Magnetically-driven dual-core micro-nano robot for targeted therapy of colorectal cancer and use method of magnetically-driven dual-core micro-nano robot

Abstract

The invention relates to the field of medical micro-nano robots, in particular to a magnetic-driven dual-core micro-nano robot for targeted therapy of colorectal cancer and a using method thereof.The micro-nano robot is provided with a calcium alginate outer membrane, the micro-nano robot is provided with a water-drop-shaped tail structure, and gelatin microspheres A and gelatin microspheres B are arranged in the calcium alginate outer membrane; the method comprises the steps that firstly, the magnetic drive micro-nano robot penetrates through the gastric acid environment to reach the intestinal tract; 2, controlling the micro-nano robot to stop in the lesion area through a magnetic field, and breaking the micro-nano robot to release the gelatin microspheres A and the gelatin microspheres B; 3, sequentially breaking the gelatin microspheres A and the gelatin microspheres B through a rotating magnetic field; the three technical bottlenecks of gastric acid inactivation of oral medicines, low mucus penetration efficiency and multi-medicine synergistic sequential control are overcome.

Description

Technical Field

[0001] The present invention relates to the field of medical micro-nano robots, and more specifically to a magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer and a method of use thereof. Background Art

[0002] Colorectal cancer is one of the common malignant tumors of the digestive tract. At present, its incidence rate is on the rise, it progresses rapidly, and its overall survival rate is low, posing a great threat to people's health. Colorectal cancer is a complex genetic disease with strong heterogeneity and large individual differences. It is difficult to diagnose early, has a high recurrence rate, and is prone to distant metastasis. This leads to a high incidence and difficulty in treatment, which seriously affects the work and quality of life of patients. For the treatment of colorectal cancer, surgery is the main treatment method for most colorectal cancer patients, combined with chemotherapy, radiotherapy or targeted therapy. However, it has high risks and a long postoperative recovery period, which has a great impact on the quality of life of patients. At the same time, the problem of recurrence and metastasis cannot be avoided. Since the programmed death receptor 1 inhibitor showed significant efficacy in some colorectal cancer patients in trials, immunotherapy as an emerging treatment method has brought hope to colorectal cancer patients. As an important chemotherapy drug, ilisimol plays a key role in the treatment of colorectal cancer, especially for patients with advanced or metastatic colorectal cancer. However, while killing cancer cells, ilisimol is also toxic to normal cells, and conventional drug administration methods make it difficult for sufficient effective drug concentrations to reach tumor cells to exert their effects. Therefore, it is crucial to use appropriate methods to deliver drugs in a targeted manner.

[0003] With the development of the emerging discipline of nanotechnology, the emergence of micro-nanorobotics offers new avenues for the treatment of colorectal cancer. Micro-nanorobotics offer the advantages of small size, light weight, and a high thrust-to-weight ratio, holding them promising for biomedical applications. Micro-nanorobotics can be used as carriers to carry drugs such as programmed death receptor 1 inhibitors and ilisimol, delivering them to the lesion site, achieving high local drug concentrations and ultimately killing tumor cells. However, existing micro-nanorobotics struggle to traverse complex biological tissue barriers for targeted drug delivery to lesions. For malignancies such as colorectal cancer, which are located in the digestive tract, the pH, digestive enzymes, and fluid environment within the tract may affect the structural stability of micro-nanorobotics. Therefore, designing a shell material that can withstand corrosion from gastric acid and is prone to rupture in the intestinal environment is a key research challenge. Furthermore, programmed death receptor 1 inhibitors are less effective in environments with low immune cell concentrations, necessitating appropriate methods to increase the concentration of immune cells near tumor cells before releasing the PD-1 inhibitors. Summary of the Invention

[0004] The purpose of the present invention is to provide a magnetically driven dual-core micro-nano robot for the targeted treatment of colorectal cancer and a method of use, which overcomes the three major technical bottlenecks of gastric acid inactivation of oral drugs, low mucus penetration efficiency, and multi-drug synergistic timing control.

[0005] The purpose of the present invention is achieved through the following technical solutions:

[0006] A magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer, wherein the micro-nano robot has a calcium alginate outer membrane and a droplet-shaped tail structure, and gelatin microspheres A and B are disposed within the calcium alginate outer membrane;

[0007] The gelatin microspheres A and B are randomly distributed;

[0008] The gelatin microspheres A are loaded with Fe3O4 magnetic nanoparticles with a particle size of 150 nm and ilisimol;

[0009] The gelatin microspheres B are loaded with Fe3O4 magnetic nanoparticles with a particle size of 20 nm and a programmed death receptor 1 inhibitor;

[0010] The micro-nano robot is controlled to move by a magnetic field;

[0011] The gelatin microspheres A and B are released by magnetic field stimulation; the release of gelatin microspheres A and B is regulated by magnetic field stimulation;

[0012] The micro-nano robots are made of gelatin materials with different cross-linking degrees;

[0013] The micro-nano robot includes the following steps:

[0014] Step 1: The magnetically driven micro-nano robot passes through the gastric acid environment and reaches the intestine;

[0015] Step 2: The micro-nano robot is controlled by a magnetic field to stay at the lesion area, and the micro-nano robot ruptures to release gelatin microspheres A and B;

[0016] Step 3: Sequentially rupture gelatin microspheres A and B using a rotating magnetic field;

[0017] The gelatin microspheres A rupture and release ilisimol, which, after being released, promotes the death of tumor cells in the lesion area and releases related damage molecules, thereby promoting immune infiltration and increasing the concentration of immune cells in the lesion area;

[0018] The gelatin microspheres B rupture to release programmed death receptor 1 inhibitors, which are used on the surface of recruited immune cells to destroy the immune escape mechanism of tumor cells, thereby enabling the immune cells to efficiently identify and kill tumor cells.

[0019] The beneficial effects of the present invention are:

[0020] The calcium alginate shell of the magnetically driven dual-core micro-nano robot allows it to overcome the corrosion of the gastric acid environment and reach the intestine, where it can easily rupture and release drugs.

[0021] After the magnetically driven dual-core micro-nano robot loaded with drugs arrives at the lesion area, it can be controlled by the magnetic field to stay in the lesion area, and then other excitations can be used to perform subsequent work such as drug release;

[0022] The magnetically driven dual-core micro-nano robot is equipped with a teardrop-shaped tail structure, which facilitates its efficient movement on the surface of the intestinal mucosa;

[0023] The magnetically driven dual-core micro-nano robot contains two gelatin microspheres with different magnetic loadings. This allows the robot to first release the drug ilisimol from gelatin microsphere A and then release the programmed cell death receptor 1 inhibitor from gelatin microsphere B, thereby inducing cell death and promoting immune infiltration, thus inhibiting the immune escape of cancer cells and enabling immune cells to efficiently identify and kill tumor cells.

[0024] The main material of the magnetically driven dual-core micro-nano robot is gelatin, and the magnetized area is Fe3O4 magnetic nanoparticles. Therefore, it is non-toxic to the human body and will degrade by itself after completing its work for a period of time. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The present invention will be further described in detail below with reference to the accompanying drawings and specific implementation methods.

[0026] Figure 1 This is a schematic diagram of the structure of the magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer according to the present invention;

[0027] Figure 2 This is a schematic diagram of the use process of the magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer of the present invention.

[0028] In the figure: gelatin microsphere B1; calcium alginate outer membrane 2; droplet-shaped tail structure 3; gelatin microsphere A4; macrophage 5; dendritic cell 6; T cell 7. DETAILED DESCRIPTION

[0029] The present invention will be further described in detail below with reference to the accompanying drawings.

[0030] like Figure 1 As shown, the structure and function of a magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer are described in detail below;

[0031] A magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer, the micro-nano robot having a calcium alginate outer membrane 2 and a water droplet-shaped tail structure 3, wherein gelatin microspheres A4 and B1 are disposed within the calcium alginate outer membrane 2;

[0032] The stability of the calcium alginate outer membrane 2 in an acidic environment allows it to overcome gastric acid erosion and enter the intestine from the digestive tract. After entering the intestine, the outer membrane of the micro-nano robot swells and ruptures due to the instability of the calcium alginate outer membrane 2 in the alkaline environment of the intestine, releasing the gelatin microspheres A4 and B1 inside, facilitating subsequent drug release.

[0033] The micro-nano robot has a water drop-shaped tail structure 3, which enables the micro-nano robot to move efficiently on the surface of the intestinal mucosa;

[0034] The gelatin microspheres A4 and B1 are randomly distributed; under low Reynolds numbers, this unique structure can break the spatial symmetry, thereby enabling efficient movement on the intestinal mucosal surface;

[0035] The gelatin microsphere A4 is loaded with Fe3O4 magnetic nanoparticles with a particle size of 150 nm and ilisimol; the gelatin microsphere B1 is loaded with Fe3O4 magnetic nanoparticles with a particle size of 20 nm and a programmed death receptor 1 inhibitor; the micro-nano robot is controlled to move by a magnetic field, and the gelatin microspheres A4 and B1 are released by magnetic field stimulation; the magnetic field stimulation release regulates the temporal release of the gelatin microspheres A4 and B1;

[0036] Fe3O4 magnetic nanoparticles, which have good magnetic properties and are easy to control by external magnetic fields;

[0037] After reaching the lesion area, ilisimol is released earlier than the programmed death receptor 1 inhibitor because the magnetic nanoparticles loaded in the gelatin microspheres A4 are larger in size and have a poorer degree of cross-linking, making them more easily broken in a rotating magnetic field, thereby achieving distributed release of the drug. After being released, ilisimol promotes the copper death of tumor cells in the lesion area and releases related damage molecules, thereby promoting immune infiltration and increasing the concentration of immune cells in the lesion area. The subsequently released programmed death receptor 1 inhibitor acts on the surface of the recruited immune cells, destroying the immune escape mechanism of tumor cells, thereby enabling immune cells to efficiently identify and kill tumor cells.

[0038] The micro-nano robot is made of gelatin with different cross-linking degrees; the magnetized area is Fe3O4 magnetic nanoparticles, so it is non-toxic to the human body and will degrade on its own after completing its work for a period of time;

[0039] This micro-nano robot can overcome gastric acid corrosion to reach the intestines and achieve controllable movement in the intestines through its tail structure, thereby targeting the lesion area for step-by-step drug release, effectively killing colorectal cancer cells.

[0040] like Figure 2 As shown, the following is a detailed description of the steps and functions of a method for using a magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer;

[0041] Figure 2 In the process, step I is that the magnetically driven dual-core micro-nano robot reaches the lesion area in the intestine through magnetic drive targeting, first releasing ilisimol and then releasing programmed death receptor 1 inhibitor; step II is that ilisimol promotes the copper death of tumor cells and releases related damage molecules, thereby promoting immune infiltration; step III is that the subsequently released programmed death receptor 1 inhibitor acts on the surface of recruited immune cells, destroying the immune escape mechanism of tumor cells, thereby enabling immune cells to efficiently identify and kill tumor cells;

[0042] A method for using a magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer, comprising the following steps:

[0043] Step 1: The magnetically driven micro-nano robot passes through the gastric acid environment and reaches the intestine. The stability of the calcium alginate outer membrane 2 in an acidic environment enables it to overcome gastric acid erosion and enter the intestine from the digestive tract.

[0044] Step 2: The microrobot is controlled by a magnetic field to stay at the lesion area. The microrobot ruptures and releases gelatin microspheres A4 and B1. After entering the intestine, the outer membrane of the calcium alginate 2 is unstable in the alkaline environment of the intestine, so the outer membrane of the microrobot swells and ruptures, releasing the gelatin microspheres A4 and B1 inside, facilitating subsequent drug release.

[0045] Step 3: Gelatin microspheres A4 and B1 are ruptured in sequence through a rotating magnetic field; after reaching the lesion area, the magnetic nanoparticles loaded in gelatin microspheres A4 are larger in size and have poorer cross-linking, making them easier to rupture in a rotating magnetic field. Gelatin microspheres A4 rupture to release ilisimol, which, after being released, promotes the death of tumor cells in the lesion area and releases related damage molecules, thereby promoting immune infiltration and increasing the concentration of immune cells in the lesion area; gelatin microspheres B1 rupture to release programmed death receptor 1 inhibitors, which are used on the surface of recruited immune cells to destroy the immune escape mechanism of tumor cells, thereby enabling immune cells to efficiently identify and kill tumor cells.

Claims

1. A magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer, characterized by: The micro-nano robot has a calcium alginate outer membrane (2), a water drop-shaped tail structure (3), and gelatin microspheres A (4) and gelatin microspheres B (1) are arranged in the calcium alginate outer membrane (2).

2. The magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer according to claim 1, characterized in that: The gelatin microspheres A (4) and gelatin microspheres B (1) are randomly distributed.

3. The magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer according to claim 1, characterized in that: The gelatin microspheres A (4) are loaded with Fe3O4 magnetic nanoparticles with a particle size of 150 nm and ilisimol.

4. The magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer according to claim 3, characterized in that: The gelatin microspheres B (1) are loaded with Fe3O4 magnetic nanoparticles with a particle size of 20 nm and a programmed death receptor 1 inhibitor.

5. The magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer according to claim 4, characterized in that: The micro-nano robot is controlled to move by a magnetic field.

6. The magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer according to claim 5, characterized in that: The gelatin microspheres A (4) and gelatin microspheres B (1) are released by magnetic field stimulation, and the magnetic field stimulation release regulates the temporal release of the gelatin microspheres A (4) and gelatin microspheres B (1).

7. The magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer according to any one of claims 1 to 6, characterized in that: The micro-nano robots are made of gelatin materials with different cross-linking degrees.

8. The magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer according to claim 6, characterized in that: The micro-nano robot includes the following steps: Step 1: The magnetically driven micro-nano robot passes through the gastric acid environment and reaches the intestine; Step 2: The micro-nano robot is controlled by a magnetic field to stay at the lesion area, and the micro-nano robot ruptures to release gelatin microspheres A (4) and gelatin microspheres B (1); Step 3: The gelatin microspheres A (4) and B (1) are sequentially broken by a rotating magnetic field.

9. The magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer according to claim 8, characterized in that: The gelatin microspheres A (4) rupture and release ilisimol, which, after being released, promotes the death of tumor cells in the lesion area and releases related damage molecules, thereby promoting immune infiltration and increasing the concentration of immune cells in the lesion area.

10. The magnetically driven dual-core micro-nano robot for targeted treatment of colorectal cancer according to claim 9, characterized in that: The gelatin microspheres B (1) rupture and release programmed death receptor 1 inhibitors, which are used on the surface of recruited immune cells to destroy the immune escape mechanism of tumor cells, thereby enabling the immune cells to efficiently identify and kill tumor cells.

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