阅读说明：本技术 纳米载药机器人的制备方法 (Preparation method of nano drug-loaded robot ) 是由 张伯伦 杨志 于 2019-02-28 设计创作，主要内容包括：本发明属于纳米技术领域,尤其涉及纳米载药机器人的制备方法,该制备方法包括以下步骤：a)提供表面设置有SiO<Sub>2</Sub>膜层的衬底基板；b)在所述SiO<Sub>2</Sub>膜层上镀武德合金,形成武德合金膜层；c)在所述武德合金层上镀磁性材料,形成磁性膜层；d)将步骤c)得到的多层复合材料进行光刻；e)将完成光刻的多层复合材料进行加热至材料中的武德合金膜层溶化,磁性膜层与衬底基板分离,得到磁性纳米载药机器人。实验结果表明：相比于传统的化学方法(化学合成)和物理方法(物理研磨),本发明制备方法的生产工艺更为稳定,污染小,成本低,适于工业化；而且采用该方法制备的磁性纳米载药机器人具有更好的载药能力和更高的尺寸均匀性。(The invention belongs to the technical field of nanometer, and particularly relates to a preparation method of a nanometer drug-loaded robot, which comprises the following steps: a) providing a surface with SiO 2 A substrate base plate of the film layer; b) in the SiO 2 Coating the film layer with Wude alloy to form a Wude alloy film layer; c) plating a magnetic material on the Wude alloy layer to form a magnetic film layer; d) photoetching the multilayer composite material obtained in the step c); e) heating the multilayer composite material subjected to photolithography to a temperature of within the materialThe alloy film layer is dissolved, and the magnetic film layer is separated from the substrate base plate to obtain the magnetic nano drug-loaded robot. The experimental results show that: compared with the traditional chemical method (chemical synthesis) and physical method (physical grinding), the preparation method has more stable production process, less pollution and low cost, and is suitable for industrialization; the magnetic nano drug-loaded robot prepared by the method has better drug-loaded capacity and higher size uniformity.)

1. A preparation method of a nano drug-loaded robot comprises the following steps:

a) providing a surface with SiO₂A substrate base plate of the film layer;

b) in the SiO₂Coating the film layer with Wude alloy to form a Wude alloy film layer;

c) plating a magnetic material on the Wude alloy layer to form a magnetic film layer;

d) photoetching the multilayer composite material obtained in the step c);

e) and heating the multilayer composite material subjected to photoetching until the Wude alloy film layer in the material is dissolved, and separating the magnetic film layer from the substrate to obtain the magnetic nano drug-loaded robot.

2. The method according to claim 1, wherein in the step b), the plating is performed by evaporation;

the substrate temperature of the evaporation is 40-60 ℃, the evaporation temperature of the evaporation is 170-400 ℃, the evaporation speed of the evaporation is 1-5 crystal oscillation points/second, and the vacuum degree of the evaporation is 5 × 10^-4～3×10^-4Pa。

3. The method according to claim 1, wherein in the step b), the thickness of the Wude alloy film layer is 50 to 100 nm.

4. The method according to claim 1, wherein in step c), the plating is performed by magnetron sputtering;

the sputtering rate of the magnetron sputtering is 5-10 nm/s; the magnetron sputtering time is 40-120 s.

5. The method according to claim 1, wherein in step c), the thickness of the magnetic film layer is 10 to 1000 nm.

6. The method according to claim 1, wherein in step d), the pulse energy of the photolithography is 150 to 300 μ J; the diameter of the photoetching light beam is 0.01-0.02 mu m.

7. The method according to claim 1, wherein in step d), the photolithography has a depth of: without penetrating the magnetic film layer, only the magnetic film layer, from the magnetic film layer to the Wude alloy film layer, or from the magnetic film layer to SiO₂And (5) film layer.

8. The method of claim 1, wherein in step e), the multilayer composite is heated in water; the heating temperature is 75-80 ℃.

9. The method of claim 1, wherein step e) further comprises:

and cutting the magnetic film layer after the magnetic film layer is separated from the substrate base plate.

10. The method for preparing the alloy material according to claim 9, wherein the cutting manner in step e) is laser cutting.

Technical Field

The invention belongs to the technical field of nanometer, and particularly relates to a preparation method of a nanometer drug-loaded robot.

Background

The nano drug-loaded robot refers to a small drug-loaded robot with the scale of nano level, and has very important potential application in the field of biomedicine, such as minimally invasive surgery, targeted therapy, cell operation and the like, so that the nano drug-loaded robot is widely concerned by researchers at home and abroad and is rapidly developed in recent years.

Compared with the traditional medicine carrying robot, the nano medicine carrying robot has the advantages that the Reynolds coefficient of the working environment of the nano medicine carrying robot is very low, the nano medicine carrying robot can be considered to move in a very viscous, tiny and slow environment, the viscous force plays a dominant role, and the inertial force can be ignored. Under the condition, if the nano drug-loaded robot is driven, the nano drug-loaded robot must be continuously powered. Therefore, various driving methods of the nanopharmaceut are proposed, including self-driving (electrophoresis driving, diffusion driving, autophoresis driving, bubble driving, etc.) and external field driving (magnetic field, acoustic field, and optical driving). Because the magnetic field intensity that the magnetic field drive mode adopted is lower to low frequency magnetic field can pierce through biological tissue and is harmless to the organism, consequently has become one of the most promising drive mode in nanometer medicine carrying robot field. How to prepare the magnetic nano drug-loaded robot which is easy to be driven and controlled by an external magnetic field also becomes the key point of research of researchers.

At present, reported methods for preparing the magnetic nano drug-loaded robot include a chemical synthesis method and a physical grinding method. However, the methods still stay in the experimental stage, and have the problems of poor process stability, large pollution, high cost, poor drug loading capacity and size uniformity of products and the like.

Disclosure of Invention

In view of the above, the invention aims to provide a preparation method of a nano drug-loaded robot, which has the advantages of stable production process, low pollution, low cost and suitability for industrialization; the medicine carrying robot prepared by the method has good magnetism, good medicine carrying capacity and high size uniformity.

The invention provides a preparation method of a nano drug-loaded robot, which comprises the following steps:

a) providing a surface with SiO₂A substrate base plate of the film layer;

b) in the SiO₂Coating the film layer with Wude alloy to form a Wude alloy film layer;

c) plating a magnetic material on the Wude alloy layer to form a magnetic film layer;

d) photoetching the multilayer composite material obtained in the step c);

e) and heating the multilayer composite material subjected to photoetching until the Wude alloy film layer in the material is dissolved, and separating the magnetic film layer from the substrate to obtain the magnetic nano drug-loaded robot.

Preferably, in the step b), the plating mode is evaporation;

the substrate temperature of the evaporation is 40-60 ℃, the evaporation temperature of the evaporation is 170-400 ℃, the evaporation speed of the evaporation is 1-5 crystal oscillation points/second, and the vacuum degree of the evaporation is 5 × 10^-4～3×10^-4Pa。

Preferably, in the step b), the thickness of the Wude alloy film layer is 50-100 nm.

Preferably, in the step c), the plating mode is magnetron sputtering;

the sputtering rate of the magnetron sputtering is 5-10 nm/s; the magnetron sputtering time is 40-120 s.

Preferably, in the step c), the thickness of the magnetic film layer is 10-1000 nm.

Preferably, in the step d), the pulse energy of the photoetching is 150-300 muJ; the diameter of the photoetching light beam is 0.01-0.02 mu m.

Preferably, in step d), the lithography depth is: without penetrating the magnetic film layer, only the magnetic film layer, from the magnetic film layer to the Wude alloy film layer, or from the magnetic film layer to SiO₂And (5) film layer.

Preferably, in step e), the multilayer composite is heated in water; the heating temperature is 75-80 ℃.

Preferably, the step e) further comprises:

and cutting the magnetic film layer after the magnetic film layer is separated from the substrate base plate.

Preferably, in step e), the cutting mode is laser cutting.

Compared with the prior art, the invention provides a preparation method of a nano drug-loaded robot. The preparation method provided by the invention comprises the following steps: a) providing a surface with SiO₂A substrate base plate of the film layer; b) in the SiO₂Coating the film layer with Wude alloy to form a Wude alloy film layer; c) plating a magnetic material on the Wude alloy layer to form a magnetic film layer; d) photoetching the multilayer composite material obtained in the step c); e) and heating the multilayer composite material subjected to photoetching until the Wude alloy film layer in the material is dissolved, and separating the magnetic film layer from the substrate to obtain the magnetic nano drug-loaded robot. The experimental results show that: compared with the traditional chemical method (chemical synthesis) and physical method (physical grinding), the preparation method has more stable production process, less pollution and low cost, and is suitable for industrialization; the magnetic nano drug-loaded robot prepared by the method has better drug-loaded capacity and higher size uniformity.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.

FIG. 1 is a schematic structural view of a multilayer composite provided by an embodiment of the present invention;

FIG. 2 is a schematic structural diagram of a multilayer composite material with a single-layer magnetic film layer according to an embodiment of the present invention;

FIG. 3 is a schematic structural diagram of a multi-layer composite material with a magnetic film layer having a two-layer structure according to an embodiment of the present invention;

FIG. 4 is a schematic structural diagram of a multilayer composite material with three magnetic film layers according to an embodiment of the present invention;

FIG. 5 is a schematic illustration of the lithographic depth provided by an embodiment of the present invention;

fig. 6 is a schematic structural diagram of a magnetic nano drug-loaded robot provided in an embodiment of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. 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 invention provides a preparation method of a nano drug-loaded robot, which comprises the following steps:

a) providing a surface with SiO₂A substrate base plate of the film layer;

b) in the SiO₂Coating the film layer with Wude alloy to form a Wude alloy film layer;

c) plating a magnetic material on the Wude alloy layer to form a magnetic film layer;

d) photoetching the multilayer composite material obtained in the step c);

e) and heating the multilayer composite material subjected to photoetching until the Wude alloy film layer in the material is dissolved, and separating the magnetic film layer from the substrate to obtain the magnetic nano drug-loaded robot.

In the preparation method provided by the invention, firstly, SiO is arranged on the surface₂A substrate of the film layer. The substrate can be a polyethylene terephthalate (PET) substrate, a Polyimide (PI) substrate, a Polyethylene (PE) substrate or other flexible substrates, and can also be a glass substrate, the glass substrate is optimized, the glass substrate can be recycled, the cost is saved, and the technology is mature; the shape of the substrate base plate can be rectangular, circular or irregular; the thickness of the substrate base is preferably 0.1 to 5mm, more preferably 0.2 to 1mm, and specifically may be 0.2mm, 0.3mm, 0.4mm, 0.5mm, 0.6mm,0.7mm, 0.8mm, 0.9mm or 1 mm. In the present invention, the SiO₂The thickness of the film layer is preferably 10-50 nm, more preferably 20-30 nm, and specifically may be 20nm, 21nm, 22nm, 23nm, 24nm, 25nm, 26nm, 27nm, 28nm, 29nm or 30 nm. In the present invention, the SiO is provided₂The primary purposes of the film layers include: 1) filling the substrate base plate to ensure the uniformity of the thickness of the film layer in the subsequent process; 2) sodium ions, potassium ions or other impurities in the substrate can easily pollute other film layers, and the barrier protection effect is achieved.

In the preparation method provided by the invention, the SiO₂The film layer is preferably arranged on the surface of the substrate in a vacuum magnetron sputtering coating mode, and the vacuum magnetron sputtering coating has the advantages of being easy to control the thickness of the film, high in film forming speed, convenient for large-area coating and the like, so that the preparation method has the advantages of being easy to control the reaction and suitable for industrial production. In the invention, SiO is arranged on the surface of the substrate base plate₂Before the film layer, the surface of the substrate is preferably washed, so that stains on the surface of the substrate are removed, and the influence of the stains on the surface of the substrate on the subsequent process is avoided. In the invention, vacuum magnetron sputtering is carried out to plate SiO₂In the film layer process, the target material is selected from a silicon target, the atmosphere of the film coating chamber is oxygen, and the total air pressure of the film coating chamber is preferably 0.2-0.7 Pa, and specifically can be 0.5 Pa; the distance between the target and the substrate is preferably 30-80 mm, more preferably 40-60 mm, and specifically can be 40mm, 45mm, 50mm, 55mm or 60 mm; the sputtering rate is preferably 2-8 nm/s, more preferably 3-5 nm/s, and specifically can be 3nm/s, 4nm/s or 5 nm/s; the coating time is preferably 3 to 15s, more preferably 5 to 10s, and specifically may be 5s, 6s, 7s, 8s, 9s or 10 s.

In the preparation method provided by the invention, the obtained surface is provided with SiO₂After the substrate of the film layer, in the SiO₂The film layer is plated with Wude alloy. Wherein the plating mode is evaporation plating; the Wude alloy target used for evaporation preferably comprises 44-55 wt% of bismuth, 23-27 wt% of lead, 12-14 wt% of tin and 10-15 wt% of cadmium; the substrate temperature for the vapor deposition is preferably 40 to 60 ℃, and specifically 40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃, 45 ℃, 46 ℃, 47 ℃,48 ℃, 49 ℃, 50 ℃, 51 ℃, 52 ℃, 53 ℃, 54 ℃, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃ or 60 ℃, the evaporation temperature of the evaporation is preferably 170-400 ℃, specifically 170 ℃, 175 ℃, 180 ℃, 185 ℃, 190 ℃, 195 ℃, 200 ℃, 210 ℃, 220 ℃, 230 ℃, 240 ℃, 250 ℃, 270 ℃, 300 ℃, 320 ℃, 350 ℃, 370 ℃ or 400 ℃, the evaporation rate of the evaporation is preferably 1-5 crystal oscillation points/second, specifically 1 crystal oscillation point/second, 2 crystal oscillation points/second, 3 crystal oscillation points/second, 4 crystal oscillation points/second or 5 crystal oscillation points/second, and the vacuum degree of the evaporation is preferably 5 × 10^-4～3×10^-4Pa, specifically 5 × 10^-4Pa、4.5×10^-4Pa、4×10^-4Pa、3.5×10^-4Pa or 3 × 10^-4Pa; the evaporation power is preferably 3000-5000W, and specifically 3000W, 3500W, 4000W, 4500W or 5000W. After the Wude alloy plating is finished, the SiO is coated₂The Wude alloy film layer is formed on the film layer, and the thickness of the Wude alloy film layer is preferably 50-100 nm, and specifically can be 50nm, 55nm, 60nm, 65nm, 70nm, 75nm, 80nm, 85nm, 90nm, 95nm or 100 nm.

In the preparation method provided by the invention, after the Wude alloy film layer is formed, the magnetic material is plated on the Wude alloy layer to form the magnetic film layer. Wherein, the plating mode is preferably magnetron sputtering; the sputtering rate of the magnetron sputtering is preferably 5-10 nm/s; the magnetron sputtering time is preferably 40-120 s. And after the magnetic material plating is finished, forming a magnetic film layer on the Wude alloy film layer. The magnetic film layer comprises at least one magnetic film, and the magnetic film is preferably a single magnetic metal film (such as an iron film, a cobalt film, or a nickel film) or a magnetic alloy film (such as a titanium-iron-cobalt composite film). In the present invention, the magnetic film layer may further include a non-magnetic film (e.g., a stainless steel film). In the invention, the thickness of the magnetic film layer is preferably 10-1000 nm, and specifically may be 10nm, 20nm, 30nm, 40nm, 50nm, 70nm, 100nm, 150nm, 200nm, 250nm, 300nm, 400nm, 500nm, 600nm, 700nm, 800nm, 900nm or 1000 nm.

In the preparation method provided by the invention, after the magnetic film layer is formed, a multilayer composite material is obtained, and the structure of the multilayer composite material is shown in fig. 1, wherein fig. 1 is a schematic structural view of the multilayer composite material provided by the embodiment of the invention. In an embodiment of the present invention, the structure of the multilayer composite material may be specifically shown in fig. 2 to 4, fig. 2 is a schematic view of a multilayer composite material structure in which the magnetic film layer provided by the embodiment of the present invention is a single-layer structure, fig. 3 is a schematic view of a multilayer composite material structure in which the magnetic film layer provided by the embodiment of the present invention is a double-layer structure, and fig. 4 is a schematic view of a multilayer composite material structure in which the magnetic film layer provided by the embodiment of the present invention is a three-layer structure.

In the preparation method provided by the invention, after the multilayer composite material is obtained, the multilayer composite material is subjected to photoetching. Wherein the lithographic pattern includes, but is not limited to, circular, rectangular, or irregular patterns; the pulse energy of the photoetching is preferably 150-300 muJ, and specifically can be 150 muJ, 160 muJ, 170 muJ, 180 muJ, 190 muJ, 200 muJ, 210 muJ, 220 muJ, 230 muJ, 240 muJ, 250 muJ, 260 muJ, 270 muJ, 280 muJ, 290 muJ or 300 muJ; the optical beam diameter of the photoetching is preferably 0.01-0.02 μm, and specifically can be 0.01 μm, 0.011 μm, 0.012 μm, 0.013 μm, 0.014 μm, 0.015 μm, 0.016 μm, 0.017 μm, 0.018 μm, 0.019 μm or 0.02 μm. In the present invention, the depth of the lithography is preferably: without penetrating the magnetic film layer, only the magnetic film layer, from the magnetic film layer to the Wude alloy film layer, or from the magnetic film layer to SiO₂And (5) film layer. In order to more intuitively show the 4 kinds of lithography depths, a schematic diagram of the lithography depth shown in FIG. 5 is provided, in FIG. 5, 1 indicates that the magnetic film layer is not penetrated, 2 indicates that only the magnetic film layer is penetrated, 3 indicates that the magnetic film layer is penetrated to the Wude alloy film layer, and 4 indicates that the magnetic film layer is penetrated to SiO₂And (5) film layer.

In the preparation method provided by the invention, after the photoetching is finished, the multi-layer composite material which is subjected to photoetching is heated until the Wude alloy film layer in the material is dissolved (the Wude alloy film layer is dissolved at about 71 ℃). Wherein the heating is preferably carried out in water; the heating temperature is preferably 75-80 ℃, and specifically can be 75 ℃, 76 ℃, 77 ℃, 78 ℃, 79 ℃ or 80 ℃. In one embodiment of the present invention, the heating process includes: and placing the multilayer composite material subjected to photoetching in a water tank, heating the water tank to the heating temperature, and then preserving heat for a period of time. Wherein the initial temperature of the water tank is preferably 15-35 ℃, and specifically can be room temperature (25 ℃); the heating rate is preferably 1-10 ℃/min, more preferably 3-7 ℃/min, and specifically can be 3 ℃/min, 4 ℃/min, 5 ℃/min, 6 ℃/min or 7 ℃/min; the heat preservation time is preferably 3-15 min, more preferably 5-10 min, and specifically can be 5min, 6min, 7min, 8min, 9min or 10 min. After the Wude alloy film layer is dissolved, the magnetic film layer is separated from the substrate, and the separated magnetic film layer is the magnetic nano medicine-carrying robot prepared by the invention.

In the preparation method provided by the invention, after the magnetic film layer is separated from the substrate, the separated magnetic film layer can be cut according to actual requirements, so that the magnetic nano drug-loaded robot meeting the size requirement is obtained (for example, the drug-loaded robot for cardiovascular diagnosis and treatment has a sub-millimeter size, and the drug-loaded robot for gastrointestinal tract and solid tumor diagnosis and treatment has a millimeter-centimeter size). Wherein the cutting mode is preferably laser cutting; the scanning step of the laser cutting is preferably 10-200 nm/s, and specifically can be 10nm/s, 20nm/s, 30nm/s, 40nm/s, 50nm/s, 60nm/s, 70nm/s, 80nm/s, 90nm/s, 100nm/s, 110nm/s, 120nm/s, 130nm/s, 140nm/s, 150nm/s, 160nm/s, 170nm/s, 180nm/s, 190nm/s or 200 nm/s; the laser spot of the laser cutting is preferably 0.05-0.1 μm, and specifically can be 0.05 μm, 0.06 μm, 0.07 μm, 0.08 μm, 0.09 μm or 0.1 μm; the electron beam energy of the laser cutting is preferably 10-100 mJ, and specifically can be 10mJ, 20mJ, 30mJ, 40mJ, 50mJ, 60mJ, 70mJ, 80mJ, 90mJ or 100 mJ; the cutting precision of the laser cutting is preferably less than 100 nm. In the present invention, the shape of the cut is not particularly limited, including but not limited to a circle, a rectangle, or an irregular pattern. In an embodiment provided by the present invention, the magnetic nano drug-loaded robot obtained after cutting is shown in fig. 6, fig. 6 is a schematic structural view of the magnetic nano drug-loaded robot provided by the embodiment of the present invention, and in fig. 6, a is rectangular cutting and b is circular cutting.

In the preparation method provided by the invention, after the magnetic nano drug-loaded robot is prepared, the prepared magnetic nano drug-loaded robot is preferably dried and sterilized. Wherein the drying is preferably carried out in a vacuum environment of 50Pa or less; the mode of disinfection is preferably ultraviolet-ozone disinfection. In the invention, the ultraviolet-ozone disinfection is carried out to remove the residual organic matters on the surface of the nano drug-loaded robot, promote the surface oxidation and increase the smoothness and the evenness of the surface and the inner side.

The experimental results show that: compared with the traditional chemical method (chemical synthesis) and physical method (physical grinding), the preparation method has more stable production process, less pollution and low cost, and is suitable for industrialization; the magnetic nano drug-loaded robot prepared by the method has better drug-loaded capacity and higher size uniformity.

For the sake of clarity, the following examples are given in detail.