CN111449830A - Application of Implantable Metals as Precise and Efficient Magnetothermal Therapy Reagents for Tumors - Google Patents

Abstract

The invention discloses the application of an implantable metal as a precise and high-efficiency magnetothermal therapy reagent for tumors, and belongs to the technical field of biomedical engineering. The implantable metal in the present invention generates thermal energy under the alternating magnetic field due to the eddy current thermal effect, and the temperature can be changed arbitrarily by controlling its size and shape. Through the experimental simulation of its effective killing range and the use of infrared thermal imagers to monitor the temperature of the tumor site in actual tumor treatment, accurate and efficient tumor magnetothermal therapy can be achieved. Among them, magnesium alloys have good biocompatibility and biodegradability, and titanium alloys have good biocompatibility. Therefore, the use of implantable metals as precise and efficient magnetothermal therapy reagents for tumor magnetocaloric therapy shows great potential and clinical translation value.

Description

Application of Implantable Metals as Precise and Efficient Magnetothermal Therapy Reagents for Tumors

technical field

The invention relates to the application of an implantable metal as a precise and high-efficiency magnetothermal therapy reagent for tumors, and belongs to the technical field of biomedical engineering.

Background technique

Magnetothermal therapy as a non-invasive topical treatment strategy has received much attention since the 1980s. In the process of magnetocaloric therapy, a magnetocaloric reagent, usually magnetic nanoparticles, is usually injected into the tumor site. The magnetocaloric reagent can generate heat under the action of a strong alternating magnetic field, resulting in the death of tumor cells. In contrast to other types of clinically used hyperthermic stimulation modalities, such as laser, radiofrequency, microwave or high-intensity focused ultrasound, the alternating magnetic field used in magnetocaloric therapy is not limited by the depth of tissue penetration and can be used without magnetocaloric agents. The site does not produce additional thermal side effects, so it is also suitable for the treatment of deeper and larger tumors. Although magnetothermal therapy has the advantages of local tumor treatment, its clinical application is still rare. One of the main reasons hindering its clinical application is magnetocaloric reagents. On the one hand, the widely used magnetic nanoparticles (such as iron oxide) need to be heated effectively under strong alternating magnetic field strength; on the other hand, the safety of traditional inorganic magnetic nanoparticles in vivo is also greatly limited. its clinical translation.

In recent decades, various medical alloys have been widely used in implantable medical devices due to their high mechanical compatibility, excellent in vivo biocompatibility and other properties, especially in the field of orthopedics (bone plates and screws, bone tissue It is a kind of medical material with good biocompatibility. However, there is no report on the application of non-magnetic implantable alloys in tumor magnetocaloric therapy.

SUMMARY OF THE INVENTION

In order to solve the above problems, the present invention utilizes the implantable metal to exhibit very excellent eddy current thermal performance under the alternating magnetic field of low field strength due to its low resistivity, and provides an implantable metal as a precise and efficient magnetic field for tumors. Application of thermal therapeutic agents.

The first objective of the present invention is to provide the application of an implantable metal as a precise and efficient magnetothermal therapy agent for tumors.

Further, the implantable metal includes one or more of magnesium alloy, titanium alloy, and aluminum alloy.

Further, the magnesium alloy includes one or more of Mg-Al, Mg-Zn, Mg-RE, Mg-Mn, Mg-Ca, Mg-Zn, Mg-Li, Mg-Sr, Mg-Sc kind.

Further, the shape of the implantable metal is rod-like, sheet-like, annular or spherical.

Further, the diameter of the implantable metal is 0.1 mm˜5 cm.

Further, when the shape of the implantable metal is rod-like, the length of the implantable metal is 0.3 mm˜10 cm.

Further, the magnetothermal treatment is to perform eddy current heating on the magnesium alloy through a high-frequency induction heating device.

Further, the high-frequency induction heating device is used to provide an alternating magnetic field, the intensity of the alternating magnetic field is 0.1-10×10 ⁹ A·m ^-1 ·s ^-1 , and the action time is 1-120 min.

Further, the application specifically includes ^implanting a ^magnesium alloy rod with a length of 2 mm to ⁵ cm and a diameter of 0.5 mm to 2 cm into the tumor site. Treat in alternating magnetic field for 10-30min.

The second object of the present invention is to provide a tumor magnetocaloric therapy agent, which includes one or more of degradable magnesium alloys, titanium alloys, aluminum alloys and other implantable metals.

The invention utilizes the implantable metal to generate heat due to the eddy current effect under the alternating magnetic field, and can achieve any temperature by controlling the size, shape and the strength of the alternating magnetic field of the implantable metal. The implantable metal with excellent magnetic induction heating can be implanted into the tumor of the living body, and it can effectively perform magnetic thermal ablation of the tumor under the condition of alternating magnetic field for several minutes.

In the present invention, an implantable metal is used as a precise and high-efficiency magnetothermal therapy reagent for tumors, and the use method includes the following steps:

(1) Fully explore the influencing factors of the eddy current thermal effect of the implantable metal in vitro (the size (diameter, length, etc.), shape (rod, sheet, ring, etc.) of the implantable metal, and the strength of the alternating magnetic field, etc.);

(2) Selecting implantable metals of different shapes and suitable sizes to carry out the experimental simulation calculation of the effective killing range in vitro;

(3) Animal model pre-experiment;

(4) Animal model experiment: Under optimal implantation conditions, implantable metal is implanted into the tumor, and the tumor site is exposed to an alternating magnetic field, so as to realize the magnetothermal ablation of the tumor;

(5) Evaluation of implantable metal biocompatibility and magnesium alloy biodegradability.

Beneficial effects of the present invention:

1. The implantable metal used in the present invention has very excellent biocompatibility, and the magnesium alloy can be biodegraded in the environment inside and outside the body, and it does not need to be taken out twice after treatment, which avoids the need for secondary surgery to bring the patient. pain to come. According to the shape and size of the tumor, the effective killing range of the implantable metal was simulated experimentally, and the appropriate size and quantity and its optimal implantation site were selected; because the distribution of the implantable metal was uniform and reasonable, and the effective killing range was simulated At the same time, normal cells have better heat resistance than tumor cells, which greatly reduces the side effects on surrounding normal tissue cells, so that it basically does not affect the normal function of the body, so as to achieve precise and efficient tumor magnetothermal therapy. .

2. The present invention breaks the traditional way of magnetothermal therapy (mainly using magnetic nanoparticles for magnetothermal therapy). It not only broadens the application of implantable metals in the field of biomedicine, but also provides new ideas for precise and efficient minimally invasive tumor treatment. Considering the wide range of clinical applications of implantable metals, this strategy holds great promise for clinical translation.

Description of drawings

Fig. 1 is a comparison diagram of tumor growth curves of different groups of mice in each group of mice in the magnetothermal ablation therapy of a magnesium alloy rod in Example 1 as a magnetocaloric reagent;

Fig. 2 is the hematoxylin-eosin (H&E) slice diagram of the mouse tumor of Example 1 where magnesium alloy rods are used as a magnetocaloric reagent for the magnetocaloric ablation of mouse tumors with different treatment methods;

Fig. 3 is a comparison diagram of tumor growth curves in different groups of mice in each group of mice in the magnetothermal ablation treatment of each group of mice using magnesium alloy rings as a magnetocaloric reagent in Example 2;

Fig. 4 is the comparison diagram of the tumor growth curves of different groups of mice in each group of mice in the magnetothermal ablation therapy of the titanium alloy sheet of Example 3 as a magnetocaloric reagent;

Fig. 5 is the comparison chart of the tumor growth curves of different groups of rabbits in each group of rabbits in magnetothermal ablation treatment of each group of rabbits by using magnesium alloy rods as magneto-caloric reagents in Example 4;

Figure 6 is a comparison diagram of the survival curves of rabbits corresponding to different groups of rabbits in each group of rabbits in the magnetothermal ablation treatment of rabbit tumors using magnesium alloy rods as magnetocaloric reagents in Example 4.

Detailed ways

The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

Example 1: Magnesium alloy rod (MgA) as a magnetocaloric reagent for magnetocaloric ablation of tumor in mice

When the tumor volume of the mice in the subcutaneous breast cancer model grows to about 100mm ³ , the magnesium alloy rod (D=0.7mm, L=4.0mm), which has been simulated and calculated by the effective tumor killing range, is implanted at the optimal implantation position. Inside the tumor of the mouse, after the mice were anesthetized, the tumor site was exposed to an alternating magnetic field for 10 minutes. After the treatment with different methods, the tumor volume was monitored every two days for a total of 14 days.

After the treatment, the tumor volume of the mice was monitored with a vernier caliper. As shown in Figure 1, the magnesium alloy rod magnetocaloric therapeutic agent was used to compare the tumor growth curve of the tumor-bearing mice with the magnesium alloy rod magnetocaloric ablation therapy. The mice were randomly selected. Divided into 4 groups (5 in each group), the first group is the control group (Control); the second group is the material group (MgA); the third group is the alternating magnetic field group (AMF, H _appl × f _appl = 2.0 × 10 ⁹ A·m ^-1 ·s ^-1 , 10min); the fourth group is the material combined alternating magnetic field group (MgA+AMF, H _appl ×f _appl =2.0×10 ⁹ A·m ^-1 ·s ^-1 , 10min ). Relative to the control group, implantation of magnesium alloys alone or exposure of mouse tumors to alternating magnetic fields alone did not affect normal tumor growth, whereas implantation of magnesium alloys at tumor sites and exposure to alternating magnetic fields did not affect tumor growth in mice. Tumors were completely ablated by magnetothermal, and none of the treatment groups recurred within 14 days.

After the mice were treated for 12 hours, their tumors were stained with hematoxylin-eosin (H&E), as shown in Figure 2. Magnesium alloy rod magnetocaloric therapeutic agent was used for tumor magnetocaloric ablation in mice on tumor-bearing mice. Tumor treatment slice evaluation chart, mice were randomly divided into 4 groups (5 mice in each group), the first group was the control group (Control); the second group was the material group (MgA); the third group was the alternating magnetic field group (AMF, H _appl ×f _appl =2.0×10 ⁹ A·m ^-1 ·s ^-1 , 10min); the fourth group is the material combined alternating magnetic field group (MgA+AMF, H _appl ×f _appl =2.0×10 ⁹ A· m ^-1 ·s ^-1 , 10 min). Compared with the control group, only implanting magnesium alloys or exposing mouse tumors to alternating magnetic fields did not affect the state of tumor cells, while the tumor cells in the treatment group had very obvious pyknosis, indicating that all tumor cells were apoptotic.

Example 2: Magnesium alloy ring (MgR) as a magnetocaloric reagent for magnetocaloric ablation of tumor in mice

When the tumor volume of the mice in the subcutaneous breast cancer model grew to about 100 mm ³ , the magnesium alloy ring calculated by the experimental simulation of the effective tumor killing range was implanted into the tumor of the mouse. After the mice were anesthetized, the tumor site was exposed to In the alternating magnetic field for 10 minutes, after the end of treatment, the tumor volume was monitored every two days for a total of 14 days.

After the treatment, the tumor volume of the mice was monitored with a vernier caliper. As shown in Figure 3, the magnesium alloy ring magnetocaloric therapeutic agent was used to compare the tumor growth curve of the tumor-bearing mice with the magnesium alloy ring magnetocaloric ablation therapy. The mice were randomly selected. Divided into 2 groups (5 in each group), the first group is the control group (Control); the second group is the material combined alternating magnetic field group (MgR+AMF, H _appl ×f _appl =2.0×10 ⁹ A·m ^-1 · s ^-1 , 10 min). Compared with the control group, the tumor was completely ablated by magnetothermal ablation in mice with magnesium rings implanted at the tumor site and exposed to an alternating magnetic field, and there was no recurrence in the treatment group within 14 days.

Example 3: Titanium alloy sheet (TiS) as a magnetocaloric reagent for magnetocaloric ablation of mouse tumors

When the tumor volume of the subcutaneous breast cancer model mice grows to about 100mm ³ , the titanium alloy sheet calculated by the experimental simulation of the effective killing range of the tumor is implanted into the mouse tumor, and the mouse is anesthetized, and the tumor site is exposed to In the alternating magnetic field for 10 minutes, after the end of treatment, the tumor volume was monitored every two days for a total of 14 days.

After the treatment, the tumor volume of the mice was monitored with a vernier caliper. As shown in Figure 4, the titanium alloy sheet magnetocaloric therapeutic agent was used for the comparison of tumor growth curves of tumor-bearing mice for magnetothermal ablation therapy of tumors in mice. The mice were randomly selected. Divided into 2 groups (5 in each group), the first group was the control group (Control); the second group was the material combined with alternating magnetic field group (TiS+AMF, H _appl ×f _appl =1.5×10 ⁹ A·m ^-1 · s ^-1 , 10 min). Compared with the control group, when the titanium alloy sheet was implanted into the tumor site and exposed to an alternating magnetic field, the tumor of the mice was completely ablated by magnetothermal, and there was no recurrence in the treatment group within 14 days.

Example 4: Magnesium alloy rods used as magnetocaloric reagents for magnetocaloric ablation of rabbit tumors

To demonstrate the unrestricted advantage of magnetothermal therapy in terms of tissue penetration, we further used this strategy to treat larger sized subcutaneous hepatocellular carcinoma tumors grown in rabbits. In this experiment, the rabbits carrying liver cancer tumors were randomly divided into two groups (3 in each group), one of which was implanted with magnesium alloy rods, and the other group was not implanted with magnesium alloy rods as a control. Due to the large tumor volume before treatment (~ 800mm ³ ), in this experiment, three MgA rods (D=1.0mm, L=8.0mm) with larger diameter and longer length were used for the rabbit experiment. The magnesium alloy rods simulated by the effective range in vitro were implanted into the tumor of New Zealand white rabbits at the optimal implantation position. After anesthesia, the tumor site was exposed to alternating magnetic field conditions for 15 minutes. After treatment with different methods , the tumor volume was monitored every four days, and the rabbit was considered dead when the volume exceeded 10,000 ^mm3 .

After the treatment, the vernier caliper was used to monitor the tumor volume of the rabbit. As shown in Figure 5, the magnesium alloy magnetocaloric therapeutic agent was used for the comparison of the tumor growth curve of the tumor-bearing rabbits in the magnetocaloric ablation of the rabbit tumor. The rabbits were randomly divided into 2 groups (each group). Group 3), the first group was the control group (Control); the second group was the material combined alternating magnetic field group (MgA+AMF, H _appl ×f _appl =1.5×10 ⁹ A·m ^-1 ·s ^-1 , 10min). Compared with the control group, after implanting the magnesium alloy and then exposing it to an alternating magnetic field, the rabbit tumor was completely thermally ablated 4 days later, and the magnesium alloy showed excellent tumor-inhibiting effect in magnetothermal therapy for larger tumors .

The survival curve of rabbits was compared, as shown in Figure 6. Magnesium alloy rods were used as magnetocaloric reagents for tumor-bearing rabbits. The rabbits were randomly divided into 2 groups (3 in each group), the first group The second group was the material combined with alternating magnetic field group (MgA+AMF, H _appl ×f _appl =1.5×10 ⁹ A·m ^-1 ·s ^-1 , 10min). Compared with the control group, after implantation of magnesium alloy and exposure to alternating magnetic field, the rabbit tumor was completely thermally ablated. Moreover, two of the three treated rabbits did not experience tumor recurrence, the tumor was completely eliminated, and the tumor was completely eliminated. Two rabbits survived more than 90 days after treatment.

Example 5: Biocompatibility of implantable metals as magnetocaloric reagents and evaluation of degradation performance of magnesium alloys

The magnesium alloy rods were subcutaneously implanted into healthy female mice for different time periods (3 days, 10 days, 20 days, 40 days, 90 days), and the mice without magnesium alloys were used as a control group. After local implantation, the mice were first observed for abnormal conditions such as adverse inflammatory reactions. Mice were randomly selected and sacrificed at 3 days, 10 days, 20 days, 40 days, and 90 days after implantation, and the magnesium alloy rods in the body were taken out. It is gradually degraded in the body and about 20% of its weight is lost over 3 months. XRD analysis showed that its degradation products were mainly magnesium hydroxide and calcium phosphate, indicating that the magnesium alloy rods exhibited good biodegradability. Mice were randomly sacrificed at 3 days, 10 days, 20 days, 40 days, and 90 days after implantation, and the brain tissue, liver tissue, spleen tissue, heart tissue, lung tissue, kidney tissue and subcutaneous tissue were dissected and removed. Cut it in half. Half of the organs were fixed in 4% formalin, embedded in paraffin, and further H&E staining was performed according to routine procedures to assess the safety of magnesium alloy implantation. The other half of each organ and tissue was dissolved in aqua regia, and then the magnesium content of each organ was determined. At the same time, blood samples were collected for blood biochemical and hematological tests. By measuring the content of magnesium in different organs of mice, there was no significant difference compared with mice without magnesium alloy rods, indicating that the ion release generated by the degradation of magnesium alloys does not interfere with the normal physiological behavior of organs. At the same time, histological examination of major organs further confirmed that the implantation of magnesium alloy rods had no obvious side effects on mice. Compared with the control group, the blood biochemical indexes and hematological test data of the magnesium alloy rod-implanted mice were normal. The above results all demonstrate the excellent biosafety and biodegradability of magnesium alloys.

The above-mentioned embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or transformations made by those skilled in the art on the basis of the present invention are all within the protection scope of the present invention. The protection scope of the present invention is subject to the claims.

Claims (10)

1. An implantable metal is applied as a precise and efficient magnetic-thermal treatment reagent for tumors.

2. The use according to claim 1, wherein the implantable metal comprises one or more of a magnesium alloy, a titanium alloy, an aluminum alloy, a cobalt-chromium alloy, a medical grade stainless steel.

3. Use according to claim 2, wherein the magnesium alloy comprises one or more of Mg-Al, Mg-Zn, Mg-RE, Mg-Mn, Mg-Ca, Mg-Zn, Mg-L i, Mg-Sr, Mg-Sc.

4. The use according to claim 1, wherein the implantable metal is in the shape of a rod, a sheet, a ring or a sphere.

5. The use according to claim 4, wherein the implantable metal has a diameter of 0.1mm to 5 cm.

6. The use according to claim 4, wherein the implantable metal has a length of 0.3mm to 10cm when the implantable metal is in the form of a rod.

7. Use according to claim 1, characterized in that the magnetocaloric treatment consists in heating the implantable metal by eddy currents with a high-frequency induction heating device.

8. The use according to claim 7, wherein the high-frequency induction heating apparatus is used for providing an alternating magnetic field with an alternating magnetic field strength of 0.1-10 × 10⁹A·m^-1·s^-1The action time is 1-120 min.

9. The application of claim 1, wherein the application specifically comprises implanting a magnesium alloy rod with a length of 2 mm-5 cm and a diameter of 0.5 mm-2 cm at a tumor site with a strength of 0.5-3.0 × 10⁹A·m^-1·s^-1Treating for 10-30 min in the alternating magnetic field.

10. The tumor magnetic thermal treatment reagent is characterized by comprising implantable metal.

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