Drug-loaded magnesium-based micro-nanorobot and endoscope-guided micro-nanorobot delivery system

Abstract

The application discloses a drug-loaded magnesium-based micro-nano robot and an exogenous image auxiliary guided micro-nano robot delivery system, and belongs to the field of micro-nano robots. The method comprises the following steps: preparing a magnesium powder with a micron size as a main body magnesium-based drug-loaded micro-nano robot, and using hydrogen bubbles generated by the reaction of a bare magnesium notch and H+ in the environment as a self-driven driving source; establishing a stab card at an abdominal cavity part of an animal body, which is used for the insertion of an optical fiber endoscope and the injection of a magnesium-based positive and negative type micro robot in a tumor; and after the position of the tumor is found, the self-driven characteristics of the micro robot are used to inject the drug-loaded micro robot into the tumor, so that a high drug delivery effect is achieved. The magnesium-based micro-nano robot has the characteristics of a simple preparation method, good biocompatibility and self-driving, has a good application prospect in the field of cancer treatment, and improves the treatment effect of cancer.

Description

A drug-loaded magnesium-based anion-and-negative micro / nano robot and an endoscope-guided micro / nano robot delivery system Technical Field

[0001] This invention belongs to the field of micro-nano robotics technology, specifically relating to a device system that combines a visualization endoscope or an ultrasound external imaging system to guide a micro-nano robot in the treatment of pancreatic cancer. Background Technology

[0002] Micro- and nano-robots are a novel robotic technology characterized by controllability and high biocompatibility. They can be combined with various multifunctional components (such as drugs) and integrate active delivery, high-speed controllable motion, and multifunctionality. Fiber optic endoscopes are medical internal medicine observation techniques that utilize optical fibers combined with lenses and electronic display systems to achieve light transmission and imaging. They can enter the human body through natural orifices or surgical incisions and are currently used to examine internal tissue structures that are difficult to access.

[0003] Because malignant tumors are surrounded by abundant fibrotic matrix, intravenous administration of drugs is hampered by this matrix, making it difficult for them to penetrate the tumor. Furthermore, the abundant fibrotic matrix makes the tumor site hard, hindering drug delivery via conventional local injection methods; the injected drug is often squeezed out by the hard tissue, resulting in very low drug delivery efficiency. Currently, there is no method for treating pancreatic cancer that combines external imaging systems such as endoscopy or ultrasound with self-driven micro / nano robots. However, by combining visualization with endoscopic systems or ultrasound, and utilizing the self-driven characteristics of micro / nano robots to inject drugs into the tumor, the drug delivery efficiency, drug killing range, and treatment efficacy in pancreatic cancer treatment can be effectively improved. Summary of the Invention

[0004] The purpose of this invention is to address the shortcomings of existing technologies by providing a reliable treatment method for pancreatic cancer that combines external imaging technologies such as endoscopy or ultrasound with micro-nano robotics. Currently, there is no method in research that combines endoscopic or ultrasound-guided self-driven micro-nano robots to treat pancreatic cancer. This invention leverages the self-driving characteristics of micro-nano robots and the visualization advantages of endoscopic or ultrasound images to offer a reliable treatment method for pancreatic cancer.

[0005] This invention is achieved through the following technical solution:

[0006] A method for fabricating a drug-loaded magnesium-based micro / nano robot includes the following steps:

[0007] Step 1: Take micron-sized magnesium spheres, wash away impurities, dissolve them in ethanol, acetone or isopropanol, and disperse the magnesium microspheres on a glass slide to form a magnesium monolayer.

[0008] Step 2: Coat a polymer embedding layer evenly onto the magnesium monolayer and allow it to dry.

[0009] Step 3: Apply a uniform layer of the drug onto the magnesium monolayer and allow it to dry.

[0010] Step 4: Apply another layer of PLGA evenly to the magnesium monolayer and let it stand to dry;

[0011] Step 4: Scrape the magnesium microspheres coated with polymer and drug off the glass slide, collect them in centrifuge tubes, and seal and refrigerate them.

[0012] Further, the average size of the magnesium microspheres is 1-200 μm, further 10-100 μm, and further, for example, 15, 25, 50 μm.

[0013] Furthermore, the mass fraction of the polymer used for encapsulation is 0.1-10%, for example 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 5%.

[0014] Furthermore, in step two, magnesium microspheres are immobilized on a glass slide by encapsulation with a polymer that has good biocompatibility and biodegradability.

[0015] Furthermore, in step three, the drug is loaded onto the surface of the magnesium sphere by spraying or dripping, thus preparing a drug-loaded magnesium-based micro / nano robot.

[0016] A card-based endoscope-guided micro / nano robot delivery system, comprising the following steps:

[0017] Step 5: After anesthetizing the patient, fix him on the operating table, make a small incision in the patient's lower abdomen, insert the first micro-puncture card, and fix it with two clamps;

[0018] Step 6: Under endoscopic guidance, make a second small incision in the epithelium at the tumor site, insert a second micro-trigger card, and fix it in place;

[0019] Step 7: Combine the micro-nano robot injection guided by the endoscope system. Insert the optical fiber of the endoscope through the first micro-tap card and insert the needle through the second micro-tap card. Under the guidance of the endoscope, locate the tumor location, insert the needle into the tumor, and apply a slight pushing force. Utilize the self-driving characteristics of the micro-nano robot to make the micro-nano robot enter the tumor and complete the intratumoral drug delivery.

[0020] This invention fabricates a self-driven magnesium-based anion-and-ion micro / nano robot. The robot is a spherical robot with a single notch. The robot's core is magnesium-based, and from the core outwards are magnesium-based, a polymer embedding layer, a drug-loaded nanoparticle layer, and another polymer embedding layer. The magnesium-based core contacts the outside world through the single notch.

[0021] Furthermore, the polymer encapsulation layers are all polylactic acid-glycolic acid copolymers.

[0022] A verification method for the self-driven operation of a drug-loaded magnesium-based anion-and-ion micro-nano robot is characterized by adding the magnesium-based micro-nano robot onto a hydrophilic glass slide, adding an acidic solution, and adjusting the field of view to observe the movement of the magnesium-based micro-nano robot.

[0023] Furthermore, the acidic solution is a hydrochloric acid solution.

[0024] Furthermore, the temperature is 35-40°C, for example 36, 37, 38, or 39°C, preferably 37°C.

[0025] By utilizing the self-driving capability of magnesium-based anion-and-ion nanorobots and combining them with endoscopes used in internal medicine, an endoscope-guided micro-nanorobot delivery system was built. This system can treat tumors under minimally invasive conditions, improve the efficiency of drug delivery within the tumor, and has broad application prospects in tumor treatment. Attached Figure Description

[0026] To make the contents of this invention easier to understand, the following detailed description of the invention, in conjunction with the accompanying drawings, is provided based on specific embodiments of the invention, wherein:

[0027] Figure 1 is a flowchart illustrating the fabrication process of magnesium-based anion-nano robots in an embodiment of the present invention.

[0028] Figure 2 is a scanning electron microscope image of the magnesium-based anion-nano robot in an embodiment of the present invention.

[0029] Figure 3 is a motion delay diagram of the magnesium-based yin-yang type micro-nano robot in water in an embodiment of the present invention.

[0030] Figure 4 is a schematic diagram of the endoscope-guided micro-nano robot delivery system in an embodiment of the present invention. Detailed Implementation

[0031] The present invention will be further described in detail below: This embodiment is implemented based on the technical solution of the present invention and provides detailed implementation methods, but the protection scope of the present invention is not limited to the following embodiment.

[0032] Before constructing the endoscopic-guided micro / nano robotic system, a drug-loaded magnesium-based anion / ion micro / nano robotic system with self-driving capability is first fabricated. The process is shown in Figure 1 and includes the following steps:

[0033] Step 1: Take magnesium microspheres with a size of 25 ± 5 μm and wash them 5 times with ethanol to remove impurities and oxidized magnesium microspheres. Dissolve the washed magnesium microspheres in anhydrous ethanol. Then, use a dropper to take an appropriate amount of magnesium microspheres and drop them onto a glass slide. Tilt the glass slide (at an angle of about 15°) to make the droplet flow evenly and to make the magnesium microspheres evenly dispersed on the glass slide to form a magnesium monolayer. Let it stand and dry.

[0034] Step 2: Coat the glass slide evenly with a 1% (w / w) polymer embedding solution and allow it to dry.

[0035] Step 3: Prepare drug-loaded nanoparticles. Mix 10 mg / mL gemcitabine (GEM) aqueous solution and 4% polymer solution in a volume ratio of 2:1:1 and sonicate in an ice bath for 30 min to obtain a w / o type emulsion. Remove the organic phase from the emulsion by rotary evaporation. The rotary evaporation conditions are: water bath temperature 50 ℃, rotation speed 600 r / min, time 3 h. Centrifuge the liquid obtained after rotary evaporation at 5000 r / min for 20 min and discard the supernatant to obtain drug-loaded nanoparticles.

[0036] Step 4: Dissolve the drug-loaded nanoparticles prepared in Step 3 in water and disperse them, then coat them evenly onto the magnesium monolayer fixed in Step 2, and let them stand to dry.

[0037] Step 5: 1% by mass of polymer is uniformly coated onto the drug-loaded magnesium monolayer obtained in Step 4. After standing and drying, the magnesium microspheres are gently scraped off to obtain anionic / ionic microrobots with a single notch, as shown in Figure 2 (Figure 2. (a) Scale bar: 300 μm; (b) Scale bar: 30 μm). The obtained drug-loaded anionic / ionic nanorobots are sealed in 1.5 ml centrifuge tubes and stored at 4°C.

[0038] After obtaining the drug-loaded magnesium-based anion-and-nano robot, the self-driving capability of the micro-nano robot is verified, which includes the following steps:

[0039] Step 6: Treat the glass slides with a Plasma cleaner to improve the hydrophilicity of the slide surface;

[0040] Step 7: Turn on the microscope stage heating plate and adjust the temperature to 37 ℃. Add 5 μL of well-dispersed magnesium-based micro / nano robot to a hydrophilic slide, add 5 μL of 0.0002 mol / L HCl, adjust the field of view and observe the movement of the magnesium-based micro / nano robot. The recorded time delay diagram is shown in Figure 3.

[0041] After verifying the self-driving behavior of the magnesium-based anion-nano robot, the construction of an endoscope-guided micro-nano robot delivery system was initiated, which includes the following steps:

[0042] Step 8: After anesthetizing the patient with pancreatic cancer, fix him / her to the operating table;

[0043] Step 9: Make a small incision of about 0.5 cm in the patient's lower abdomen with a scalpel, insert the first micro puncture card, and fix the puncture card with two towel clamps, as shown in Figure 4;

[0044] Step 10: Insert the endoscope fiber optic cable into the first micro-touch card. Under the guidance of the endoscope, make a small incision of about 0.5 cm at the location of the tumor with a scalpel, implant and fix the second micro-touch card, insert the endoscope fiber optic cable through the first micro-touch card, and insert the needle through the second micro-touch card.

[0045] Step 11: Under the guidance of an endoscope, locate the tumor, insert the needle into the tumor, apply a slight pushing force, and use the self-driving characteristics of the micro-nano robot to enter the tumor and complete the intratumoral drug delivery.

[0046] In step one, the magnesium powder is commercially available micron-sized magnesium powder.

[0047] In step two, a 1% polymer solution or suspension is used to fix the magnesium microspheres onto the glass slide to prevent them from detaching from the glass slide in subsequent steps, which could lead to drug loading failure.

[0048] In step two, the polymer solution or suspension has good biocompatibility and biodegradability.

[0049] In step three, the drug-loaded nanoparticles play a role in sustained drug release, preventing the drug from being released too quickly.

[0050] In step five, a 1% polymer solution or suspension is used to coat the drug-loaded layer to prevent the drug from being scraped off during the release of the nanorobot, thus preventing drug loss.

[0051] In step six, the hydrophilicity of the slide is increased to prevent the microscope from having difficulty focusing due to the high liquid level when observing the movement of the micro-nano robot.

[0052] In step seven, 37 ℃ is used to simulate body temperature, and 0.0002 mol / L HCl is used to simulate the acidic microenvironment of the tumor.

[0053] In step ten, a dual-stamp card is created. The first micro-stamp card is used for the insertion of an endoscopic fiber optic cable to observe the intra-abdominal environment, and the second micro-stamp card is used for the insertion of an injection needle to deliver the micro-nano robot.

[0054] In step eleven, salts such as NaCl, CaCl2, and KCl are added to the injection needle containing the micro-nano robot to improve the self-driving capability of the micro-nano robot.

[0055] In step eleven, unlike conventional injection methods, the self-driving micro-nano robot, while controlling the injection needle piston to prevent it from retracting, applies only a slight thrust, allowing the micro-nano robot to self-drive into the tumor using air bubbles.

[0056] It will be understood by those skilled in the art that, unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It should also be understood that terms such as those defined in general dictionaries should be understood to have the same meaning as in the context of the prior art, and should not be interpreted in an idealized or overly formal sense unless specifically defined as herein.

[0057] It should be understood that the above detailed description of the technical solutions of the present invention with reference to preferred embodiments is illustrative and not restrictive. Those skilled in the art can modify the technical solutions described in the embodiments or make equivalent substitutions for some of the technical features based on reading this specification; however, these modifications or substitutions do not cause the essence of the corresponding technical solutions to depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for fabricating a drug-loaded magnesium-based anion-and-nano robot, characterized in that: Step 1: Wash away impurities from magnesium microspheres, dissolve them in ethanol or acetone solution, and disperse the magnesium microspheres on a glass slide to form a magnesium layer; Step 2: Uniformly coat the magnesium layer with polylactic acid-glycolic acid copolymer and allow it to stand and dry; Step 3: Uniformly coat the magnesium layer with drug-loaded nanoparticles and allow it to stand and dry; Step 4: Uniformly coat the magnesium microspheres with polylactic acid-glycolic acid copolymer again and allow it to stand and dry; Step 5: Scrape the magnesium microspheres coated with copolymer and drug from the glass slide; The robot is a spherical robot with a single notch; The robot's core is a magnesium microsphere, and from the core outwards are magnesium microspheres, a polymer embedding layer, a drug-loaded layer, and another polymer embedding layer. The magnesium microspheres are in contact with the outside through a single notch; The polymer embedding layers are all polylactic acid-glycolic acid copolymers.

2. The method for preparing drug-loaded magnesium-based anion / ion micro / nano robots according to claim 1, characterized in that, In step two, magnesium microspheres are immobilized on the substrate using polylactic acid-glycolic acid copolymer, which has good biocompatibility and biodegradability.

3. The method for preparing drug-loaded magnesium-based anion / ion micro / nano robots according to claim 1, characterized in that, In step three, the drug is sprayed or dripped onto the substrate of the fixed magnesium microspheres to enhance the sustained-release capability of the drug.

4. The method for preparing drug-loaded magnesium-based anion / ion micro / nano robots according to claim 1, characterized in that, The average size of the magnesium microspheres is 1-200 μm.

5. The method for preparing drug-loaded magnesium-based anion / ion micro / nano robots according to claim 1, characterized in that, Magnesium microspheres are dispersed in a monolayer on a glass slide.

6. A drug-loaded magnesium-based anion / ion micro / nano robot, characterized in that, The robot is a spherical robot with a single notch; the robot's core is a magnesium microsphere, and from the core outwards are a magnesium microsphere, a polymer embedding layer, a drug-loaded layer, and another polymer embedding layer. The magnesium microsphere contacts the outside through the single notch. The preparation method is as follows: Step 1, take magnesium microspheres, wash away impurities, dissolve them in ethanol or acetone solution, and disperse the magnesium microspheres on a glass slide to form a magnesium layer; Step 2, uniformly coat the magnesium layer with polylactic acid-glycolic acid copolymer and allow it to stand and dry; Step 3, uniformly coat the magnesium microspheres with drug-loaded nanoparticles and allow it to stand and dry; Step 4, uniformly coat the magnesium microspheres with polylactic acid-glycolic acid copolymer again and allow it to stand and dry; Step 5, scrape the magnesium microspheres coated with copolymer and drug from the glass slide; the polymer embedding layers are all polylactic acid-glycolic acid copolymer.

7. The drug-loaded magnesium-based anion / ion micro / nano robot according to claim 6, characterized in that, The average size of the magnesium microspheres is 1-200 μm.

8. The application of the drug-loaded magnesium-based anion-nano robot as described in claim 6 or 7 in the preparation of an antitumor drug delivery system.

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