CN113633789B - Liquid metal nano probe integrating light acoustic imaging and drug inclusion and preparation method thereof - Google Patents
Liquid metal nano probe integrating light acoustic imaging and drug inclusion and preparation method thereof Download PDFInfo
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- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
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Abstract
The invention discloses a liquid metal nano probe integrating light-sound imaging and drug inclusion and a preparation method thereof. The preparation method comprises the steps of mixing liquid metal and a tannic acid aqueous solution, carrying out ultrasonic treatment, taking upper-layer liquid, and further carrying out mild centrifugal purification to remove relatively large particles; and then, mixing the medicinal preparation with the liquid metal nano-particles to obtain the medicament-carrying liquid metal nano-probe. The medicine-carrying liquid metal nano probe provided by the invention is used for carrying out in-situ injection on tumors, so that the medicine-carrying liquid metal nano probe is uniformly distributed on tumor positions, the medicine-carrying liquid metal nano probe can be subjected to swelling deformation under the irradiation of laser, the medicine is released from the surface of the nano probe, and the photothermal treatment and the chemotherapy are combined for treatment, so that the tumors are killed under the effect of double management.
Description
Technical Field
The invention relates to the field of biomedical nanomaterials, in particular to a liquid metal nanoprobe integrating light-collecting acoustic imaging and drug inclusion and application thereof.
Background
Cancer is a big killer threatening human life and health. At present, the diagnosis method of tumor mainly comprises four modes of biopsy, laboratory examination, pathological section examination and Magnetic Resonance Imaging (MRI), and the treatment method develops various treatment means such as chemotherapy, radiotherapy, thermotherapy and the like from operation. Recently, many researches have focused two separate processes of diagnosis and treatment on the same nanoprobe, so as to construct a diagnosis and treatment integrated nano platform. The nano probe is a product of cross fusion of nano science and technologies such as biology, physics, chemistry and the like, has good biocompatibility and stability, can be used for multifunctional modification and encapsulation of anti-tumor drugs, and has great potential in imaging analysis, drug delivery, cancer diagnosis and treatment and the like.
The liquid metal is a novel material which has both metal characteristics and fluid flowability, wherein the liquid metal gallium indium tin alloy (galinstan, 68 wt% Ga, 22 wt% In, 10 wt% Sn) at room temperature not only has the characteristics of the traditional metal, including excellent electric conduction, heat conduction and the like, but also has high flexibility, plasticity, low toxicity and good biocompatibility. However, the liquid metal has a large surface tension and density, and is difficult to disperse into small particles of nanometer level. Therefore, the research difficulty of the liquid metal is mainly focused on dispersing the liquid metal into stable nanoparticles by using a simple means and further surface functionalization, and the functionalized liquid metal nanoparticles can be better applied to the biomedical field.
Photoacoustic imaging is to irradiate biological tissues by pulse laser or modulated light, the absorbed light energy is completely or partially converted into heat energy, so that thermoelastic expansion is generated to generate pressure waves, the pressure waves are transmitted in the biological tissues in an ultrasonic mode, and finally, the pressure waves are converted by a signal converter to obtain images. Contrast agents required for photoacoustic imaging are classified into endogenous contrast agents and exogenous contrast agents. Endogenous contrast agents are inherent components in biological tissues including hemoglobin, melanin, water, etc.; the exogenous contrast agent mainly comprises an organic small molecular material, a high molecular nano material, an inorganic non-metallic nano material, a metal nano material and the like. The contrast agent changes the local optical and acoustic properties of biological tissues, improves the contrast and the resolution, can be applied to non-invasive real-time imaging of tumor tissues, vessels, brain tissues and the like, and also can be applied to sensing of Reactive Oxygen Species (ROS), pH value, metal ions and the like. Therefore, it is of great significance to develop a photoacoustic imaging contrast agent having biocompatibility, high resolution, and high penetration depth.
Tannic acid is a green and safe natural polyphenol substance, and the chemical structure of tannic acid is formed by covalently connecting a glucose core with gallic acid group through a hydrolysable ester bond. Under neutral conditions, tannic acid is electronegative due to its high number of galloyl groups, and thus it can bind to positively charged species through electrostatic interactions. Meanwhile, a large number of aromatic rings in the structure of tannic acid can promote the interaction with hydrophobic molecules. Tannic acid, based on its structural characteristics, is thought to be capable of associating with a wide range of molecules of different groups, with great potential to modify the surface of nanoparticles, thereby controlling their interaction with specific cells or providing them with additional functions, such as coating with small molecules, synthetic polymers, proteins, polysaccharides and various classes of drugs.
In the prior art, photoacoustic imaging and drug loading diagnosis and treatment are usually realized independently, and a nano probe capable of realizing photoacoustic imaging and drug loading construction diagnosis and treatment integration is rarely available. In order to realize wider application of liquid metal nanoparticles in the field of biomedical nanomaterials, a diagnosis and treatment integrated nanoprobe is expected to be constructed by combining photoacoustic imaging and drug loading, and has a certain application prospect in clinical detection and treatment of cancers.
Object of the Invention
The invention aims to provide a liquid metal nano probe integrating light-collecting acoustic imaging and drug inclusion and a preparation method thereof, which are based on the defects of the prior art.
Disclosure of Invention
According to one aspect of the invention, a preparation method of a liquid metal nanoprobe integrating photoacoustic imaging and drug inclusion is provided, which comprises the following steps:
mixing a liquid metal (1) with a tannic acid aqueous solution (2), performing ultrasonic treatment, taking an upper layer liquid, and then removing micron-sized particles through mild centrifugal purification to obtain liquid metal nanoparticles;
and step two, mixing the medicinal preparation with the liquid metal nanoparticles in the step one to obtain the medicine-carrying liquid metal nanoprobe (6).
Preferably, the liquid metal is a gallium-based alloy containing 68 wt% gallium, 22 wt% indium and 10 wt% tin; the diameter of the liquid metal nano-particles is 15nm-150 nm.
Preferably, the ratio of the volume concentration of the liquid metal and the tannic acid is 1:2, and the ultrasonication is carried out for 15min by a cell disruptor (3) using a probe of 6mm phi with the model Scientz-IID, the power is set at 160W, and an ice bath is used during the ultrasonication to ensure that the temperature of the sample is controlled at 0 ℃.
Preferably, the pharmaceutical preparation in the second step is doxorubicin hydrochloride (4), and the doxorubicin hydrochloride and the liquid metal nanoparticles are mixed overnight at normal temperature by using a magnetic stirrer (5).
According to another aspect of the present invention, there is provided a liquid metal nanoprobe manufactured according to the above manufacturing method.
Preferably, the drug-loaded liquid metal nanoprobe is used for photoacoustic imaging of breast cancer.
More preferably, the drug-loaded liquid metal nanoprobe performs photoacoustic imaging under the excitation of laser with wavelength of 808 nm.
Preferably, the drug-loaded liquid metal nanoprobe is used for combined photothermal therapy and chemotherapy of breast cancer.
Preferably, the drug-loaded liquid metal nanoprobe generates thermal expansion deformation under the laser irradiation with the wavelength of 808nm and the power of 1W to promote the release of the drug.
Drawings
FIG. 1 is a flow chart of the preparation of a drug-loaded liquid metal nanoprobe,
FIG. 2 is a schematic view of the photothermal therapy-chemotherapy combination treatment process of the drug-loaded liquid metal nanoprobe at a tumor site,
FIG. 3 shows the experimental results of the combined photothermal therapy and chemotherapy for tumor therapy,
reference numerals are as follows:
wherein, 1-liquid metal, 2-tannic acid, 3-cell crushing instrument, 4-doxorubicin hydrochloride, 5-magnetic stirrer, 6-drug-loaded liquid metal nano probe and 7-laser.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, but the technical solutions are not intended to limit the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The experimental reagents are commercially available without special instructions, and the experimental methods are conventional experimental methods without special instructions.
Example 1: preparation of liquid metal nanoparticles
The preparation process of the liquid metal nanoparticles is shown in fig. 1, and specifically comprises the following steps:
(1) 200mg of tannic acid powder was dissolved in 20mL of water and uniformly dispersed as a 10mg/mL TA solution. 100mg of liquid metal (Ga) 68 In 22 Sn 10 ) Put into a 50mL sample tube containing 20mL of tannic acid solution, and sonicated (power 160W) by a cell disruptor using a 6mm phi probe (Scientz-IID) for 15min with an ice bath during sonication to ensure that the temperature of the sample is controlled at 0 ℃.
(2) After sonication, the largest particles precipitated quickly, and the supernatant liquid was then removed from the vial and further purified by gentle centrifugation (1,000rpm) to remove micron-sized particles.
(3) And taking the supernatant to perform transmission microscope characterization on the morphological characteristics. From the experimental results, the liquid metal nanoparticles obtained in this example had a statistical average particle diameter of 82nm (N ═ 100).
(4) And washing the precipitate with water for three times, dissolving in 1mL of water to obtain a liquid metal nanoparticle solution, and performing photoacoustic and photothermal tests. From the experimental results, the relative value of the photoacoustic signal of the liquid metal nanoparticles prepared in the present example is 1365(a.u.), and the photothermal conversion efficiency is 55%.
Example 2: preparation of liquid metal nanoparticles
The preparation process of the liquid metal nanoparticles is shown in fig. 1, and specifically comprises the following steps:
(1) the difference from example 1 is that the concentration of the tannic acid solution involved in the ultrasonic treatment was 5 mg/mL.
(2) And taking the supernatant to perform transmission microscope characterization on the morphological characteristics. As can be seen from the experimental results, the liquid metal nanoparticles prepared in this example have a statistical average particle diameter of 48nm (N ═ 100).
(3) And washing the precipitate with water for three times, dissolving in 1mL of water to obtain a liquid metal nanoparticle solution, and carrying out photoacoustic and photothermal tests. From the experimental results, the relative value of the photoacoustic signal of the liquid metal nanoparticles prepared in this example reaches 643(a.u.), and the photothermal conversion efficiency is 48%.
Example 3: preparation of liquid metal nanoparticles
The preparation process of the liquid metal nanoparticles is shown in fig. 1, and specifically comprises the following steps:
(1) the difference from example 1 is that the concentration of the tannic acid solution involved in the ultrasonic treatment was 15 mg/mL.
(2) And taking the supernatant to perform transmission microscope characterization on the morphology characteristics. From the experimental results, the liquid metal nanoparticles prepared in this example had a statistical average particle diameter of 53nm (N ═ 100).
(3) And washing the precipitate with water for three times, dissolving in 1mL of water to obtain a liquid metal nanoparticle solution, and performing photoacoustic and photothermal tests. From the experimental results, the relative value of the photoacoustic signal of the liquid metal nanoparticles prepared in this example is 718(a.u.), and the photothermal conversion efficiency is 47%.
Example 4: preparation of drug-loaded liquid metal nano probe
The preparation process of the drug-loaded liquid metal nanoprobe is shown in figure 1, and specifically comprises the following steps:
(1) 1mL of the liquid metal nanoparticles of example 1 at a concentration of 500. mu.g/mL was mixed with 1mL of doxorubicin hydrochloride at a concentration of 10. mu.g/mL and incubated at 37 ℃ for 1 hour.
(2) Centrifuging at 8000r/min for 30min, removing supernatant, and adding 1mL water to obtain liquid metal nanoprobe solution carrying medicine.
Example 5: biocompatibility of liquid metal nanoparticles
According to the cell verification experiment, according to the relevant regulations of the national standard GB/T16886.5 (medical apparatus biological evaluation: in vitro cytotoxicity test) of the people's republic of China and the international medical apparatus biological evaluation standard ISO10993-5, the in vitro biological safety evaluation is carried out on the drug-loaded liquid metal nano probe in the embodiment 4 by taking the mouse breast cancer cell 4T1 as a research object.
1mL of the liquid metal nanoparticle solution of example 1 was subjected to ultraviolet sterilization for 4 hours, and RPMI-1640 basic culture medium (containing 10% fetal bovine serum) was added to prepare experimental group media having concentrations of 100, 200, 300, 400, and 500. mu.g/mL, respectively. 4T1 cells with vigorous growth are selected to be inoculated in a 96-well plate at about 50000 cells/well, each well of an experimental group is added with 100 mu L of experimental group culture medium with each concentration, each well of a control group is added with 100 mu L of complete culture medium, and a blank group is added with only complete culture medium without cells. Placing at 37 ℃ and 5% CO 2 After 6h in the incubator, 10 mu LCCK8 reagent is added, and after 4h of incubation, the absorbance of each well solution at 450nm is measured by a microplate reader. And according to a calculation formula: cell viability ═ [ (experimental group-blank group A)/(control group A-blank group A) ]]X 100% viability of cells was calculated. Through calculation, the cell survival rate does not change obviously with the increase of concentration by using the liquid metal nanoparticles and the 4T1 cells for co-culture, which shows that the liquid metal nanoparticles have no obvious cytotoxicity and good biological safety.
Example 6: photoacoustic imaging diagnosis of tumor by using drug-loaded liquid metal nanoprobe
Injecting 0.1ml of 10-density subcutaneous injection into the right inguinal of Balb/c nude mice 7 When the tumor volume reaches about 100mm, the mouse breast cancer 4T1 cells 3 It can be used for in vivo experiment. The liquid metal nanoprobe with drug loading of example 4 was injected in situ into the tumor, and photoacoustic images of the tumor at 808nm were measured at 0, 6, 12, and 24h after injection, respectively.
Example 7: drug-loaded liquid metal nanoprobe for photothermal therapy-chemotherapy combined therapy of tumors
The example 4 drug-loaded liquid metal nanoprobes were used for this tumor treatment as shown in figure 2. Injecting a drug-loaded liquid metal nanoprobe to the tumor in situ. After 24 hours of injection, a 808nm laser is adopted to irradiate a tumor part for 10 minutes, after laser irradiation, the drug-loaded liquid metal nano probe can generate swelling deformation, tannic acid and adriamycin can be released from the surface of the nano probe, the tannic acid can enhance the killing effect of the adriamycin on breast cancer cells, and photothermal therapy and chemotherapy are combined to kill tumors in a double-tube manner.
The tumor part is injected with the drug-loaded liquid metal nanoprobe to implement the photothermal therapy-chemotherapy combined treatment group, meanwhile, the tumor is not treated as a blank control group, and the tumor part is injected with the liquid metal nanoparticles of the embodiment 1 as a thermotherapy group. The experimental result is shown in figure 3, the tumor cells can be more effectively killed and killed under the combined action of the thermotherapy and the chemotherapy, and the tumor can be treated by combining the chemotherapy and the thermotherapy.
In conclusion, the invention has the following beneficial effects:
1. the liquid metal nanoprobe modified by the tannic acid is synthesized by the tannic acid through an ultrasonic method in one step.
2. The liquid metal nano probe can be prepared by simply mixing the adriamycin hydrochloride and the liquid metal nano particles.
3. The synthetic process is simple, the cost is low, the efficiency is high, and the product has good dispersibility and stability in water and good biocompatibility.
4. Not only can realize the light-sound imaging diagnosis of the tumor, but also can carry out the combined treatment of photothermal therapy and chemotherapy on the tumor.
Claims (6)
1. A preparation method of a liquid metal nanoprobe integrating light-sound imaging and drug inclusion is characterized by comprising the following steps:
mixing liquid metal (1) with a tannin (2) aqueous solution, performing ultrasonic treatment, taking upper-layer liquid, and then removing micron-sized particles through mild centrifugal purification to obtain liquid metal nanoparticles; the liquid metal (1) is a gallium-based alloy containing 68 wt% of gallium, 22 wt% of indium and 10 wt% of tin; the diameter of the liquid metal nanoparticles is 15nm-150 nm; the concentration ratio of the aqueous solution of the liquid metal (1) to the aqueous solution of the tannic acid (2) is 1:2, a 6mm phi probe with the model of Scientz-IID is used, ultrasonic treatment is carried out for 15min by a cell disruptor (3), the power is set to be 160W, and an ice bath is used in the ultrasonic treatment process to ensure that the temperature of a sample is controlled at 0 ℃;
step two, mixing the medicinal preparation with the liquid metal nanoparticles in the step one to obtain a medicine-carrying liquid metal nanoprobe (6); the pharmaceutical preparation is doxorubicin hydrochloride (4), and the doxorubicin hydrochloride and liquid metal nanoparticles are mixed overnight at normal temperature by a magnetic stirrer (5).
2. A drug-loaded liquid metal nanoprobe, which is prepared by the preparation method of claim 1.
3. The drug-loaded liquid metal nanoprobe of claim 2, which is used for photoacoustic imaging of breast cancer.
4. The drug-loaded liquid metal nanoprobe of claim 3, wherein photoacoustic imaging is performed under laser excitation at a wavelength of 808 nm.
5. The drug-loaded liquid metal nanoprobe of claim 2, which is used for combined photothermal therapy-chemotherapy treatment of breast cancer.
6. The drug-loaded liquid metal nanoprobe of claim 5, which generates thermal expansion deformation under the laser irradiation with wavelength of 808nm and power of 1W to promote drug release.
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