% TiCl with 2-15 volumes of deoxygenated water3(ii) a Stirring, adding 0.5-2M NaHCO3Dropwise addition of diluted TiCl3In solution; adding the final product after the mixture turns into blue solutionDropwise addition of excess NaHCO3Using deoxygenated water to centrifuge gold nanorod stock solution with volume of 0.1-2, diluting into volume of 0.1-1.8, and adding C with volume concentration of 0.2M to 0.1-314Mixing the TAB solution; then adding the blue solution into the blue solution; gently stirring/shaking the dispersion for more than 1 hour; centrifuging, washing to obtain final product, and storing in C16TAB solution.
Preferably, in the above technical solution, in order to further accurately guide the illumination position of the near infrared light, the method further includes modifying the surface of the final product composite nanostructure obtained in step (4) by azo bonds with fluorescent molecules emitting at 650-.
Preferably, in the above technical solution, the fluorescent molecule comprises ENBS-PEG-SH, PEG-SH and PEG-COOH to modify the synthesized composite nanoparticle for standby.
A third aspect of the present application consists in the use of said composite material in a product for the photothermal and photodynamic co-therapy of hypoxic tumours.
Has the advantages that:
the asymmetric composite nano particle has the advantages of low price of synthetic raw materials, simple and easy operation of the method, easy separation and the like.
The composite nano particle has small size, is absorbed in near infrared, has good biocompatibility, and solves various problems of the application of titanium dioxide nano in the biological field.
The asymmetric composite nano particle can be used for accurately performing appropriate photo-thermal and better photodynamic cooperative therapy on hypoxic tumors under near infrared light.
Drawings
FIG. 1 is a transmission electron micrograph of gold nanorods and gold nanorod-titanium dioxide asymmetric composite nanostructures, wherein: a is a transmission electron microscope picture of the gold nanorods, and B is a transmission electron microscope picture of the asymmetric composite nano structure of the gold nanorods and the titanium dioxide.
Fig. 2 is an elemental scan of a gold nanorod-titanium dioxide asymmetric composite nanostructure, wherein: a is a scanning view of the gold nanorod-titanium dioxide asymmetric composite nanostructure, B is elemental analysis of gold in the gold nanorod-titanium dioxide asymmetric composite nanostructure, and C is elemental analysis of titanium in the gold nanorod-titanium dioxide asymmetric composite nanostructure.
FIG. 3 shows the absorption diagram of gold nanorods and composite nanoparticles and the potential change of asymmetric nanostructure-modified PEG, wherein: a is an electron microscope picture of the gold nanorod (in water) and the gold nanorod-titanium dioxide asymmetric composite nanostructure (in ethanol), and B is a potential change picture of the gold nanorod-titanium dioxide asymmetric composite nanostructure in the modification process; 1: c on surface of asymmetric composite nano-structure gold rod16TAB is replaced by SH-PEG; 2: obtaining C on the surface of titanium dioxide on the basis of 116TAB is replaced by HOOC-PEG; 3: the modified fluorescent molecule PEG is replaced on the basis of 2.
Fig. 4 photo-thermal performance and active oxygen generation capacity ESR test of the nanomaterial, wherein: a is a photo-thermal experiment of the gold nanorod, the gold nanorod-titanium dioxide asymmetric composite nanostructure and the aqueous solution, and B is the capture condition of active oxygen of the gold nanorod and the gold nanorod-titanium dioxide asymmetric composite nanostructure.
FIG. 5 time detection of cellular uptake of asymmetric composite nanoparticles.
FIG. 6 is the killing effect of different concentrations of asymmetric composite nanoparticles on human breast cancer cells under hypoxic conditions. A is a gold nanostructure fully coated by titanium dioxide, and has almost no killing effect on cells; b is the compound which has better phototoxicity effect on human breast cancer cells under the condition of hypoxia;
FIG. 7 shows the imaging position and time guidance of the mouse tumor position before and after the fluorescence modification of asymmetric composite nanoparticles.
Fig. 8 is photothermal imaging of a tumor with nanoparticles under near-infrared laser irradiation.
Fig. 9 is the change volume of the mouse tumor and the change in weight of the mouse, where: a is the change in tumor volume over time in the mice under different treatment conditions, and B is the change in body weight over time in the mice under different treatment conditions.
Detailed Description
The following non-limiting examples are presented to enable those of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way. The synthesis of the composite nanoparticles of the present invention is illustrated below by way of example (but not limited thereto).
Example 1
A specific synthesis method of composite nano particles for photo-thermal and photodynamic synergistic therapy of hypoxic tumors.
And (3) synthesis of gold nanorods:
10 volume C16The TAB (0.1M) solution was mixed with 0.1 volume of chloroauric acid solution (25mM) in a 20 volume reaction flask, then stirred well at room temperature, and 1 volume of freshly prepared 100mM NaBH was added4The solution (ice-cooled) was quickly poured into the solution mixture. The solution was stirred rapidly for 2 minutes and allowed to stand at room temperature for aging.
3.6g C16TAB was dissolved in 100 volumes of deionized water and growth solutions of gold nanorods were prepared in 250 volumes of conical flasks. After cooling, 5 volumes of silver nitrate (4mM) were added. The mixture was left undisturbed at room temperature for 15 minutes, then 10 volumes of chloroauric acid solution (1mM) were added. The mixture then turned colorless and, after stirring well, 0.89 volume of concentrated hydrochloric acid was added to adjust the pH of the mixture. After further slow stirring, 0.50 volume of ascorbic acid (64mM) was added, and after vigorous stirring, 0.32 volume of gold seed solution was injected into the growth liquid. After vigorous stirring again, the resulting mixture was left undisturbed at room temperature for 12 hours for gold nanorod growth. The final product was separated by centrifugation and the supernatant removed (FIG. 1). FIG. 1A shows that the structure of the gold nanorods has relatively uniform morphology distribution, the length-diameter ratio is about 3, and the diameter is about 10-20 nm.
Synthesizing the gold nanorod-titanium dioxide asymmetric composite nanostructure:
0.1 ml of 10-15% TiCl is diluted with 10 volumes of deoxygenated water in a reaction flask3(different suppliers or batches may affect subsequent usage). Under stirring, 1M NaHCO3Dropwise addition of diluted TiCl3In solution. After the mixture turned into a blue solution, the last few drops of NaHCO were added3. Thereafter, the mixture (stock solution of 0.8 volume gold nanorods with deoxygenated water)After centrifugation, the mixture is diluted into 1.0-3.2 volume and 1.6 volume of 0.2M C14TAB solution mixed) was added to the above solution. The dispersion was then gently stirred/shaken for more than one hour. Collecting the product with a centrifuge, washing with ethanol once, and then with C16TAB solution (0.1M) was washed once and finally stored in C16TAB solution (fig. 1 and 2). The titanium dioxide was shown by fig. 1B and fig. 2 to grow asymmetrically directly on a single end of the gold nanorods, and the structure was further confirmed by elemental analysis.
The fluorescent molecule modifies the composite nanostructure:
modifying the synthesized composite nanoparticles by fluorescent molecules ENBS-PEG-SH, PEG-SH and PEG-COOH for later use.
Example 2
And (3) synthesis of gold nanorods:
1 volume C16The TAB (0.1M) solution was mixed with 0.01-0.2 volume of chloroauric acid solution (25mM) in a 20 volume reaction flask, followed by stirring at 30 ℃ for 5 minutes and addition of 0.06-0.1 volume of freshly prepared 100mM NaBH4The solution (ice-cooled) was quickly poured into the solution mixture. The solution was stirred rapidly for 2 minutes and allowed to stand at 30 ℃ for 30 minutes for aging.
C is to be16TAB was dissolved in a certain amount of deionized water (50 ℃) and a growth solution of gold nanorods was prepared in an erlenmeyer flask. After cooling to 30 ℃ 1 volume of silver nitrate (4mM) was added. The mixture was left undisturbed at 30 ℃ for 15 minutes, then 1.5-2 volumes of chloroauric acid solution (1mM) were added. The mixture then turned colorless and after stirring for 90 minutes (700 rpm), 0.2 volume of hydrochloric acid (37 wt% in water, 12.1M) was added to adjust the pH of the mixture. After stirring slowly for another 15 minutes (400 rpm), 0.1 to 0.2 volume of ascorbic acid (64mM) was added, stirring vigorously, and finally 0.01 to 0.02 volume of gold seed solution was injected into the growth liquid. After further vigorous stirring, the resulting mixture was left undisturbed at 30 ℃ for 12 hours for gold nanorod growth. The final product was centrifuged at 8000 rpm for 15 minutes and the supernatant removed.
Synthesizing a gold nanorod-titanium dioxide full-coating composite nanostructure:
in 5 bodyDiluting 0.04-0.05 vol.% 15% TiCl with 0.8-1 vol.% deoxygenated water in a reaction flask3(different suppliers or batches may affect subsequent usage). Under stirring, 1M NaHCO3Dropwise addition of diluted TiCl3In solution. After the mixture turned into a blue solution, the last 5-8 drops of NaHCO were added3. Thereafter, the mixture (0.1 volume of gold nanorod stock solution was centrifuged with deoxygenated water (8000 rpm) and diluted to 0.4 volume and 0.1 volume of 0.2M C14TAB solution mixed) was added to the dark blue solution. The dispersion was then gently stirred/shaken for more than one hour. The product was collected in a centrifuge for 10 minutes and washed once with ethanol and then with C16TAB solution (0.1M) was washed once and finally stored in C16TAB solution.
The fluorescent molecule modifies the composite nanostructure:
modifying the synthesized composite nanoparticles by fluorescent molecules ENBS-PEG-SH, PEG-SH and PEG-COOH for later use.
Example 3
A specific synthesis method of composite nano particles for photo-thermal and photodynamic synergistic therapy of hypoxic tumors.
And (3) synthesis of gold nanorods:
10 volume C16The TAB (0.1M) solution was mixed with 0.1 volume of chloroauric acid solution (25mM) in a 20 volume reaction flask, then stirred at room temperature for 5 minutes, and 1 volume of freshly prepared 100mM NaBH was added4The solution (ice-cooled) was quickly poured into the solution mixture. The solution was stirred rapidly for 2 minutes and allowed to stand at room temperature for aging.
7.2g C16TAB was dissolved in 200 volumes of deionized water (50 ℃) and growth solutions of gold nanorods were prepared in 250 volumes of conical flasks. After cooling to 30 ℃,10 volumes of silver nitrate (4mM) were added. The mixture was left undisturbed at 30 ℃ for 15 minutes, and then 20 volumes of chloroauric acid solution (1mM) were added. The mixture then turned colorless and after stirring for 90 minutes (700 rpm), 1.72 volumes of concentrated hydrochloric acid were added to adjust the pH of the mixture. After stirring slowly for another 15 minutes (400 rpm), 1 volume of ascorbic acid (64mM) was added, and the mixture was vigorously stirred for 30 seconds, and finally added to the growth solution0.64 volume of gold seed solution was injected. After further vigorous stirring for 30 seconds, the resulting mixture was left undisturbed at 30 ℃ for 12 hours for gold nanorod growth. The final product was centrifuged at 8000 rpm for 15 minutes and the supernatant removed.
Synthesizing the gold nanorod-titanium dioxide asymmetric composite nanostructure:
0.4 ml of 15% TiCl are diluted with 8 volumes of deoxygenated water in a 50-volume reaction flask3(different suppliers or batches may affect subsequent usage). Under stirring, 1M NaHCO3Dropwise addition of diluted TiCl3In solution. After the mixture turned into a dark blue solution, the last two or three drops of NaHCO were added3. Thereafter, the mixture (1 volume of gold nanorod stock solution centrifuged with deoxygenated water (8000 rpm) was diluted to 3.6 volumes and 1 volume of 0.2M C14TAB solution mixed) was added to the dark blue solution. The dispersion was then gently stirred/shaken for 30 minutes. The product was collected by centrifuge at 6000 rpm for 10 minutes and washed once with ethanol and then with C16TAB solution (0.1M) was washed once and finally stored in C16TAB solution.
The fluorescent molecule modifies the composite nanostructure:
modifying the synthesized composite nanoparticles by fluorescent molecules ENBS-PEG-SH, PEG-SH and PEG-COOH for later use.
Example 4
A specific synthesis method of composite nano particles for photo-thermal and photodynamic synergistic therapy of hypoxic tumors.
And (3) synthesis of gold nanorods:
10 volume C16The TAB (0.1M) solution was mixed with 0.1 volume of chloroauric acid solution (25mM) in a 20 volume reaction flask, followed by stirring at 30 ℃ for 5 minutes, and 1 volume of freshly prepared 100mM NaBH was added4The solution (ice-cooled) was quickly poured into the solution mixture. The solution was stirred rapidly for 2 minutes and allowed to stand at 30 ℃ for 30 minutes for aging.
14.4g C16TAB was dissolved in 200 volumes of deionized water (50 ℃ C.) and growth of gold nanorods was prepared in 500 volumes of Erlenmeyer flasksAnd (3) solution. After cooling to 30 ℃ 20 volumes of silver nitrate (4mM) were added. The mixture was left undisturbed at 30 ℃ for 15 minutes, then 40 volumes of chloroauric acid solution (1mM) were added. The mixture then turned colorless and after stirring for 90 minutes (700 rpm), 3.44 volumes of hydrochloric acid (37 wt% in water, 12.1M) were added to adjust the pH of the mixture. After stirring slowly for another 15 minutes (400 rpm), 2 volumes of ascorbic acid (64mM) were added, the mixture was stirred vigorously for 30 seconds, and finally 1.28 volumes of the gold seed solution were injected into the growth liquid. After further vigorous stirring for 30 seconds, the resulting mixture was left undisturbed at 30 ℃ for 12 hours for gold nanorod growth. The final product was centrifuged at 8000 rpm for 15 minutes and the supernatant removed.
Synthesizing the gold nanorod-titanium dioxide asymmetric composite nanostructure:
0.4 ml of 15% TiCl was diluted with 16 volumes of deoxygenated water in a 50-volume reaction flask3(different suppliers or batches may affect subsequent usage). Under stirring, 1M NaHCO3Dropwise addition of diluted TiCl3In solution. After the mixture turned into a dark blue solution, the last two or three drops of NaHCO were added3. Thereafter, the mixture (2 volumes of gold nanorod stock solution centrifuged with deoxygenated water (8000 rpm) was diluted to 7.2 volumes and 2 volumes of 0.2M C14TAB solution mixed) was added to the dark blue solution. The dispersion was then gently stirred/shaken for 30 minutes. The product was collected by centrifuge at 6000 rpm for 10 minutes and washed once with ethanol and then with C16TAB solution (0.1M) was washed once and finally stored in C16TAB solution.
The fluorescent molecule modifies the composite nanostructure:
modifying the synthesized composite nanoparticles by fluorescent molecules ENBS-PEG-SH, PEG-SH and PEG-COOH for later use.
The gold nanorod-titanium dioxide asymmetric composite nano structure and the gold nanorod-titanium dioxide full-wrapped composite nano particles are dispersed in an aqueous solution to prepare a solution with the volume of 5mg, test solutions with different concentrations are prepared according to requirements, and the change of the absorption spectrum of the test solutions is detected.
Example 5
The absorption spectrum and the surface modified potential of the gold nanorods and the gold nanorod-titanium dioxide asymmetric composite nanoparticles are changed.
The gold nanorods in the figure 3 and the asymmetric composite nano particles of the gold nanorods and the titanium dioxide are detected by an ultraviolet-visible spectrophotometer, wherein the absorption spectrum of the visible gold nanorods in the figure A is about 780nm, and after the titanium dioxide is modified, the absorption spectrum of the nano is subjected to red shift and the absorption is about 810 nm. And in the aqueous solution, PEG is modified by a replacement method, and C on the surface is removed16TAB, which is accompanied by a gradual decrease in potential. It can be proved by zeta potential instrument (as figure 3B) and the potential of the nano particle is reduced gradually after PEG-SH, PEG-COOH and ENBS-PEG-SH are modified step by step.
Example 6
The gold nanorod-titanium dioxide asymmetric composite nano has photo-thermal and active oxygen generation performances.
The gold nanorods and the asymmetric composite nano structure are put in water solution (100 micrograms/milliliter) and utilize 808nm and 800mW/cm2The laser light is illuminated and the infrared camera is used to collect the real-time temperature. By fig. 4, the temperature of the gold nanorods can rise to more than 70 ℃ in 9 minutes, while the temperature of the nanoparticles is only 48 ℃. And 2,2,6, 6-tetramethyl piperidine and 2, 2-dimethyl pyrroline nitrogen oxide are respectively added into the aqueous solution to capture singlet oxygen and hydroxyl free radicals generated by subsequent illumination, and then an electron paramagnetic resonance instrument is used for testing. From the electron paramagnetic resonance wave spectrum measured in fig. 4B, it can be found that the nanoparticle can generate a large amount of hydroxyl radicals and a small amount of singlet oxygen with hydrogen peroxide under the illumination of 808 nm.
Example 7
The intake time of the gold nanorod-titanium dioxide asymmetric composite nanoparticles by human breast cancer cells.
Fluorescein FITC was modified on the surface of the nanoparticles by PEG for intracellular tracking. Adding the nanoparticles modified with the fluorescent groups into a culture medium, co-incubating in a carbon dioxide incubator, and performing cell imaging by using an inverted fluorescence microscope at 0, 15, 30, 45, 60, 75 and 90min respectively. FIG. 5 shows that the nanoparticle uptake by human breast cancer cells varies with time, and it can be found that the uptake reaches a maximum value at 60 minutes, and then the uptake hardly varies for 30 minutes, indicating that the uptake of the nanoparticles by human breast cancer cells reaches a maximum value at about 1 hour
Example 8
The gold nanorod-titanium dioxide full-wrapping nanostructure and the gold nanorod-titanium dioxide asymmetric composite nano-scale have killing effect on human breast cancer cells.
And mixing the gold nanorod-titanium dioxide fully-encapsulated nanostructure into a cell culture medium, and incubating the cells in a carbon dioxide incubator. After 2 hours of incubation, the supernatant was removed, washed twice with phosphate buffered saline solution, replaced with fresh medium and then illuminated (808nm, 800 mW/cm)210min), then placed in the incubator for another 24 hours, and then added with the medium containing thiazole blue (0.5 mg/volume), and incubated for another 4 hours. The solution in the 96-well plate was then carefully removed, the crystals were dissolved in DMSO, and absorbance measurements were taken for each well using a microplate reader. After the treatment, the data are shown in fig. 6A, and it can be found that the titanium dioxide fully-wrapped gold nanostructure has almost no killing effect on cells. Under the condition of 2% oxygen, the other conditions are kept the same, and the test is carried out on the gold nanorod-titanium dioxide asymmetric composite nano-meter, so that the nano-meter has better phototoxicity effect (the cell survival rate is about 10%) on human breast cancer cells under the condition of low oxygen, and the cell survival rate without illumination is more than 80% in the figure 6B, which shows that the nano-meter has better biocompatibility and cell killing effect after modification.
Example 9
The nanoparticles were guided in tumor imaging location and time in mice.
Tumor implants were established by subcutaneous injection of 5X 106-1X 107 cells suspended in 100. mu.L PBS, after 7 days when the tumor volume reached about 90-100mm3Subsequent experiments were performed on tumor-bearing mice. To better guide the position of the tumor for phototherapy, the position of the tumor is controlledCan reduce the damage to the surrounding normal tissues and modify azo amino nile blue on the surface of the nanometer. The in vivo experiment is carried out by injecting azo amino nile blue and PEG modified nano particles into tail vein. After the nanometer is modified with azo ENBS, the nanometer reaches the tumor, and azo fracture can occur at the tumor with oxygen deficiency, so that the released fluorescent molecules can be used for fluorescence imaging at the tumor, and the subsequent photo-thermal-photodynamic therapy light position is guided. In fig. 7, the fluorescent dye enb is modified on the surface of the nanoparticle through azo bond, and when the nanoparticle modified with the fluorescent dye reaches an acidic tumor microenvironment, the azo bond connecting the dye is broken, and the fluorescent molecule fluoresces at the tumor. From the results, it can be seen that the fluorescence-modified nanoparticles can be observed to be enriched to the maximum value at the tumor under the excitation of 633nm light within 12 hours, so that the time and the position of the near-infrared illumination can be accurately guided. (the experimental mice were purchased from SPF laboratory animal center, university of Dalian medical science, the study was conducted according to the guidelines for Care and use of laboratory animals published by the national institutes of health, USA.) the animal experimental protocol was approved by the local research ethical review Committee, namely the university of Dalian university of Industrial science (ethical approval number is 2018-043).)
Example 10
The nano particles are used for photothermal imaging of tumors in mice.
The mouse is accurately illuminated in the near infrared two regions (808nm, 800 mW/cm) through the illumination position of the near infrared light guided by the fluorescence210min) treatment. Fig. 8 shows that the illumination temperature of the gold nanorods can reach about 55 ℃, while the temperature of the asymmetric nanoparticles is only 44 ℃. The temperature reached by the asymmetric nano particles can have a better killing effect on the tumor, and can not damage normal tissues around the tumor.
Example 11
The treatment effect of the nanoparticles on tumors in mice and the monitoring of the weight of the mice.
Mice were measured for tumor volume every two days. Fig. 9 shows the tumor change curves and the body weight changes of the mice in different experimental groups. Through comparison of tumor volumes of different experimental groups, the asymmetric nanostructure has a better inhibition effect on tumors, and compared with the photothermal treatment of a pure gold nanorod, the photothermal and photodynamic synergistic treatment mode also has the effect of preventing tumor recurrence. And the body weight of the mouse is basically not changed, which indicates that the nanometer is safe and low-toxicity.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed.
Claims (10)
1. An asymmetric nano composite material of titanium dioxide-gold nanorods, which is characterized in that: the nano composite material takes one end of the gold nanorod as a growth point of the titanium dioxide nano, so that the titanium dioxide is directly contacted with one end of the gold nanorod and has an asymmetric structure, wherein the length-diameter ratio of the gold nanorod is about 2.5-3.5, and the thickness of the directly contacted titanium dioxide is 7-20 nm.
2. The asymmetric nanocomposite of titanium dioxide-gold nanorods according to claim 1, characterized in that: the surface of the asymmetric nano composite material of the titanium dioxide-gold nanorod is further modified by a fluorescent molecule which emits at 650-900 nm through an azo bond.
3. The asymmetric nanocomposite of titanium dioxide-gold nanorods according to claim 1, characterized in that: the fluorescent molecule comprises: cyanine dyes, hemicyanine dyes, nile blue, methylene blue, rhodamine-based dyes.
4. A method of synthesizing composite nanoparticles according to claim 1, wherein: the method specifically comprises the following steps:
(1)C16mixing TAB with chloroauric acid solution, and then adding NaBH4Injecting the solution, standing and aging to obtain a gold seed solution;
(2) c is to be16After dissolving the TAB, adding silver nitrate, chloroauric acid, concentrated hydrochloric acid and ascorbic acid one by one, and uniformly stirring to obtain a gold nanorod growth solution;
(3) injecting the gold seed solution into the growth solution of the gold nanorods, mixing overnight and separating to obtain the gold nanorods with the length-width ratio of about 2.5-3.5 and the diameter of 10-20 nanometers;
(4) NaHCO is added3Dropwise addition of diluted TiCl3Obtaining Ti solution in the solution, and then adding gold nanorods and C16Adding the mixture of TAB into the Ti solution to react to obtain the final product, wherein the final product is an asymmetric structure formed by directly contacting and growing the titanium dioxide at one end of the gold nanorod, the length-diameter ratio of the gold nanorod is about 2.5-3.5, the thickness of the directly contacted titanium dioxide is 7-20 nanometers, and finally storing the titanium dioxide in a C storage tank16TAB solution.
5. The method for preparing the asymmetric nanocomposite of titanium dioxide-gold nanorods according to claim 4, characterized in that: the method for preparing the gold seed solution in the step (1) comprises the following steps: mixing 5-20 volumes of C with concentration of 0.1-0.5M16Mixing the TAB solution with a 10-50mM concentration of 0.1-3 volumes of chloroauric acid solution, and rapidly adding 0.6-1.2 volumes of NaBH while stirring4And standing and aging the solution to obtain the gold seed solution.
6. The method for preparing the asymmetric nanocomposite of titanium dioxide-gold nanorods according to claim 4, characterized in that: the method for preparing the gold nanorod growth solution in the step (2) comprises the following steps: a certain amount of C16Dissolving TAB in 50-1000 volume of deionized water, cooling, and adding 2-10 volume of 1-10mM silver nitrate; stirring the mixture, and adding 5-20 volumes of chloroauric acid solution with the concentration of 0.5-2 mM; then the mixture turns colorless, and after stirring, 0-2 volumes of concentrated hydrochloric acid are addedTo adjust the pH of the mixture; slowly stirring, adding 0.2-0.8 volume of ascorbic acid with concentration of 40-100mM, and stirring vigorously.
7. The method for preparing the asymmetric nanocomposite of titanium dioxide-gold nanorods according to claim 4, characterized in that: the method, in which the step (3) of preparing gold nanorods comprises: injecting 0.2-0.5 volume of the gold seed solution prepared in the step (1) into the gold nanorod growth solution prepared in the step (2); after vigorous stirring for a short time, the resulting mixture was allowed to stand overnight to obtain a stock solution of gold nanorods; and (5) carrying out centrifugal separation to obtain the gold nanorods.
8. The method for preparing the asymmetric nanocomposite of titanium dioxide-gold nanorods according to claim 4, characterized in that: the step of preparing the final product in the step (4) of the method comprises the following steps: diluting 0-0.5 ml of 10-30% TiCl with 2-15 volumes of deoxygenated water3(ii) a Stirring, adding 0.5-2M NaHCO3Dropwise addition of diluted TiCl3In solution; after the mixture turned into a blue solution, the final few drops of excess NaHCO were added3Using deoxygenated water to centrifuge gold nanorod stock solution with volume of 0.1-2, diluting into volume of 0.1-1.8, and adding C with volume concentration of 0.2M to 0.1-314Mixing the TAB solution; then adding the blue solution into the blue solution; gently stirring/shaking the dispersion for more than 1 hour; centrifuging, washing to obtain final product, and storing in C16TAB solution.
9. The method for preparing the asymmetric nanocomposite of titanium dioxide-gold nanorods according to claim 4, characterized in that: and (3) modifying the surface of the final product composite nanostructure obtained in the step (4) by using azo bonds to emit fluorescent molecules at 650-900 nm.
10. Use of the composite material of claim 1 in a product for the photothermal and photodynamic co-therapy of hypoxic tumors.
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