阅读说明：本技术 一种多功能液态金属栓塞剂及其制备和应用 (Multifunctional liquid metal embolic agent, preparation and application thereof ) 是由 汪达伟 饶伟 于 2019-02-02 设计创作，主要内容包括：本发明提供一种多功能液态金属栓塞剂及其制备和应用；所述多功能液态金属栓塞剂包括液态金属、功能性纳米颗粒和高分子材料；所述液态金属呈球状,构成栓塞剂的内核,在液态金属表面分散所述功能性纳米颗粒,所述高分子材料包覆在所述内核和功能性纳米颗粒的外部。本发明提出的多功能液态金属栓塞剂,可以实现栓塞、CT成像、MRI成像、载药、热转换、磁性、等功能,有望实现将靶向的栓塞治疗与化疗、热疗、放疗相结合；本发明提出的多功能液态金属微球栓塞剂制备方法,为更加快速、便捷地制备多功能化、多疗效、诊疗一体的微球栓塞剂提供了可能。(The invention provides a multifunctional liquid metal embolic agent, and preparation and application thereof; the multifunctional liquid metal embolic agent comprises liquid metal, functional nano-particles and a high polymer material; the liquid metal is spherical and forms an inner core of the embolic agent, the functional nano particles are dispersed on the surface of the liquid metal, and the high polymer material is coated outside the inner core and the functional nano particles. The multifunctional liquid metal embolic agent provided by the invention can realize the functions of embolization, CT imaging, MRI imaging, drug loading, heat conversion, magnetism and the like, and is expected to realize the combination of targeted embolization treatment with chemotherapy, thermotherapy and radiotherapy; the preparation method of the multifunctional liquid metal microsphere embolic agent provided by the invention provides possibility for more rapidly and conveniently preparing the multifunctional microsphere embolic agent with multiple curative effects and integrated diagnosis and treatment.)

1. The multifunctional liquid metal embolic agent is characterized by comprising liquid metal, functional nano particles and a high polymer material;

the liquid metal is spherical and forms an inner core of the embolic agent, the functional nano particles are dispersed on the surface of the liquid metal, and the high polymer material is coated outside the inner core and the functional nano particles.

2. The multifunctional liquid metal embolic agent of claim 1, wherein the liquid metal is a metal or alloy that assumes a liquid state below 30 degrees celsius; the functional nanoparticles are one or more of magnetic nanoparticles, photo-thermal nanoparticles, microwave-sensitive nanoparticles, drug-loaded nanoparticles and radioactive nanoparticles; the high polymer material is one or more of gelatin, starch, polyvinyl alcohol, collagen, albumin, polylactic acid and gel.

3. The multifunctional liquid metal embolic agent of claim 2, wherein the liquid metal is one of a gallium indium alloy, a gallium indium tin zinc alloy, or a gallium indium tin zinc bismuth alloy;

the magnetic nano material is a magnetic or magnetic conductive nano material and is selected from one or more of iron nano particles, ferric oxide nano particles, ferrous oxide nano particles and ferroferric oxide nano particles; the photo-thermal nano-particles are nano-particles with photosensitive characteristics and are selected from one or more of gold nanoshells, carbon nano-particles and copper nano-particles; the microwave nano material is a nano material with microwave sensitivity and is ZrO₂A nanoshell; the radioactive nanoparticles are nanoparticles with radioactivity and are selected from one of Y90, Co60 and Cs137 nanoparticles.

4. A preparation method of a multifunctional liquid metal embolic agent is characterized by comprising the following steps:

(1) taking liquid metal and functional nanoparticles as raw materials, and preparing the functional liquid metal by utilizing a liquid metal endocytosis effect;

(2) preparing liquid metal micro-nano particles wrapping functional nano particles by a liquid metal micro-nano particle preparation method, and modifying a polymer surface material on the surface; the preparation method of the liquid metal micro-nano particles comprises one or more of an ultrasonic method, a model method and a micro-flow focusing method;

(3) mixing functional liquid metal micro-nano particles with a substrate solution of a high polymer material, preparing micro-droplets wrapping the functional liquid metal micro-nano particles by a microsphere preparation method, and solidifying to obtain multifunctional liquid metal embolic agent microspheres; the preparation method of the microsphere comprises one or more of an orifice coagulation bath method, an electrostatic spinning method, an emulsifying ion crosslinking method, a complex coacervation method and a microemulsion method; the curing mode is crosslinking curing and/or cooling curing;

(4) then placing the obtained embolism microsphere in washing liquid, and drying after washing; the washing solution is one or more of neutral buffer solution, absolute ethyl alcohol and deionized water.

5. The preparation method according to claim 4, wherein in the step (1), the liquid metal is dropped on the nanoparticle layer to make the nanoparticles adhere to the spherical liquid metal surface, the oxide layer on the liquid metal surface is removed by electric field and/or chemical treatment, and the functional liquid metal is obtained after the particles are swallowed into the liquid metal body.

6. The preparation method according to claim 4, wherein in the step (1), the mass ratio of the liquid metal to the nanoparticles is 10: (1-4).

7. The method according to claim 4, wherein in the step (2), the polymer surface material is one of Pluronic F127, PEG and glycerol.

8. The preparation method according to claim 4, wherein in the step (2), the functional liquid metal is put into the solution of the polymer surface material, and the ultrasonic treatment is carried out for 10-20 min; the concentration of the solution of the polymer surface material is 1-10 wt%, and the solvent of the solution is one of ethanol, acetone, ethylene glycol and trichloroethane.

9. The preparation method according to any one of claims 4 to 8, wherein in the step (3), the functional liquid metal micro-nano particles are mixed into a substrate solution of a high polymer material with a concentration of 1 to 10 wt%, and the multifunctional liquid metal embolic agent microspheres coated with the functional liquid metal micro-nano particles are prepared by a microsphere preparation method; preferably, the concentration of the coated functional liquid metal micro-nano particles is 2-500 mg/ml.

10. Use of the multifunctional liquid metal embolic agent of any of claims 1 to 3 for imaging, drug loading, local heating, local application of a magnetic field.

Technical Field

The invention belongs to the field of metal materials, and particularly relates to a functional liquid metal embolic agent, and a preparation method and application thereof.

Background

Embolization, also known as embolization, is a controlled injection of embolization material into the blood supply vessel of a diseased tissue or organ via an arterial or intravenous catheter to occlude the vessel and block the blood supply, thereby achieving the purpose of controlling bleeding, treating vascular lesions, tumors and eliminating the function of the diseased organ. The embolism treatment is mainly realized by various kinds of embolic agents, and the embolic agents can be divided into liquid embolic agents and solid embolic agents according to the physical properties of the embolic agents. The liquid embolic agent comprises absolute ethyl alcohol, calcium alginate gel, liquid silica gel, alpha-cyano n-butyl acrylate, iodized oil and the like. Solid embolic agents include mechanical embolic agents such as: removable balloons, micro-spring rings, etc., and a wide variety of particulate embolic agents such as: gelatin microspheres, starch microspheres, polyvinyl alcohol beads, collagen particles, albumin microspheres, polylactic acid microspheres, calcium alginate microspheres and the like. The existing embolization materials in the market at present mainly comprise iodized oil and polyvinyl alcohol beads, but the iodized oil as a liquid embolization agent can not embolize large blood vessels effectively, and can generate missed embolization and wrong embolization in the blood flowing process; however, the polyvinyl alcohol beads lack developing ability, and the embolization material cannot be tracked in real time, so that diagnosis and treatment are difficult.

In addition, the traditional embolism treatment has single curative effect, and for some difficult and complicated diseases such as cancer, tumor cells still survive after the embolism treatment, which causes treatment failure. Therefore, there is a need to introduce supplemental treatment modalities to improve the effectiveness of embolization therapy. With the development of micro-nano materials and precise medicine, many materials are applied to develop more excellent intravascular embolization agents, but at present, no method can be used for quickly and conveniently preparing embolization agents with multiple functions, multiple curative effects and diagnosis and treatment.

Disclosure of Invention

The invention aims to solve the problems of high price, lack of developing capability and single curative effect of the traditional suppository in clinic, and particularly provides a novel multifunctional liquid metal suppository to realize the functions of embolism, CT imaging, MRI imaging, drug loading, heat conversion, magnetism and the like, and provide possibility for the combination of targeted embolism treatment with chemotherapy, thermotherapy and radiotherapy.

The invention also aims to provide a preparation method of the multifunctional liquid metal embolic agent.

It is a further object of the present invention to propose the use of said multifunctional liquid metal embolic agent.

The technical scheme for realizing the above purpose of the invention is as follows:

a multifunctional liquid metal embolic agent comprises liquid metal, functional nanoparticles and a high polymer material;

the liquid metal is spherical and forms an inner core of the embolic agent, the functional nano particles are dispersed on the surface of the liquid metal, and the high polymer material is coated outside the inner core and the functional nano particles.

Wherein the liquid metal is a metal or alloy which is in a liquid state at a temperature of less than 30 ℃; the functional nanoparticles are one or more of magnetic nanoparticles, photo-thermal nanoparticles, microwave-sensitive nanoparticles, drug-loaded nanoparticles and radioactive nanoparticles; the high polymer material is one or more of gelatin, starch, polyvinyl alcohol, collagen, albumin, polylactic acid and gel.

The gel can be one of alginic acid gel, glucomannan gel and chitosan gel, or a compound of two of alginic acid gel, glucomannan gel and chitosan gel.

More preferably, the liquid metal is silvery white at less than 30 degrees celsius.

Further, the liquid metal is one of gallium-indium alloy, gallium-indium-tin-zinc alloy or gallium-indium-tin-zinc-bismuth alloy;

the magnetic nano material is a magnetic or magnetic conductive nano material selected from iron nanoparticles and oxygenOne or more of ferric oxide nanoparticles, ferrous oxide nanoparticles and ferroferric oxide nanoparticles; the photo-thermal nano-particles are nano-particles with photosensitive characteristics and are selected from one or more of gold nanoshells, carbon nano-particles and copper nano-particles; the microwave nano material is a nano material with microwave sensitivity and is ZrO₂A nanoshell; the radioactive nanoparticles are nanoparticles with radioactivity and are selected from one of Y90, Co60 and Cs137 nanoparticles.

The invention also provides a preparation method of the multifunctional liquid metal embolic agent, which comprises the following steps:

(1) taking liquid metal and functional nanoparticles as raw materials, and preparing the functional liquid metal by utilizing a liquid metal endocytosis effect;

(2) preparing liquid metal micro-nano particles wrapping functional nano particles by a liquid metal micro-nano particle preparation method, and modifying a polymer surface material on the surface; the preparation method of the liquid metal micro-nano particles comprises one or more of an ultrasonic method, a model method and a micro-flow focusing method;

(3) mixing functional liquid metal micro-nano particles with a substrate solution of a high polymer material, preparing micro-droplets wrapping the functional liquid metal micro-nano particles by a microsphere preparation method, and solidifying to obtain multifunctional liquid metal embolic agent microspheres; the preparation method of the microsphere comprises one or more of an orifice coagulation bath method, an electrostatic spinning method, an emulsifying ion crosslinking method, a complex coacervation method and a microemulsion method; the curing mode is crosslinking curing and/or cooling curing;

(4) then placing the obtained embolism microsphere in washing liquid, and drying after washing; the washing solution is one or more of neutral buffer solution, absolute ethyl alcohol and deionized water.

In the step (1), the liquid metal is dripped on the nanoparticle layer to enable the nanoparticles to be adhered to the surface of the spherical liquid metal, and then the functional liquid metal is obtained through oxidation reaction.

In the step (1), the mass ratio of the liquid metal to the nanoparticles is 10: (1-4).

Wherein, in the step (2), the polymer surface material is one of Pluronic F127, PEG and glycerol. The polymer surface material is modified to prevent fusion.

In the step (2), functional liquid metal is placed into the solution of the polymer surface material, and ultrasonic treatment is carried out for 10-20 min; the concentration of the solution of the polymer surface material is 1-10 wt%, and the solvent of the solution is one of ethanol, acetone, ethylene glycol and trichloroethane.

In the step (3), mixing the functional liquid metal micro-nano particles into a substrate solution of a high polymer material with the concentration of 1-10 wt%, and preparing multifunctional liquid metal embolic agent microspheres wrapping the functional liquid metal micro-nano particles by using a microsphere preparation method; preferably, the concentration of the coated functional liquid metal micro-nano particles is 2-500 mg/ml.

In the step (3), the functional liquid metal micro-nano particles are mixed into a substrate solution of a high polymer material, and the concentration of the substrate solution is adjusted according to the viscosity characteristic. For example, when the base solution is an alginate aqueous solution, the concentration is preferably 1 to 2 wt%.

The preparation method of the microspheres in the step (3) can be selected according to the characteristics of the substrate solution, for example, the substrate solution is a gelatin aqueous solution, and an orifice coagulation bath method, an electrostatic spinning method and a micro-droplet method can be selected, and preferably the micro-droplet method is adopted.

The curing mode in the step (3) can be selected according to the characteristics of the substrate solution, for example, the substrate solution is a gelatin aqueous solution, and cooling and curing can be selected; the base solution is alginate aqueous solution, and can be divalent cation-containing solution (0.1-5.0 wt% Ca)²⁺Or Sr²⁺) And (4) crosslinking and curing.

The neutral buffer solution in the step (4) can be selected according to the characteristics of the substrate solution, and the buffer and washing solution can be deionized water or absolute ethyl alcohol, and is preferably deionized water.

The multifunctional liquid metal embolic agent is applied to radiography, medicine carrying, local heating and local magnetic field application.

The invention has the beneficial effects that:

the multifunctional liquid metal embolic agent provided by the invention can realize the functions of embolization, CT imaging, MRI imaging, drug loading, heat conversion, magnetism and the like, and is expected to realize the combination of targeted embolization treatment with chemotherapy, thermotherapy and radiotherapy; the preparation method of the multifunctional liquid metal microsphere embolic agent provided by the invention provides possibility for more rapidly and conveniently preparing the multifunctional microsphere embolic agent with multiple curative effects and integrated diagnosis and treatment.

Drawings

Fig. 1 is a schematic diagram of a preparation method of functional liquid metal micro-nano particles in the invention.

FIG. 2 is a schematic diagram of the preparation method of the magnetic liquid metal seaweed gel microsphere embolic agent.

FIG. 3 is a photograph of a magnetic liquid metal seaweed gel microsphere embolic agent obtained in example 1.

Detailed Description

The technical solution of the present invention will be described below by way of specific examples.