CN109589408A - A kind of meter of shape liquid metal nanoparticle and its synthetic method and application - Google Patents

A kind of meter of shape liquid metal nanoparticle and its synthetic method and application Download PDF

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Publication number
CN109589408A
CN109589408A CN201811478965.6A CN201811478965A CN109589408A CN 109589408 A CN109589408 A CN 109589408A CN 201811478965 A CN201811478965 A CN 201811478965A CN 109589408 A CN109589408 A CN 109589408A
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nanoparticle
liquid metal
melanin
gallium indium
metal nanoparticle
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CN109589408B (en
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严骏杰
杨敏
王辛宇
潘栋辉
徐宇平
杨润琳
王立振
赵富宽
张波
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Jiangsu Institute of Nuclear Medicine
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Jiangsu Institute of Nuclear Medicine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The present invention discloses the synthetic method of a kind of meter of shape liquid metal nanoparticle altogether, liquid metal is gallium indium eutectic, gallium indium eutectic is stablized with melanin nanoparticle in above-mentioned synthetic method, by controlling ultrasonic time >=15min, melanin nanoparticle concentration≤0.25mg/mL, rice shape liquid metal nanoparticle has been obtained.The photothermal conversion efficiency of rice shape liquid metal nanoparticle is high, photo and thermal stability is high, is a kind of preferable photo-thermal therapy material.The invention discloses a kind of meter of shape liquid metal nanoparticle, liquid metal nanoparticle is gallium indium eutectic nanoparticle, and the chelated surface melanin nanoparticle of gallium indium eutectic nanoparticle, the aspect ratio of liquid metal nanoparticle is 2:1-3:1.Photothermal conversion efficiency height, light and heat stability, the biocompatibility of rice shape liquid metal nanoparticle are high, and tumour ablation effect is good, and the photo-thermal therapy of tumour can be used for as photo-thermal therapy material.

Description

A kind of meter of shape liquid metal nanoparticle and its synthetic method and application
Technical field
The present invention relates to liquid metal technical fields, and in particular to a kind of meter of shape liquid metal nanoparticle and its synthesis side Method and application.
Background technique
Nano material is due to small-size effect, skin effect, quantum size effect and macro quanta tunnel effect etc. Property gets more and more people's extensive concerning.The performance of nanoparticle is formed with it, pattern is closely related, with specific shape Metal nanoparticle or alloy nano particle due to its special light, electricity, heat, mechanics, magnetism and catalytic performance, new energy, The fields such as photoelectric information storage, catalytic chemistry, imaging, sensing and biology medicine have broad application prospects.
The preparation method of metal or alloy nanoparticle mainly includes two classes: from top to bottom under method (top-down) and oneself And upper method (bottom-up).Method mainly uses physical method that metal or alloy material is separated into nanoscale small from top to bottom Particle, such as mechanical lapping, calcining, stretching, photoetching, microflow control technique etc..Method generallys use chemical reduction method from bottom to top, will The ion or complex of metal or alloy are reduced to metal or alloy atom, and atom is collected as nanoparticle；According to reduction mode Difference, chemical reduction method, Photoinduced Reduction method, electrodeposition process etc. can also be divided into.In the above way prepare metal or During alloy nano particle, by controlling the growth of nano material, it can obtain with different shape, size and size point The particle of cloth.
As a kind of metal of special shape, the flexibility, mobility and metal that liquid metal combines liquid are excellent Conductive performance, be applied to wearable electronic, reconfigurable circuit and function microfluidic device etc..Wherein, gallium base fluid State metal is due to having obtained extensive research with hypotoxicity, low viscosity and adjustable fusing point (below room temperature or room temperature).With Traditional a large amount of liquid metal is compared, micron and nanoscale liquid metal particle further expanded its in chemical catalysis, receive The application in the fields such as rice/micron electronic device, biomedicine, the energy.However, by liquid metal low melting point, good flowing properties, easily The influence of the factors such as aggregation causes the pattern in liquid metal nanoparticle synthesis process to control difficult, it is difficult to obtain having spy The liquid metal nano particle of setting shape.
Summary of the invention
Therefore, the technical problem to be solved in the present invention is that overcoming the pattern control of liquid metal nanoparticle in the prior art Difficult defect is made, to provide the preparation method of a kind of meter of shape liquid metal nanoparticle.
For this purpose, the invention provides the following technical scheme:
In a first aspect, the present invention provides the synthetic method of a kind of meter of shape liquid metal nano particle, the liquid metal For gallium indium eutectic, comprising the following steps:
Preparation includes the mixed solution of melanin nanoparticle and gallium indium eutectic, melanin nanoparticle in the mixed solution Concentration≤0.25mg/mL of son；
The mixed solution is ultrasonically treated, ultrasonic time >=15min, obtains a meter shape liquid metal nano particle.
Preferably, above-mentioned synthetic method, the concentration of melanin nanoparticle is 0.25mg/mL in the mixed solution.
Preferably, above-mentioned synthetic method, the ultrasonic treatment further include: control temperature≤60 of the mixed solution ℃。
Preferably, above-mentioned synthetic method, the preparation include the mixed solution of melanin nanoparticle and gallium indium eutectic The step of include: that melanin nanoparticle and gallium indium eutectic are added in solvent, inert gas is passed through into solvent, is included The mixed solution of melanin nanoparticle and gallium indium eutectic；Preferably, the solvent is water, and the inert gas is argon gas.
Preferably, above-mentioned synthetic method, the partial size of the melanin nanoparticle are 2-4nm.
Preferably, the preparation step of above-mentioned synthetic method, the melanin nanoparticle includes:
Soda acid processing is carried out to melanin granule, so that the partial size of the melanin granule is reduced into nanoscale, obtains black Plain nano-particle solution；
The melanin nano-particle solution obtains melanin nanoparticle through ultrafiltration, washing and drying process.
It is further preferred that above-mentioned synthetic method, the soda acid processing includes: that black is added into sodium hydroxide solution Crude granule obtains melanin solution, the use of the pH that hydrochloric acid solution adjusts the melanin solution is 7, obtains melanin nanoparticle Sub- solution；
The molecular cut off of the hyperfiltration treatment is 30kDa.
Preferably, above-mentioned synthetic method, further includes:
After being ultrasonically treated to the mixed solution, precipitating is discarded, takes upper layer slurries；The slurries are carried out at centrifugation Reason, discards precipitating, obtains being dispersed with a meter solution for shape liquid metal nano particle；Preferably, the condition of the centrifugal treating is 1000rpm, centrifugation time 5min.
Second aspect, the present invention provides a kind of meter of shape liquid metals nanoparticle, the liquid metal nanoparticle is Gallium indium eutectic nanoparticle, the chelated surface melanin nanoparticle of the gallium indium eutectic nanoparticle；The liquid metal is received The aspect ratio of rice corpuscles is 2:1-3:1；Preferably, the aspect ratio of the liquid metal nanoparticle is 2.3.
Preferably, above-mentioned rice shape liquid metal nanoparticle, the rice shape liquid metal nanoparticle is by claim The described in any item method synthesis of 1-8.
The third aspect, the present invention provides above-mentioned rice shape liquid metal nanoparticles, or synthesized by above-mentioned method Application of the rice shape liquid metal nanoparticle as photo-thermal therapy material.
Fourth aspect, the present invention provides above-mentioned rice shape liquid metal nanoparticles, or synthesized by above-mentioned method Application of the rice shape liquid metal nanoparticle in the reagent of preparation treatment tumour.
5th aspect, the present invention provides a kind of photo-thermal therapy agent, the photo-thermal therapy agent includes above-mentioned rice shape liquid Metal nanoparticle, or the rice shape liquid metal nanoparticle synthesized by above-mentioned method.
6th aspect, the present invention provides a kind of oncotherapy kit, the kit includes above-mentioned rice shape liquid Metal nanoparticle, the rice shape liquid metal nanoparticle synthesized by above-mentioned method or above-mentioned photo-thermal therapy agent.
Technical solution of the present invention has the advantages that
1. the synthetic method of provided by the invention meter of shape liquid metal nanoparticle stablizes gallium indium with melanin nanoparticle Eutectic.By ultrasonic treatment, gallium indium eutectic is processed as small nano particle, meanwhile, the cavitation bubble in liquid is in ultrasonication Lower generation vibration grows and collapses closure, when break up gas bubbles, generates high temperature, the high pressure of transient state, induces solution and lifts generation electricity From and excitation.Heat and active oxygen in ultrasonic procedure induce the Surface Creation monohydroxy gallium oxide in gallium indium eutectic nanoparticle (GaOOH).The gallium oxide hydroxide layer of catechol group and gallium indium eutectic nanoparticle surface in melanin nanoparticle is more Valence chelating, significantly improves gallium indium eutectic nanoparticle solubility in the solution and stability.In addition, in ultrasonic procedure with The increase of solution temperature, gallium indium eutectic nanoparticle are further assembled, are grown.The present invention passes through the study found that with melanin During nanoparticle and gallium indium eutectic ultrasound prepare rice shape liquid metal nanoparticle, the pattern of liquid metal nanoparticle Certain dependence is presented in concentration and ultrasonic time to melanin nanoparticle: when ultrasonic time is less than 15min, melanin is received It when the concentration of rice corpuscles is greater than 0.25mg/mL, is only capable of obtaining spherical liquid metal nanoparticle, passes through melanin in control solution Concentration≤the 0.25mg/mL and ultrasonic time >=15min of nanoparticle, can synthesize the liquid metal nanoparticle of meter shape Son.In addition, the pattern of liquid metal nanoparticle has the type of liquid metal and the ligand species of stable liquid metal It is selective, when changing ligand species (such as: changing into hyaluronic acid, PDMAPS etc. by melanin nanoparticle), Huo Zhegai Change liquid metal type (such as: gallium indium tin eutectic, gallium tin alloy etc. are changed by gallium indium eutectic), liquid metal nanoparticle Rice shape pattern also changes correspondingly.
The present invention stablizes gallium indium eutectic for the first time with melanin nanoparticle, by modulating melanin nanoparticle concentration and surpasses The sonication time has obtained the liquid metal nanoparticle with specific morphology.The pattern of nanoparticle and its physics, chemically Can be closely related, determine the property of nanoparticle.The rice shape liquid metal obtained with preparation method provided by the invention Nanoparticle has preferable light- heat transfer efficiency, after by near infrared light (NIR) irradiation, absorbs luminous energy and is converted into thermal energy. Wherein, the melanin nanoparticle of the rice shape pattern of liquid metal nanoparticle and chelated surface cooperates, and is conducive to mention The photothermal conversion efficiency of high nanoparticle.In the liquid metal nanoparticle of three kinds of nanotopographies provided by the invention, rice shape For liquid metal nanoparticle after using near-infrared laser (808nm) irradiation, the increasing extent of temperature (32.2 DEG C) in 10 minutes is bright It is aobvious to be higher than stick gallium indium eutectic nanoparticle (28.8 DEG C) and spherical gallium indium eutectic nanoparticle (23.7 DEG C)；Meanwhile rice shape The photo and thermal stability of liquid metal nanoparticle is high, and apparent temperature range does not occur in heating-cooling cyclic process and becomes Change, be dispersed with a meter suspension for shape liquid metal nanoparticle and keep high degree of dispersion in heating-cooling cyclic process, in suspension It is generated without precipitating.The light- heat transfer of rice shape liquid metal nanoparticle is high-efficient, photo and thermal stability is high, is suitable for photo-thermal and controls Treat photo-thermal therapy (PTT, Photothermaltherapy) of the agent for diseases such as tumours.
2. the synthetic method of provided by the invention meter of shape liquid metal nanoparticle, when melanin nanoparticle in mixed solution When the concentration of son is greater than 0.25mg/mL, it is only capable of the liquid metal nanoparticle of synthesizing spherical；It is dense when melanin nanoparticle When degree control is 0.25mg/mL, a meter shape liquid metal nanoparticle can not only obtain, liquid metal nanoparticle is in the solution Dispersion stabilization further increase, send out do not form precipitating in the solution.It is lower than the melanin nanoparticle of 0.25mg/mL with concentration The liquid metal nanoparticle that son obtains is compared, and melanin nanoparticle concentration can obtain stability most when being 0.25mg/mL Good liquid metal nanoparticle.
3. the synthetic method of provided by the invention meter of shape liquid metal nanoparticle controls ultrasonic temperature≤60 DEG C, passes through The locating temperature environment of control ultrasonic treatment, is conducive to a meter formation for shape liquid metal nanoparticle, avoids liquid metal nanometer The pattern of particle changes, and (for example, when ultrasonic temperature is higher than 70 DEG C, the pattern of liquid metal nanoparticle changes into stick Shape).In ultrasonic procedure, by being ultrasonically treated under ice bath environment, temperature in ultrasonic procedure is controlled.Ultrasonic mistake Solution temperature increases by 0 DEG C in journey, and final control is at 60 DEG C or less.
4. the synthetic method of provided by the invention meter of shape liquid metal nanoparticle, melanin nanoparticle and gallium indium are total to Crystalline substance is added in solvent, and inert gas is passed through into solvent, obtains the mixed solution comprising melanin nanoparticle and gallium indium eutectic. By being passed through inert gas to protect liquid metal, avoids it from forming oxide layer before ultrasound, keep liquid metal nanoparticle logical The active oxygen generated in ultrasonic procedure is crossed, increasingly generates monohydroxy gallium oxide (GaOOH) on its surface.
5. the synthetic method of provided by the invention meter of shape liquid metal nanoparticle, in the preparation of melanin nanoparticle Cheng Zhong makes the functional group on melanin granule surface through acid, alkaline solution treatment by carrying out water-soluble processing to melanin granule Afterwards, it is unitized；Meanwhile in soda acid treatment process, the partial size of melanin granule is reduced significantly, and obtaining partial size is nanoscale Melanin nano-particle solution；Melanin nano-particle solution effectively removes residual in melanin nanoparticle after hyperfiltration treatment The NaCl stayed, last washed and drying process, obtains melanin nanoparticle.When melanin granule is processed into nanoscale Afterwards, metal chelation abilities significantly increase, and are conducive to melanin nanoparticle and gallium indium eutectic nanoparticle surface monohydroxy oxygen Change the multivalence chelating of gallium layer.
6. the present invention provides a kind of meter of shape liquid metal nanoparticles, wherein liquid metal is gallium indium eutectic nanoparticle Son, the chelated surface melanin nanoparticle of gallium indium eutectic nanoparticle.Melanin nanoparticle passes through gallium indium eutectic nanoparticle The monohydroxy gallium oxide layer in sublist face and its multivalence chelate, and obtain the rice shape liquid metal nanometer stable by melanin nanoparticle Particle, the aspect ratio of liquid metal nanoparticle are 2:1-3:1.The photothermal conversion efficiency of rice shape liquid metal nanoparticle (36.7%) high, better than stick gallium indium eutectic nanoparticle (28.8%) and spherical gallium indium eutectic nanoparticle (33.3%), energy It is enough effectively to absorb near infrared light and be converted into thermal energy.Melanin nanoparticle is matched with gallium indium eutectic nanoparticle, is not only had There are higher photothermal conversion efficiency, photo and thermal stability also with higher, point of rice shape liquid metal nanoparticle in the solution It is high to dissipate stability, dispersion can be kept not generate precipitating for a long time.
7. the rice shape that provided by the invention meter of shape liquid metal nanoparticle or synthetic method provided by the present invention obtain Liquid metal nanoparticle has high photothermal conversion efficiency and photo and thermal stability, meanwhile, rice shape liquid metal nanoparticle Dispersion stabilization is good, cytotoxicity is low, biocompatibility is high, is a kind of good photo-thermal therapy material, can be efficiently applied to Photo-thermal therapy.
8. provided by the invention meter of shape liquid metal nanoparticle, or the liquid obtained with synthetic method provided by the invention Metal nanoparticle is when being applied to the reagent of preparation treatment tumour, since rice shape liquid metal nanoparticle swashs by nearly feux rouges After hair, heat can be discharged, rice shape liquid metal nanoparticle can effective ablated tumor tissue, while not causing apparent body Mitigate again, there is preferable biocompatibility.Since rice shape liquid metal nanoparticle has both high photothermal conversion efficiency and life Object compatibility, it is good for the therapeutic effect of tumour with the reagent that it is prepared, it is applied to tumour suitable for preparing oncotherapy reagent Clinical treatment.
Detailed description of the invention
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution in the prior art Embodiment or attached drawing needed to be used in the description of the prior art be briefly described, it should be apparent that, it is described below Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor It puts, is also possible to obtain other drawings based on these drawings.
Fig. 1 is the synthesis process figure of the rice shape liquid metal nanoparticle of one embodiment of the invention；
Fig. 2 is the high resolution TEM image (HRTEM) of the melanin nanoparticle of one embodiment of the invention；
Fig. 3 is the pattern of the rice shape liquid metal nanoparticle of one embodiment of the invention and the characterization result figure of structure；
Fig. 4 is the scanning transmission electron microscope (STEM) of the rice shape liquid metal nanoparticle of one embodiment of the invention With energy dispersion X ray spectrum figure (EDS)；
Fig. 5 is the X-ray diffractogram (XRD) of the rice shape liquid metal nanoparticle of one embodiment of the invention；
Fig. 6 is the rice shape liquid metal nanoparticle of the rice shape liquid metal nanoparticle of one embodiment of the invention FTIR spectrogram；
Fig. 7 is the XPS spectrum figure of the rice shape liquid metal nanoparticle of one embodiment of the invention；
Fig. 8 is the daylight figure of the rice shape liquid metal suspension of one embodiment of the invention；
Fig. 9 is transmission electron microscope (TEM) image of the liquid metal nanoparticle of an experimental example of the invention；
Figure 10 is transmission electron microscope (TEM) image of the liquid metal nanoparticle of an experimental example of the invention；
Figure 11 is dynamic light scattering (DLS) testing result figure of the liquid metal nanoparticle of an experimental example of the invention；
Figure 12 is the zeta potential diagram of the liquid metal nanoparticle of an experimental example of the invention；
Figure 13 is the UV-visible absorption spectrum (UV- of the liquid metal nanoparticle of an experimental example of the invention vis)；
Figure 14 is transmission electron microscope (TEM) image of the liquid metal nanoparticle of an experimental example of the invention；
Figure 15 is the day light image of the liquid metal nanoparticle suspension of an experimental example of the invention；
Figure 16 is dynamic light scattering (DLS) testing result figure of the liquid metal nanoparticle of an experimental example of the invention
Figure 17 is the zeta potential diagram of the liquid metal nanoparticle of an experimental example of the invention；
Figure 18 is the transmission electron microscopy of the stable gallium indium eutectic nanoparticle of the different ligands of an experimental example of the invention Mirror (TEM) image；
Figure 19 is the stability result figure of the stable gallium indium eutectic nanoparticle of the different ligands of an experimental example of the invention；
Figure 20 is transmission electron microscope (TEM) image of the liquid metal nanoparticle of an experimental example of the invention；
Figure 21 is transmission electron microscope (TEM) image of the liquid metal nanoparticle of an experimental example of the invention；
Figure 22 is transmission electron microscope (TEM) image of the liquid metal nanoparticle of an experimental example of the invention；
Figure 23 is the ultraviolet-ray visible absorbing light of the liquid metal nanoparticle of the different-shape of an experimental example of the invention Spectrum；
Figure 24 is the photothermal response curve of the liquid metal nanoparticle of the different-shape of an experimental example of the invention；
Figure 25 is the near-infrared laser irradiation rice shape gallium indium eutectic nanoparticle of the different frequency of an experimental example of the invention Photothermal response curve；
Figure 26 is the photothermal response of the rice shape gallium indium eutectic nanoparticle suspension of the various concentration of an experimental example of the invention Curve；
Figure 27 is the circulation light thermal response curve of the rice shape gallium indium eutectic nanoparticle of an experimental example of the invention；
Figure 28 is temperature-Ln cooling time of the liquid metal nanoparticle of the different-shape of an experimental example of the invention The linearity curve of (Δ T/ Δ Tmax) fitting；
Figure 29 is irradiating laser and not irradiating the rice shape gallium indium eutectic nanoparticle under laser for one experimental example of the present invention The cytotoxicity of son detects (MTT) result figure；
Figure 30 is the Calcein AM/PI colored graph of the 4T1 cell of an experimental example of the invention；
Figure 31 is the dynamic transmission that the continuous laser of one experimental example of the present invention irradiates lower rice shape gallium indium eutectic nanoparticle Electron microscope image；
Figure 32 is the thermal-induced imagery of mouse under the laser irradiation of different time of an experimental example of the invention；
Figure 33 is one experimental example of the present invention respectively with PBS processing, PBS and laser irradiation processing, rice shape gallium indium eutectic The biology of 4T1 tumour growth in the mouse of nanoparticle processing and rice shape gallium indium eutectic nanoparticle and laser irradiation processing Illuminated diagram；
Figure 34 is one experimental example of the present invention with rice shape gallium indium eutectic nanoparticle and laser irradiation processing, rice shape gallium indium 4T1 tumor tissues is immune in the mouse of the processing of eutectic nanoparticle, PBS and frame pipe treatment with irradiation and laser irradiation processing Histochemical stain figure；
Figure 35 is the tumour growth and mouse survival state-detection knot of the different treatment group mouse of an experimental example of the invention Fruit figure.
Specific embodiment
Technical solution of the present invention will be clearly and completely described below, it is clear that described embodiment is this hair Bright a part of the embodiment, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art are not having Every other embodiment obtained under the premise of creative work is made, shall fall within the protection scope of the present invention.In addition, below Technical characteristic involved in described different embodiments of the present invention as long as they do not conflict with each other can be mutual In conjunction with.
The instrument being related in following embodiments is as follows:
Nuclear Magnetic Resonance Varian Mercury 400；Scanning electron microscope FEI Verios 460L；Freezing scanning electricity Sub- microscope JEOL 7600F；Transmission electron microscope JEOL 2000FX, FEI Titan 80-300；X-ray diffractometer Rigaku SmartLab；Dynamic light scattering Malvern Zetasizer Nano ZS；Laser confocal microscope Carl Zeiss LSM 710；Ultrasound Instrument FisherbrandTM Model 505。
Experiment reagent used in following embodiments is as follows:
Gallium indium eutectic, gallium indium tin eutectic sow tin alloy and are purchased from AlfaAesar；Hyaluronic acid is purchased from FredaBiochemCo.；Other reagents are purchased from Sigma.
The 4T1 cell origin of cytotoxicity detection in following experimental examples is in U.S.'s ATCC cell bank.
Embodiment 1
The present embodiment provides the synthetic methods of a kind of meter of shape liquid metal nanoparticle, wherein liquid metal is total for gallium indium Brilliant (also known as: gallium-indium alloy).The synthesis process of rice shape liquid metal nanoparticle is as shown in Figure 1, the specific steps are as follows:
1, the melanin nanoparticle of synthesizing water-solubility
With vigorous stirring, the melanin granule of 50mg is dissolved in the 0.1NNaOH of 20mL, obtains melanin solution, It is 7 that the pH for instilling 0.1NHCl to solution into alkaline plain solution while ultrasonic, which is neutralized, obtains melanin nano-particle solution. In soda acid treatment process, unify the surface functional group of melanin granule, melanin granule is big by partial size, water-soluble low Particle changes into readily soluble nanometer particle.
It usesSuper filter tube carries out purification process to melanin nano-particle solution, the retention phase of super filter tube to point Protonatomic mass is 30 kDa.Solution after purification is washed with deionized, to remove sodium chloride, then freeze-drying obtains black Plain nanoparticle powder, yield: 65.4%.
The chemical structure of melanin nanoparticle is as follows:
2, rice shape liquid metal nanoparticle is synthesized
The gallium indium eutectic of the melanin nanoparticle of 3.0mg and 80 μ L are added in 12mL deionized water, Xiang Shuizhong is passed through Argon gas 10 minutes, obtain the mixed solution comprising melanin nanoparticle and gallium indium eutectic.
Under ice bath environment, mixed solution is ultrasonically treated, ultrasonic time 15min.Ultrasound Instrument parameter is as follows: frequency Rate, 20kHz；Rated power, 500 watts；Probe diameter is 3 millimeters；Amplitude 35%.
After ultrasonic treatment, the precipitating of bulky grain is discarded, takes upper layer slurries；Under the revolving speed of 1000rpm by upper layer slurries from The heart handles 5min, further removes the precipitating of bulky grain, makes solution purification, obtains evenly dispersed having a meter shape liquid metal nanoparticle The suspension namely rice shape gallium indium eutectic nanoparticle suspension of son.
The pattern and structural characterization of melanin nanoparticle are as follows:
The pattern of melanin nanoparticle is observed using high resolution TEM (HRTEM).As a result such as Fig. 2 a With shown in Fig. 2 b, Fig. 2 a is the high resolution TEM image of melanin nanoparticle, and scale 10nm is as shown in Figure 2, black Pigment nanoparticle has dispersibility well, and partial size is small, levels off to spherical shape.To the melanin nanoparticle in HRTEM image Partial size counted, obtain shown in Fig. 2 b as a result, by Fig. 2 b it is found that the particle diameter distribution Relatively centralized of melanin nanoparticle, Average grain diameter is 3.1 ± 0.6nm.
Rice shape liquid metal nanoparticle is characterized as below:
1, pattern and structural characterization
Fig. 3 is the pattern of rice shape liquid metal nanoparticle and the characterization result figure of structure.Wherein, Fig. 3 b shows rice shape liquid Transmission electron microscope (TEM) image of state metal nanoparticle, scale, 200nm.By Fig. 3 b it is found that liquid metal nanoparticle The pattern of son is in rice shape, counts to the aspect ratio of liquid metal nanoparticle, obtains liquid metal nanoparticle in length and breadth Than in the range of 2:1-3:1, the average value of aspect ratio is 2.3.Fig. 3 c shows the height of rice shape liquid metal nanoparticle Resolution Transmission Electronic Speculum (HRTEM) image, scale, 50nm；Fig. 3 d shows that the dark field scanning of rice shape liquid metal nanoparticle is saturating Penetrate electron microscope (STEM) image, scale, 50nm.By Fig. 3 c and Fig. 3 d it is found that rice shape liquid metal nanoparticle is by small Nano particle assembles.Scanning electron microscope (SEM) image of Fig. 3 e display rice shape liquid metal nanoparticle, scale, 500nm；Freezing scanning electron microscope (Cryo-SEM) image of Fig. 3 f display rice shape liquid metal nanoparticle, scale, 250nm.By Fig. 3 e and Fig. 3 f it is found that rice shape liquid metal nanoparticle is assembled by small nano particle.Fig. 3 e and Fig. 3 f Display rice shape liquid metal nanoparticle in drying regime and the shape appearance figure that is scattered under the liquid condition in solution, by Fig. 3 e and Fig. 3 f is not it is found that the drying of rice shape liquid metal nanoparticle or liquid condition have an impact the pattern of nanoparticle.
2, structure and elemental analysis
Rice shape liquid metal is received using scanning transmission electron microscope and energy dispersion X-ray spectrum (STEM-EDS) Structure and the element composition of rice corpuscles are analyzed.As a result as shown in Figure 4: Fig. 4 g shows the angle of elevation of scanning transmission electron microscope Annular dark field image, scale, 200nm.Fig. 4 h- Fig. 4 j shows the rice shape liquid metal nanoparticle using STEM-EDS observation Distribution diagram of element, Fig. 4 K be Fig. 4 h- Fig. 4 j fusion figure, by Fig. 4 h- Fig. 4 k it is found that rice shape liquid metal nanoparticle In Ga element and In element in gallium indium eutectic is not only distributed with, be also evenly distributed with oxygen element.
Fig. 5 is the X-ray diffractogram of rice shape liquid metal nanoparticle, and EGaInnanorice indicates rice shape liquid in figure Metal nanoparticle (namely: rice shape gallium indium eutectic nanoparticle).As shown in Figure 5, in rice shape liquid metal nanoparticle by In, GaOOH composition, is consistent with the observed result of STEM-EDS.
3, surface group, elemental analysis
It is characterized by surface group of the Fourier transform infrared spectroscopy (FTIR) to rice shape liquid metal nanoparticle, Fig. 6 shows the FTIR spectrogram of rice shape liquid metal nanoparticle, and the EGaInnanorice in Fig. 6 indicates that rice shape liquid metal is received Rice corpuscles (namely: rice shape gallium indium eutectic nanoparticle), MNPs indicates melanin nanoparticle.It will be appreciated from fig. 6 that rice shape liquid gold Belong to the Fourier transform infrared spectroscopy of nanoparticle by with 1370cm-1, 1593cm-1, 1716cm-1And 3370cm-1Centered on it is several A master tape composition, 1593 cm-1And 3370cm-1The band at place is attributed to the stretching vibration of C=C and OH key respectively.1716cm-1Place Signals assignment C=O, show the presence of quinone.Melanin nanoparticle and gallium indium eutectic interact to form a meter shape gallium indium eutectic After nanoparticle, 1716cm-1The significant decline of the absorption at place；Meanwhile in 1023cm-1And 1261cm-1There are two new suctions in place Peak is received, they are the bending vibration band of Ga-OH and the stretching vibration band of the C-OH from carboxyl or phenol respectively.These tables of data Bright, the quinone intermediate of melanin nanoparticle may be converted to catechol, and the monohydroxy gallium oxide with gallium indium eutectic surface (GaOOH) it is coordinated.
Further divided using surface-element of the x-ray photoelectron spectroscopy (XPS) to rice shape liquid metal nanoparticle Analysis, the XPS spectrum figure of rice shape liquid metal nanoparticle are as shown in Figure 7.Wherein, Fig. 7 a shows the full spectrum of x-ray photoelectron spectroscopy Figure, by Fig. 7 a it is found that the surface of rice shape liquid metal nanoparticle mainly contains C, O, N and Ga element.Fig. 7 b is shown by C1s The high-resolution C1s spectrogram of fitting, Fig. 7 b disclose four kinds of different types of carbon: CHx, C-NH2；C-O, C-N；C=O and π → π*.Fig. 7 c shows the high-resolution O1s spectrogram being fitted by O1s, and 531.6eV corresponds to metal oxide (O-Ga) in Fig. 7 c It is formed, and the O=C signal peak at the 530.3eV at the signal peak ratio 534.5eV of O-C is much better than.Fig. 7 c is shown by Ga 3d The high-resolution Ga 3d spectrogram of fitting, Fig. 7 c demonstrate Ga and Ga3+Presence.By the rice shape liquid metal nanoparticle of Fig. 7 XPS spectrum figure known to: melanin nanoparticle passes through the monohydroxy gallium oxide of catechol and gallium indium eutectic nanoparticle surface GaOOH multivalence chelating, to successfully be bonded in the surface of gallium indium eutectic nanoparticle.
By observing freshly prepared rice shape liquid metal nanoparticle suspension and the rice shape liquid after gravity induced precipitation The daylight figure (Fig. 8) of metal suspension, detects melanin nanoparticle and the bond strength of gallium indium eutectic, MNPs in Fig. 8 Indicate that melanin nanoparticle suspension, Nanorice indicate rice shape liquid metal nanoparticle suspension.It can by Fig. 8 testing result Know, after gravity induction rice shape liquid metal nanoparticle precipitating, does not observe the face of melanin nanoparticle in supernatant Color illustrates that there are strong interactions between melanin nanoparticle and gallium indium eutectic.
The forming process of rice shape liquid metal nanoparticle is inferred by the characterization result of rice shape liquid metal nanoparticle: super Gallium indium eutectic is processed as small nano particle by strong shearing force by sound, and the cavitation bubble in liquid generates high temperature, the height of transient state Pressure ring border, the heat and active oxygen that generate in ultrasonic procedure make the Surface Creation monohydroxy gallium oxide of gallium indium eutectic nanoparticle (GaOOH).The monohydroxy gallium oxide layer of catechol group and gallium indium eutectic nanoparticle surface in melanin nanoparticle Multivalence chelating obtains the gallium indium eutectic nanoparticle that water-soluble and dispersion stabilization improves.Meanwhile with temperature in ultrasonic procedure Further raising, gallium indium eutectic nanoparticle further assembles, grows, finally obtain a meter shape liquid metal nanoparticle ( That is, rice shape gallium indium eutectic nanoparticle).
Comparative example 1
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: the ultrasonic time being ultrasonically treated in step 2 to mixed solution is 2min.
Comparative example 2
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: the ultrasonic time being ultrasonically treated in step 2 to mixed solution is 4min.
Comparative example 3
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: the ultrasonic time being ultrasonically treated in step 2 to mixed solution is 6min.
Comparative example 4
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: the ultrasonic time being ultrasonically treated in step 2 to mixed solution is 8min.
Comparative example 5
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: the ultrasonic time being ultrasonically treated in step 2 to mixed solution is 10min.
Comparative example 6
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: the ultrasonic time being ultrasonically treated in step 2 to mixed solution is 20min.
Comparative example 7
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: the ultrasonic time being ultrasonically treated in step 2 to mixed solution is 30min.
Comparative example 8
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: the ultrasonic time being ultrasonically treated in step 2 to mixed solution is 40min.
Comparative example 9
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: in step 2 by the gallium indium eutectic of the melanin nanoparticle of 0.6mg and 80 μ L be added 12mL deionized water In.
Comparative example 10
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: in step 2 by the gallium indium eutectic of the melanin nanoparticle of 1.2mg and 80 μ L be added 12mL deionized water In.
Comparative example 11
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: in step 2 by the gallium indium eutectic of the melanin nanoparticle of 1.8mg and 80 μ L be added 12mL deionized water In.
Comparative example 12
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: in step 2 by the gallium indium eutectic of the melanin nanoparticle of 4.8mg and 80 μ L be added 12mL deionized water In.
Comparative example 13
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: in step 2 by the gallium indium eutectic of the melanin nanoparticle of 7.2mg and 80 μ L be added 12mL deionized water In.
Comparative example 14
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: in step 2 by the gallium indium eutectic of the melanin nanoparticle of 9.0mg and 80 μ L be added 12mL deionized water In.
Comparative example 15
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: with gallium indium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 16
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 2 Difference be only that: with gallium indium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 17
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 3 Difference be only that: with gallium indium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 18
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 4 Difference be only that: with gallium indium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 19
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 5 Difference be only that: with gallium indium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 20
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 6 Difference be only that: with gallium indium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 21
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in embodiment 1 Difference be only that: with gallium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 22
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 2 Difference be only that: with gallium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 23
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 3 Difference be only that: with gallium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 24
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 4 Difference be only that: with gallium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 25
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 5 Difference be only that: with gallium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 26
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 6 Difference be only that: with gallium tin eutectic replace step 2 in gallium indium eutectic.
Comparative example 27
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, the specific steps are as follows:
1, synthesizing methyl propylene acidification hyaluronic acid (HA)
At 4 DEG C, the hyaluronic acid of 2.0g is dissolved in 50mL deionized water, then by the methacrylic acid of 1.6mL Acid anhydride is added dropwise in solution, obtains reaction mixture.The pH of reaction mixture is adjusted to 8-9 by the way that 1NNaOH is added, and It is stirred 30 hours at 4 DEG C, obtains the polymer of double bond modification.
Resulting polymers were subjected to purification process with deionized water dialysis 3 days, is then lyophilized, obtains methacrylated Bright matter acid, yield: 84.7%.
The structure of methacrylated hyaluronic acid is as follows:
2, synthesizing liquid metal nanoparticle
The gallium indium eutectic of the methacrylated hyaluronic acid of 5.0mg and 80 μ L are added in 12mL deionized water, Xiang Shui In be passed through argon gas 10 minutes, obtain the mixed solution comprising methacrylated hyaluronic acid and gallium indium eutectic.
Under ice bath environment, mixed solution is ultrasonically treated, ultrasonic time 15min.Ultrasound Instrument parameter is as follows: frequency Rate, 20kHz；Rated power, 500 watts；Probe diameter is 3 millimeters；Amplitude 35%.
After ultrasonic treatment, the precipitating of bulky grain is discarded, takes upper layer slurries；Under the revolving speed of 1000rpm by upper layer slurries from The heart handles 5min, further removes the precipitating of bulky grain, makes solution purification, obtains methacrylated hyaluronic acid (HA) and stablizes Liquid metal nanoparticle.
Comparative example 28
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, the specific steps are as follows:
1, poly- [2- (methacryloxy) ethyl] dimethyl-(3- sulfopropyl) ammonium hydroxide (PDMAPS) is synthesized
By DMAPS (279.4mg, 1.0mmol), PEG950 (850mg, 0.895mmol), 4- cyano -4- (thio phenyl Formyl) valeric acid (18.6mg, 0.067mmol) and 4,4 '-azo bis- (4- cyanopentanoic acid) (4.7mg, 0.0168mmol) dissolution In 0.5M sodium chloride solution, pH value of solution is adjusted to 7.Then, by freezing-evacuating-thaw cycles deoxygenation three times.
To react 20 hours in the oil bath that the mixture of deoxygenation is preheated at 70 DEG C, then in deionized water dialysis 3 days into Row purification process obtains baby pink spongy powder, as PDMAPS.Yield: 87.6%.
The chemical structure of PDMAPS is as follows:
2, synthesizing liquid metal nanoparticle
The gallium indium eutectic of the PDMAPS of 5.0mg and 80 μ L are added in 12mL deionized water, Xiang Shuizhong is passed through argon gas 10 and divides Clock obtains the mixed solution comprising PDMAPS and gallium indium eutectic.
Under ice bath environment, mixed solution is ultrasonically treated, ultrasonic time 15min.Ultrasound Instrument parameter is as follows: frequency Rate, 20kHz；Rated power, 500 watts；Probe diameter is 3 millimeters；Amplitude 35%.
After ultrasonic treatment, the precipitating of bulky grain is discarded, takes upper layer slurries；Under the revolving speed of 1000rpm by upper layer slurries from The heart handles 5min, further removes the precipitating of bulky grain, makes solution purification, PDMAPS stable liquid metal nanoparticle.
Comparative example 29
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, the specific steps are as follows:
The gallium indium eutectic of the polyetherimide (PEI) of 5.0mg and 80 μ L are added in 12mL deionized water, Xiang Shuizhong is passed through Argon gas 10 minutes, obtain the mixed solution comprising polyetherimide and gallium indium eutectic.
Under ice bath environment, mixed solution is ultrasonically treated, ultrasonic time 15min.Ultrasound Instrument parameter is as follows: frequency Rate, 20kHz；Rated power, 500 watts；Probe diameter is 3 millimeters；Amplitude 35%.
After ultrasonic treatment, the precipitating of bulky grain is discarded, takes upper layer slurries；Under the revolving speed of 1000rpm by upper layer slurries from Heart processing, further removes the precipitating of bulky grain, makes solution purification, PEI stable liquid metal nanoparticle.Wherein, PEI Chemical structure is as follows:
Comparative example 30
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 27 Difference be only that: in step 2 by the gallium indium eutectic of the methacrylated hyaluronic acid (HA) of 4.8mg and 80 μ L be added 12mL In deionized water.
Comparative example 31
This comparative example provides a kind of synthetic method of liquid metal nanoparticle, with the synthetic method provided in comparative example 27 Difference be only that: in step 2 by the gallium indium eutectic of the methacrylated hyaluronic acid (HA) of 7.2mg and 80 μ L be added 12mL In deionized water.
Experimental example 1
This experimental example by uv-visible absorption spectra, dynamic light scattering (DLS), transmission electron microscope (TEM) with And zeta current potential characterizes the liquid metal nanoparticle in embodiment 1 and comparative example 1-8, when monitoring different ultrasounds Between the dynamic process that is formed of lower liquid metal nanoparticle.Monitoring result is as follows:
Fig. 9 shows transmission electron microscope (TEM) figure of liquid metal nanoparticle in embodiment 1 and comparative example 1-6 Picture, scale, 100nm；Figure 10 shows transmission electron microscope (TEM) image of liquid metal nanoparticle in comparative example 7-8. By Fig. 9 and Figure 10 it is found that the pattern of liquid metal nanoparticle is spherical in shape in the time < 15min of ultrasonic treatment, super When the sound time reaches 15min, liquid metal particle growth is rice shape.Further extend ultrasonic time, mixed solution can be made Temperature increase, rice shape liquid metal nanoparticle little aggregates, partial size increases, but remains to retain its meter of shape pattern.When ultrasonic Between when extending to 30min and 40min, the temperature of mixed solution can further increase, when the partial size of liquid metal nanoparticle does not have Have significant change, and the pattern of rice shape liquid metal nanoparticle is effectively maintained.
Figure 11 shows dynamic light scattering (DLS) detection of embodiment 1 and the liquid metal nanoparticle in comparative example 1-6 Result figure, as shown in Figure 11, under the sonication treatment time of 2min-10min, the size of liquid metal nanoparticle is not bright Aobvious variation, after 10min, liquid metal nanoparticle starts to deform and merge, and when arriving 15min, is grown to polydispersity index (PDI) the rice shape liquid metal nanoparticle for being 0.083.
Figure 12 shows the zeta potential diagram of embodiment 1 and the liquid metal nanoparticle in comparative example 1-6, can by Figure 12 Know, with the extension of ultrasonic time, the zeta current potential of liquid metal nanoparticle is gradually decreased, show in addition to catechol it Outside, the hydroxyl of melanin nanoparticle and carboxyl may also take part in the cohesive process with gallium indium eutectic nanoparticle.
Figure 13 shows the uv-visible absorption spectra of embodiment 1 and the liquid metal nanoparticle in comparative example 1-6 Figure, as shown in Figure 13, with the extension of ultrasonic time, the absorption peak at the place 400nm or so of liquid metal nanoparticle is slow Increase, the color of liquid metal nanoparticle suspension gradually becomes light grey by Dark grey.
Experimental example 2
This experimental example by transmission electron microscope (TEM), observe liquid metal nanoparticle suspension day light image, Dynamic light scattering (DLS) and zeta current potential carry out table to the liquid metal nanoparticle in embodiment 1 and comparative example 9-14 Sign, to detect liquid metal nanoparticle to the concentration dependent of melanin nano particle.Testing result is as follows:
Figure 14 shows the transmission electron microscope (TEM) of embodiment 1 and the liquid metal nanoparticle of comparative example 12-14 Image, scale, 250nm.As shown in Figure 14, when the concentration of melanin nanoparticle is 0.25mg/mL, a meter shape can be obtained Liquid metal nanoparticle, and the melanin nanoparticle of higher concentration feeds intake, liquid metal particle growth is spherical shape.
Figure 15 shows the day light image of embodiment 1 and the liquid metal nanoparticle suspension of comparative example 9-14.It can by Figure 15 Know, when the concentration of melanin nanoparticle is lower than 0.25mg/mL, the stability of liquid metal nanoparticle is affected, It is precipitated after placement.
Figure 16 and Figure 17 shows that the dynamic optical of the liquid metal nanoparticle in embodiment 1 and comparative example 12-14 dissipates respectively Penetrate (DLS) testing result figure and zeta potential diagram.By Figure 16 and Figure 17 it is found that the high melanin nanoparticle to feed intake reduces The size of liquid metal nanoparticle, and with the increase of liquid metal nanoparticle surface zeta negative potential, illustrate black After the concentration increase of plain nanoparticle, more binding sites are provided for gallium indium eutectic nanoparticle, reduce gallium indium eutectic The probability of nanoparticle fusion, assembling.
Experimental example 3
This experimental example receives the liquid metal in embodiment 1 and comparative example 27-31 by transmission electron microscope (TEM) Rice corpuscles is characterized, to detect the pattern variation of the stable gallium indium eutectic nanoparticle of different ligands.Testing result is as follows:
Figure 18 shows transmission electron microscope (TEM) image of the stable gallium indium eutectic nanoparticle of different ligands, in figure Laterally the first column successively indicates the stable gallium indium eutectic nanoparticle of the melanin nanoparticle (MNP) in embodiment 1 from left to right The stable gallium indium eutectic nanoparticle of polyetherimide (PEI) in son and comparative example 29；In figure laterally the second column from a left side The stable gallium indium eutectic nanoparticle of methacrylated hyaluronic acid (HA) in comparative example 27 is successively indicated to the right, and Poly- [2- (methacryloxy) ethyl] dimethyl-(3- sulfopropyl) ammonium hydroxide (PDMAPS) in comparative example 28 is steady Fixed gallium indium eutectic nanoparticle.As shown in Figure 18, positively charged PEI has good stabilizing power, can be made by electrostatic Uniform nanosphere is dispersed into indium eutectic nanoparticle will be sowed.HA can also be stablized by hydroxyl sows indium eutectic particle, obtains To nanosphere, but there is wider polydispersity index.And when PDMAPS is as ligand, it can be only formed random gallium indium eutectic Nanoparticle.Figure 18 shows that the polymer (such as: PEI, HA) with reactive group (amino, mercaptan and hydroxyl etc.) can be with Stablize gallium indium eutectic nanoparticle, but can control the pattern of gallium indium eutectic nanoparticle only as spherical shape, only selection is with melanin When nanoparticle stablizes gallium indium eutectic nanoparticle, the good rice shape liquid metal nanoparticle of dispersion stabilization can be obtained.
Figure 19 shows the stability of the stable gallium indium eutectic nanoparticle of different ligands, wherein successively indicate from left to right with Poly- diethanol-sulfydryl (PEG-SH), PEI and melanin nanoparticle are ligand.It appears from figure 19 that melanin nanoparticle is steady Fixed gallium indium eutectic nanoparticle, stability are significantly higher than containing sulfydryl and with the molecule of positive charge, illustrate a meter shape liquid gold The stability for belonging to nanoparticle is good.
Figure 20 shows the transmission electron microscope of comparative example 27 and the liquid metal nanoparticle in comparative example 30-31 (TEM) image, scale, 200nm.As shown in Figure 20, different from the liquid metal nanoparticle that melanin nanoparticle is stable, no With concentration hyaluronic acid (HA) to the pattern of liquid metal nanoparticle without obvious effect, HA stable gallium indium eutectic nanoparticle Son remains nanosphere with the increase of HA concentration.
Experimental example 4
This experimental example of this experimental example is by transmission electron microscope (TEM) to the liquid metal nanometer in comparative example 15-26 Particle is characterized, to detect melanin nanoparticle under different ultrasonic times stable gallium indium tin nanoparticle and gallium tin The pattern of nanoparticle changes.Testing result is as follows:
Figure 21 shows transmission electron microscope (TEM) figure of liquid metal nanoparticle in comparative example 15- comparative example 20 Picture, Figure 22 show transmission electron microscope (TEM) image of liquid metal nanoparticle in comparative example 21- comparative example 26.By scheming 21 and Figure 22 is received it is found that under different ultrasonic times (4min, 6min, 8min, 10min, 15min, 20min) with melanin The stable gallium indium tin eutectic nanoparticle (Figure 21) of rice corpuscles, and the gallium tin eutectic nanoparticle stable with melanin nanoparticle Nanometer spherical can be only presented in the pattern of sub (Figure 22).
Experimental example 5
(rice shape gallium indium is total to the liquid metal nanoparticle by the stable different-shape of melanin nanoparticle for this experimental example Brilliant nanoparticle, spherical gallium indium eutectic nanoparticle and stick gallium indium eutectic nanoparticle) photo-thermal property detected, detect Method is as follows:
1, by uv-visible absorption spectra to rice shape gallium indium eutectic nanoparticle, stick gallium indium eutectic nanoparticle, It is characterized with the optical absorption property of spherical gallium indium eutectic nanoparticle.
It 2, is 808nm with wavelength, power is 2.0W cm-2Near-infrared laser irradiation different-shape liquid metal nanometer Particle suspension 10min draws liquid metal nanometer according to temperature increase of the suspension in irradiation process using water as control The photothermal response curve of particle.
3, it is drawn according to the temperature increase of the rice shape gallium indium eutectic nanoparticle after the irradiation of the near-infrared laser of different capacity Photothermal response curve processed.
4, the temperature increase that the rice shape gallium indium eutectic nanoparticle of various concentration is irradiated according to near-infrared laser draws light Thermal response curve.
5, the circulation light thermal response curve of rice shape liquid metal nanoparticle is drawn to detect a meter shape gallium indium eutectic nanoparticle The photo and thermal stability of son.
6, photothermal conversion efficiency calculates:
Photothermal conversion efficiency (η) is calculated by Roper method.
Wherein Δ TmaxIndicate temperature change of sample at a temperature of maximum steady state；ΔTmax, s expression is in maximum steady state temperature Lower solvent (such as H2O temperature change)；I is NIR laser power, is equal to power density multiplied by irradiated area；A is that sample exists Absorbance at 808nm；msAnd CsIt is the quality and thermal capacitance of solvent respectively；τ is sampling system time constant, can pass through temperature The linear curve fit of cooling time determines ln (Δ T/ Δ Tmax)。
Testing result is as follows:
Figure 23 shows the uv-visible absorption spectra of the liquid metal nanoparticle of different-shape, as shown in Figure 23, rice shape The light absorption > stick gallium indium eutectic nanoparticle > spherical shape gallium indium eutectic nanoparticle of gallium indium eutectic nanoparticle.Figure 24 is shown The photothermal response curve of the liquid metal nanoparticle of different-shape, as shown in Figure 24, with the near-infrared laser of 808nm (power: 2.0W cm-2) irradiation different-shape liquid metal nanoparticle suspension (concentration is respectively 0.5mg/mL), rice shape gallium indium eutectic The temperature of nanoparticle suspension increases most (32.2 DEG C) in 10 minutes, and stick gallium indium eutectic nanoparticle and spherical gallium indium The temperature of eutectic nanoparticle suspension increases 28.8 DEG C and 23.7 DEG C respectively.On the contrary, under identical experiment condition, water only table Reveal slight temperature and increases (< 2 DEG C).Compared with stick gallium indium eutectic nanoparticle and spherical gallium indium eutectic nanoparticle, rice Shape gallium indium eutectic nanoparticle can effectively absorb near infrared light, and be converted into thermal energy.
Figure 25 shows the photothermal response curve of the near-infrared laser irradiation rice shape gallium indium eutectic nanoparticle of different frequency, by Figure 25 is it is found that the photothermal conversion effect of rice shape gallium indium eutectic nanoparticle is related to laser frequency, with the increase of laser frequency, The temperature increase of rice shape gallium indium eutectic nanoparticle increases, and shows the dependence to laser frequency.Figure 26 display is different dense The photothermal response curve of the rice shape gallium indium eutectic nanoparticle suspension of degree, as shown in Figure 26, rice shape gallium indium eutectic nanoparticle Photothermal conversion effect is related to suspension concentration, and with the increase of concentration, the temperature increase of rice shape gallium indium eutectic nanoparticle increases Add, shows the dependence to suspension concentration.
Figure 27 shows the circulation light thermal response curve of rice shape gallium indium eutectic nanoparticle, and 4 plus hot-cold have been monitored in Figure 27 But the temperature change of cyclic process.As shown in Figure 27, in heating-cooling cyclic process, without the change of apparent temperature range To change, and rice shape gallium indium eutectic nanoparticle suspension keeps high degree of dispersion in heating-cooling cyclic process, no precipitating generates, Illustrate that the photo and thermal stability of meter shape gallium indium eutectic nanoparticle is high, can be avoided and melt under the irradiation of duplicate near-infrared laser And lose typical absorption peak.
Figure 28 shows temperature-Ln cooling time (the Δ T/ Δ T of the liquid metal nanoparticle of different-shapemax) fitting Linearity curve.By the method for Roper, it is outstanding to calculate rice shape gallium indium eutectic nanoparticle suspension, stick gallium indium eutectic nanoparticle The photothermal conversion efficiency (η) of liquid and spherical gallium indium eutectic nanoparticle suspension, as a result respectively 36.7%, 28.8% and 33.3%.
By above-mentioned testing result it is found that rice shape gallium indium eutectic nanoparticle absorbs after by near infrared light (NIR) irradiation Luminous energy is converted into thermal energy, has preferable light- heat transfer efficiency.Melanin nanoparticle is in gallium indium eutectic nanoparticle surface Multivalence chelating, obtained rice shape gallium indium eutectic nanoparticle not only have more higher than stick, spherical gallium indium eutectic nanoparticle Photothermal conversion efficiency, photo and thermal stability and dispersion stabilization also with higher can be in heating-cooling cyclic processes not Apparent temperature range variation occurs, and keeps the high degree of dispersion of suspension.Based on the preferable of rice shape gallium indium eutectic nanoparticle Light thermal property, rice shape gallium indium eutectic nanoparticle is a kind of preferable photo-thermal therapy material, can be applied to photo-thermal therapy.
Experimental example 6
This experimental example is used as tumor thermal therapy to rice shape liquid metal nanoparticle (rice shape gallium indium eutectic nanoparticle) The effect of agent is detected, wherein rice shape gallium indium eutectic nanoparticle is made by embodiment 1.Detection method is as follows:
1, vitro cytotoxicity detects
10 are inoculated in 96 orifice plates4A 4T1 cell (mouse mastopathy cell) is simultaneously cultivated 24 hours.Then, it is added different The rice shape gallium indium eutectic nanoparticle of concentration (0,50,100,250,500,1000 μ g/mL, 100 holes μ L/) is incubated for 4 hours.PBS After washing, continue to be incubated for RPMI 1640 (50 μ L) culture medium.It then, the use of 808nm laser is 1.6W cm in power level-2 Under to cell carry out 5 minutes Continuous irradiations.Control group is without laser irradiation.It is living finally by CCK-8 kit measurement cell Power.
Rice shape gallium indium eutectic nanoparticle is measured to the cytotoxicity of 4T1 by standard CC K-8.6 are inoculated in 96 orifice plates ×103A cell, then by (50,100,250, the 500 and 1000 μ g ml of cell and various concentration-1) rice shape gallium indium eutectic receives Rice corpuscles is incubated with 24 hours, is then washed 2 times with 1640 culture medium of RPMI, and it is molten that 10 μ L CCK-8 are added into every hole Liquid, 90 μ l RPMI 1640 are simultaneously incubated for 1 hour.450nm extinction is acquired by microplate reader (Infinite M200PRO, Tecan) Degree.
2, Calcein AM/PI is dyed
10 are inoculated in 96 orifice plates4A 4T1 cell, up to stand density to 80~90%.After PBS washing, by 4T1 cell It is incubated with 4 hours with rice shape gallium indium eutectic nanoparticle.Then it is washed 4T1 cell 3 times with PBS, is incubated in 200 μ L RPMI In 1640 culture mediums, then laser irradiation (808nm, 1.6W cm-2) 5 minutes.It will be handled with rice shape gallium indium eutectic nanoparticle 4T1 cell and independent laser irradiation group as control.After removing 1640 culture medium of RPMI, tried using Calcein AM/PI Agent box measures living cells and dead cell.
3, internal photo-thermal tumor resection
In order to establish Transplanted tumor model, by female BAl BIc/c mouse (6 weeks, Jackson Lab) with 1 × 1064T1 cell It is inoculated in dorsal sc.5 days after tumor inoculation, gross tumor volume is about 90mm3.Mouse is divided into four groups, and (group 1: rice shape gallium indium is total Brilliant nanoparticle+laser；Group 2: rice shape gallium indium eutectic nanoparticle；Group 3:PBS+ laser；Group 4:PBS) (n=6).Injection system Just use intratumor injection.In typical photo-thermal therapy, the rice shape gallium indium eutectic nanoparticle of 50 μ L 0.5mg/mL is injected into small In the tumour of mouse.Then, using 5 minutes (1.6W cm of laser Continuous irradiation tumour-2).It is swollen subsequently through biloluminescence method monitoring Tumor shoots image using IVIS Lumina imaging system (Perkin Elmer).By vernier caliper measurement tumor size, swell Knurl product (V) calculation formula is V=L × W2/ 2, wherein L and W is the length and width of tumour respectively.
Testing result is as follows:
Figure 29 is shown in irradiation laser and does not irradiate the cytotoxicity of the rice shape gallium indium eutectic nanoparticle under laser.By scheming 29 it is found that when not irradiating laser, though rice shape gallium indium eutectic nanoparticle suspension at concentrations up to 500 μ g/mL, rice shape gallium indium Eutectic nanoparticle is negligible to the cytotoxicity of 4T1 cell.However, ought continuously be irradiated with 808nm near-infrared laser 5min(1.6W cm-2) after.Then kill the 4T1 cell more than 90%.Figure 30 shows the Calcein AM/PI dye of 4T1 cell Chromatic graph, wherein Calcein AM reagent dyes living cells, and PI reagent is to dead cell stain；In figure Nanorice indicate only with The cell of rice shape gallium indium eutectic nanoparticle processing, Laser indicate the cell only irradiated with near-infrared laser, Nanorice+ Laser is indicated after being handled with rice shape gallium indium eutectic nanoparticle, uses the cell of near-infrared laser irradiation.It is possible to observe from figure 30 that Rice shape sows the substantially all death of 4T1 cell of indium eutectic nanoparticle and laser irradiation processing, and is applied alone a meter shape to sow indium eutectic and receives When rice corpuscles or laser irradiation, most of 4T1 cells are still survived.
Figure 31 shows that continuous laser irradiates the dynamic transmission electron microscope image of lower rice shape gallium indium eutectic nanoparticle, mark Ruler, 100nm.Wherein, optical maser wavelength 808nm, power 1.6W cm-2, the Continuous irradiation time is 5min.As shown in Figure 31, even During continuous laser irradiation (5 minutes), the pattern of rice shape gallium indium eutectic nanoparticle retains well, and there is no significantly turning Become.
Figure 32 is shown in the thermal-induced imagery of mouse under the laser irradiation of different time, and EGaIn nanorice is indicated in figure The mouse of intratumor injection rice shape gallium indium eutectic nanoparticle, PBS indicate the mouse of intratumor injection PBS.Simultaneously by two groups of mouse anesthesias Tumour is subjected to 808nm laser irradiation (1.6W cm-2) 5 minutes, the REAL TIME INFRARED THERMAL IMAGE thermal image and photo-thermal of mouse are recorded per minute The temperature change of tumor region, obtains result shown in Figure 32 during treating.As shown in Figure 32, injection rice shape gallium indium eutectic is received The mouse of rice corpuscles, the temperature of irradiation area in 2 minutes from 32.4 DEG C it is significant increase to~46.9 DEG C, and connected at 5 minutes It is continuous to increase to~50.3 DEG C, the temperature sufficiently effective ablated tumor.In contrast, the only control group of laser irradiation is identical Under the conditions of only obtain slight temperature and increase (~2.5 DEG C), this shows that a meter shape gallium indium eutectic nanoparticle can be effectively by light Thermal energy can be converted to, and the laser irradiation condition used will not generate hyperthermia in thermotherapy, and normal tissue is avoided to cause to damage Evil.
Figure 33 show respectively with PBS handle, PBS and laser irradiation processing, rice shape gallium indium eutectic nanoparticle processing, and The bioluminescence figure of 4T1 tumour growth in the mouse of rice shape gallium indium eutectic nanoparticle and laser irradiation processing, as shown in Figure 33, Dark burn wound is produced at the tumour handled with rice shape gallium indium eutectic nanoparticle and laser irradiation, the 8th day after the treatment Bioluminescence method can't detect tumour, illustrate effectively melt with rice shape gallium indium eutectic nanoparticle and laser irradiation processing Tumour.
Figure 34 is shown at rice shape gallium indium eutectic nanoparticle and laser irradiation processing, rice shape gallium indium eutectic nanoparticle The immunohistochemical staining figure of 4T1 tumor tissues in the mouse of reason, PBS and frame pipe treatment with irradiation and laser irradiation processing, Scale, 200 μm.As shown in Figure 34, the mouse handled with rice shape gallium indium eutectic nanoparticle and laser irradiation, tumor tissues quilt It effectively eliminates, testing result is consistent with Figure 33.
Figure 35 shows the tumour growth and mouse survival state-detection result figure of different treatment group mouse.Wherein, Figure 35 a is The tumor growth curve (n=6) of different treatment group mouse.Data are shown as mean+SD, and P < 0.001 * * * uses The two-way ANOVA of Tukey post-hoc check analysis.Figure 35 b shows the survivorship curve (n=6) of different treatment group mouse.Make It is examined with Log-Rank (Mantel-Cox), P < 0.001 * * *.By Figure 35 a and 35b it is found that for a meter shape gallium indium eutectic is applied alone The control group of nanoparticle or laser radiation, gross tumor volume increase rapidly, show and do not treat mouse and (be applied alone PBS) similar trend, and all these mouse are dead in 27 days after the treatment, and use rice shape gallium indium eutectic nanoparticle And laser radiation, at next 60 days, does not observe tumor recurrence, the life cycle of mouse after effective ablated tumor It is long.Figure 35 c shows the weight curve (n=6) of different treatment group mouse.Data are shown as mean+SD.It can by Figure 35 Know, as photo-thermal therapy agent rice shape gallium indium eutectic nanoparticle can effectively ablated tumor, and photo-thermal therapy is not led Significant weight loss is caused, shows that meter shape gallium indium eutectic nanoparticle has good biocompatibility.
By above-mentioned testing result it is found that rice shape gallium indium eutectic nanoparticle is due to its preferable photothermal conversion efficiency, After the excitation of nearly feux rouges, heat can be discharged, effective ablated tumor tissue has preferable oncotherapy effect.Meanwhile swollen After tumor ablation, prognosis bona is able to maintain and does not recur for a long time.The cytotoxicity of rice shape gallium indium eutectic nanoparticle is low, is being used for While ablated tumor tissue, the damage of normal tissue is not caused, and the unobvious mitigation of mouse weight illustrates its biocompatibility Height is a kind of novel, effective, safe tumor thermal therapy agent.
It should be noted that all results are expressed as mean+SD in above-described embodiment and experimental example.When than When data more more than two (Multiple range test), examined using two-way ANOVA (ANOVA) and Tukey post-hoc.It uses IBM SPSS statistical data 19 carries out all statistical analysis.The threshold value of the significant property of statistics is P < 0.05.
Obviously, the above embodiments are merely examples for clarifying the description, and does not limit the embodiments.It is right For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or It changes.There is no necessity and possibility to exhaust all the enbodiments.And it is extended from this it is obvious variation or It changes still within the protection scope of the invention.

Claims (14)

1. the synthetic method of a kind of meter of shape liquid metal nano particle, the liquid metal is gallium indium eutectic, which is characterized in that packet Include following steps:
Preparation includes the mixed solution of melanin nanoparticle and gallium indium eutectic, melanin nanoparticle in the mixed solution Concentration≤0.25mg/mL；
The mixed solution is ultrasonically treated, ultrasonic time >=15min, obtains a meter shape liquid metal nano particle.
2. synthetic method according to claim 1, which is characterized in that melanin nanoparticle is dense in the mixed solution Degree is 0.25mg/mL.
3. synthetic method according to claim 1 or 2, which is characterized in that the ultrasonic treatment further include: control is described mixed Close temperature≤60 DEG C of solution.
4. synthetic method according to claim 1-3, which is characterized in that the preparation includes melanin nanometer The step of mixed solution of particle and gallium indium eutectic includes: that melanin nanoparticle and gallium indium eutectic are added in solvent, Xiang Rong It is passed through inert gas in agent, obtains the mixed solution comprising melanin nanoparticle and gallium indium eutectic；Preferably, the solvent is Water, the inert gas are argon gas.
5. synthetic method according to claim 1-4, which is characterized in that the grain of the melanin nanoparticle Diameter is 2-4nm.
6. synthetic method according to claim 1-5, which is characterized in that the system of the melanin nanoparticle Include: for step
Soda acid processing is carried out to melanin granule, so that the partial size of the melanin granule is reduced into nanoscale, obtains melanin and receive Rice corpuscles solution；
The melanin nano-particle solution obtains melanin nanoparticle through ultrafiltration, washing and drying process.
7. synthetic method according to claim 6, which is characterized in that the soda acid processing includes: to sodium hydroxide solution Middle addition melanin granule, obtains melanin solution, the use of the pH that hydrochloric acid solution adjusts the melanin solution is 7, obtains black Pigment nano-particle solution；
The molecular cut off of the hyperfiltration treatment is 30kDa.
8. synthetic method according to claim 1-7, which is characterized in that further include:
After being ultrasonically treated to the mixed solution, precipitating is discarded, takes upper layer slurries；Centrifugal treating is carried out to the slurries, Precipitating is discarded, obtains being dispersed with a meter solution for shape liquid metal nano particle；Preferably, the condition of the centrifugal treating is 1000rpm, centrifugation time 5min.
9. a kind of meter of shape liquid metals nanoparticle, which is characterized in that the liquid metal nanoparticle is gallium indium eutectic nanometer Particle, the chelated surface melanin nanoparticle of the gallium indium eutectic nanoparticle；The liquid metal nanoparticle is in length and breadth Than for 2:1-3:1；Preferably, the aspect ratio of the liquid metal nanoparticle is 2.3.
10. according to claim 9 meter of shape liquid metal nanoparticle, which is characterized in that the rice shape liquid metal is received Rice corpuscles is synthesized by the described in any item methods of claim 1-8.
11. as claimed in claim 9 meter of shape liquid metal nanoparticle, or closed by the described in any item methods of claim 1-8 At application of the rice shape liquid metal nanoparticle as photo-thermal therapy material.
12. as claimed in claim 9 meter of shape liquid metal nanoparticle, or closed by the described in any item methods of claim 1-8 At rice shape liquid metal nanoparticle preparation treatment tumour reagent in application.
13. a kind of photo-thermal therapy agent, which is characterized in that the photo-thermal therapy agent includes rice shape liquid gold as claimed in claim 9 Belong to nanoparticle, or the rice shape liquid metal nanoparticle synthesized by the described in any item methods of claim 1-8.
14. a kind of oncotherapy kit, which is characterized in that the kit includes rice shape liquid gold as claimed in claim 9 Belong to nanoparticle, the rice shape liquid metal nanoparticle or right synthesized by the described in any item methods of claim 1-8 is wanted Photo-thermal therapy agent described in asking 13.
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