WO2021203577A1

WO2021203577A1 - Use of implantable metal as accurate and efficient magnetocaloric tumor treatment reagent

Info

Publication number: WO2021203577A1
Application number: PCT/CN2020/103303
Authority: WO
Inventors: 刘庄; 程亮; 杨乃霖; 赵琪
Original assignee: 苏州大学
Priority date: 2020-04-08
Filing date: 2020-07-21
Publication date: 2021-10-14
Also published as: CN111449830A

Abstract

Disclosed is the use of an implantable metal as a accurate and efficient magnetocaloric tumor treatment reagent, and belongs to the technical field of biomedical engineering. The implantable metal generates heat energy under an alternating magnetic field due to an eddy current heat effect, and the temperature can be changed at will by means of controlling the size and the shape of the implantable metal. Accurate and efficient magnetocaloric tumor treatment can be realized by means of experimental simulation of the effective killing range of implantable metal and the monitoring of the temperature of a tumor part in an actual tumor treatment by means of using an infrared thermal imager. A magnesium alloy has good biocompatibility and biodegradability, and a titanium alloy has good biocompatibility, etc. Therefore, when the implantable metal is used as a accurate and efficient magnetocaloric tumor treatment reagent for magnetocaloric tumor treatment, large potential and clinical conversion value are shown.

Description

Application of implantable metals as accurate and high-efficiency magnetocaloric treatment reagents for tumors

Technical field

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

Background technique

As a non-invasive local treatment strategy, magnetic thermal therapy has attracted much attention since the 1980s. In the process of magnetocaloric therapy, the tumor is usually injected with a magnetocaloric reagent, which is usually magnetic nanoparticles. The magnetocaloric reagent can generate heat under the action of a strong alternating magnetic field, leading to the death of tumor cells. Compared with other types of clinically used hyperthermia stimulation methods, such as laser, radio frequency, microwave or high-intensity focused ultrasound, the alternating magnetic field used in magnetothermal therapy is not limited by the depth of tissue penetration, and in the absence of magnetocaloric reagents The site does not produce additional thermal side effects, so it is also applicable to the treatment of deeper and larger tumors. Although magnetic thermal therapy has the advantages of local tumor treatment, its clinical application is still relatively small. One of the main reasons hindering its clinical application is the magnetocaloric reagent. On the one hand, the more widely used magnetic nanoparticles (such as iron oxide) need to be effectively heated under a strong alternating magnetic field strength; on the other hand, the safety of traditional inorganic magnetic nanoparticles in the body is also greatly restricted. In order to achieve its clinical transformation.

In recent decades, various medical alloys have been widely used in implantable medical devices due to their high mechanical compatibility and excellent biocompatibility in the body, especially in the field of orthopedics (bone plates and screws, bone tissue Porous stents), cardiovascular fields (vascular stents, vascular suture threads) and dental implants are a class of medical materials with good biocompatibility. However, there is no report that non-magnetic implantable alloys can be used in tumor magnetothermal treatment.

Summary of the invention

In order to solve the above-mentioned problems, the present invention uses implantable metal due to its low resistivity and exhibits very excellent eddy current thermal performance under an alternating magnetic field of low field strength, and provides an implantable metal as a precise and efficient magnet for tumors. Application of heat treatment reagents.

The first object of the present invention is to provide an application of implantable metal as an accurate and high-efficiency magnetothermal treatment 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-shaped, sheet-shaped, ring-shaped or spherical.

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

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

Further, the said magnetothermal treatment is eddy current heating of magnesium alloy by high-frequency induction heating equipment.

Further, the high-frequency induction heating device is used to provide an alternating magnetic field, the alternating magnetic field intensity of which is 0.1-10×10 ⁹ A·m ^-1 ·s ^-1 , and the action time is 1 to 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, with a strength of 0.5 to 3.0×10 ⁹ A·m ^-1 ·s ^-1 Treat for 10-30min in alternating magnetic field.

The second object of the present invention is to provide a tumor magnetothermal treatment reagent, which includes one or more of implantable metals such as degradable magnesium alloy, titanium alloy, and aluminum alloy.

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

The method of using the implantable metal in the application of the accurate and high-efficiency magnetocaloric treatment reagent for tumors in the present invention includes the following steps:

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

(2) Select appropriate size and different shape of implantable metal to simulate and calculate the effective killing range in vitro;

(3) Preliminary experiments on animal models;

(4) Animal model experiment: Under optimal implantation conditions, implantable metal is implanted inside 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.

The beneficial effects of the present invention:

1. The implantable metal used in the present invention has very excellent biocompatibility, and the magnesium alloy is biodegradable in both internal and external environments, and does not need to be taken out twice after treatment, which avoids the need for secondary surgery to bring to the patient The pain that comes. According to the shape and size of the tumor, the effective killing range of the implantable metal is simulated through experiments, and the appropriate size and quantity and the best implantation site are selected; the distribution of the implantable metal is uniform and reasonable and the effective killing range is simulated At the same time, normal cells have better heat resistance than tumor cells, thereby greatly reducing the side effects on surrounding normal tissue cells, so that they will basically not affect the normal function of the body, so as to achieve precise and efficient tumor magnetothermal treatment .

2. The present invention breaks the traditional magnetic thermal treatment method (mainly using magnetic nanoparticles for magnetic thermal treatment). It not only broadens the application of implantable metals in the biomedical field, but also provides new ideas for precise and efficient minimally invasive treatment of tumors. Considering the extensive clinical application of implantable metals, this strategy has great application prospects in clinical transformation.

Description of the drawings

Figure 1 is a comparison diagram of the growth curves of different groups of mice in each group of mice with a magnesium alloy rod used as a magnetocaloric reagent for the treatment of mouse tumor magnetothermal ablation in Example 1;

Fig. 2 is a sectional view of mouse tumor hematoxylin-eosin (H&E) with different treatment methods of using a magnesium alloy rod as a magnetocaloric reagent for the treatment of mouse tumors by magnetic thermal ablation;

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

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

Fig. 5 is a comparison diagram of the growth curves of different groups of tumors in each group of rabbits with a magnesium alloy rod used as a magnetocaloric reagent for the treatment of rabbit tumors by magnetothermal ablation in Example 4;

Fig. 6 is a comparison diagram of the survival curves of rabbits corresponding to different groups of rabbits in each group of rabbits with a magnesium alloy rod used as a magnetocaloric reagent for the treatment of rabbit tumors by magnetothermal ablation.

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 and implement the present invention, but the examples cited are not intended to limit the present invention.

Example 1: Magnesium alloy rod (MgA) is used as a magnetocaloric reagent for magnetothermal ablation of mouse tumors

When the mouse tumor volume of the subcutaneous breast cancer model grows to ^{about 100mm 3} , the magnesium alloy rod (D=0.7mm, L=4.0mm) that has been simulated and calculated through the tumor effective killing range experiment is implanted at the optimal implant position Go inside the mouse tumor, anesthetize the mouse, expose the tumor site to an alternating magnetic field for 10 minutes, and monitor the tumor volume every two days for a total of 14 days after treatment with different methods.

After the treatment, the tumor volume of the mice was monitored with a vernier caliper. As shown in Figure 1, the comparison chart of the tumor growth curve of the tumor-bearing mice with the magnesium alloy rod magnetothermal treatment agent used for the mouse tumor magnetothermal ablation treatment, the mice were random 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 ). Compared with the control group, only implanting the magnesium alloy or exposing the mouse tumor to the alternating magnetic field will not affect the normal growth of the tumor, while implanting the magnesium alloy into the tumor site and exposing it to the alternating magnetic field, the mice The tumor was completely ablated by magnetic heat, and there was no recurrence in the treatment group 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, the magnesium alloy rod magnetothermal therapeutic agent was used for the treatment of tumor-bearing mice by magnetic thermal ablation. Tumor treatment slice evaluation chart, mice were randomly divided into 4 groups (5 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 combined alternating magnetic field group of materials (MgA+AMF, H _appl ×f _appl ＝2.0×10 ⁹ A· m ^-1 ·s ^-1 , 10min). Compared with the control group, only implanting the magnesium alloy or only exposing the mouse tumor to the alternating magnetic field will not affect the tumor cell status, while the tumor cell nucleus shrinkage of the mice in the treatment group is very obvious, indicating that the tumor cells are all apoptosis.

Example 2: Magnesium alloy ring (MgR) is used as a magnetocaloric reagent for magnetocaloric ablation of mouse tumors

When the mouse tumor volume of the subcutaneous breast cancer model grows to ^{about 100 mm 3} , a magnesium alloy ring calculated through the simulation of the effective tumor killing range experiment is implanted into the mouse tumor. After the mouse is anesthetized, the tumor site is exposed to After 10 minutes in the alternating magnetic field, after the 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 comparison chart of the tumor growth curve of the tumor-bearing mice with the magnesium alloy ring magnetic thermal treatment agent used in the mouse tumor magnetic thermal ablation treatment, the mice were random 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 , 10min). Compared with the control group, when a magnesium ring was implanted into the tumor site and exposed to an alternating magnetic field, the mouse tumor was completely ablated by magnetothermal, and there was no recurrence in the treatment group within 14 days.

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

When the mouse tumor volume of the subcutaneous breast cancer model grows to ^{about 100mm 3} , the titanium alloy sheet calculated by the simulation calculation of the effective tumor killing range experiment is implanted into the mouse tumor. After the mouse is anesthetized, the tumor site is exposed to After 10 minutes in the alternating magnetic field, after the 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 comparison chart of the tumor growth curve of the tumor-bearing mice with the titanium alloy sheet magnetic thermal treatment agent used in the mouse tumor magnetic thermal ablation treatment, the mice were random Divide 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 (TiS+AMF, H _appl ×f _appl = 1.5×10 ⁹ A·m ^-1 ·S ^-1 , 10min). Compared with the control group, when a titanium alloy sheet was implanted into the tumor site and exposed to an alternating magnetic field, the mouse tumor 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 the ablation of rabbit tumors

In order to prove the unrestricted advantage of magnetic thermal therapy in terms of tissue penetration, we further used this strategy to treat larger-sized subcutaneous liver cancer tumors growing in rabbits. In this experiment, rabbits carrying liver cancer tumors were randomly divided into two groups (3 in each group). One group was implanted with magnesium alloy rods, and the other group was not implanted with magnesium alloy rods as a control, because the tumor volume before treatment was large (~ 800mm ³ ). In this experiment, 3 MgA rods (D = 1.0 mm, L = 8.0 mm) with a larger diameter and a longer length were used for rabbit experiments. The magnesium alloy rod simulated by the effective range in vitro is implanted into the tumor of New Zealand white rabbit at the optimal implant position. After it is anesthetized, the tumor site is exposed to the alternating magnetic field for 15 minutes. After different treatments are completed , Monitor the tumor volume every four days. When the volume exceeds 10000mm ³ , the rabbit is considered dead.

After the treatment, the tumor volume of the rabbits was monitored with a vernier caliper. As shown in Figure 5, the comparison of the growth curve of the tumor-bearing rabbits on the tumor-bearing rabbits with the magnesium alloy magnetocaloric therapeutic agent used in the rabbit tumor magnetic thermal ablation treatment. The rabbits were randomly divided into 2 groups (each Group 3), the first group is the control group (Control); the second group is 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 ablated after 4 days. Magnesium alloy showed excellent tumor suppression effect in magnetothermal treatment for larger tumors. .

Comparing the survival curves of rabbits, as shown in Figure 6, the survival curves of the magnesium alloy rods used as a magnetocaloric reagent for the treatment of rabbit tumors by magnetothermal ablation on tumor-bearing rabbits. The rabbits were randomly divided into 2 groups (3 in each group), the first group It is the control group (Control); the second group is the material combined alternating magnetic field group (MgA+AMF, H _appl × f _appl = 1.5×10 ⁹ A·m ^-1 ·s ^-1 , 10 min). Compared with the control group, after the magnesium alloy was implanted and then exposed to an alternating magnetic field, the rabbit tumors were completely thermally ablated. Moreover, two of the three treated rabbits did not have tumor recurrence, and the tumors were completely eliminated. Two rabbits survived more than 90 days after treatment.

Example 5: Evaluation of the biocompatibility of implantable metals as magnetocaloric reagents and the degradation performance of magnesium alloys

The magnesium alloy rods were subcutaneously implanted into healthy female mice for different periods of time (3 days, 10 days, 20 days, 40 days, and 90 days). Mice without magnesium alloy implants served as a control group. After local implantation, first observe whether the mice have abnormalities such as adverse inflammatory reactions. After implantation, the mice were randomly taken at 3 days, 10 days, 20 days, 40 days, and 90 days. The magnesium alloy rods in the body were taken out. With the increase of time, a large number of corrosion cracks appeared on the surface of the magnesium alloy rods. It gradually degrades in the body, and its weight loss is about 20% in 3 months. XRD analysis showed that its degradation products were mainly magnesium hydroxide and calcium phosphate, indicating that magnesium alloy rods showed good biodegradability. After implantation, mice were randomly selected and sacrificed on 3 days, 10 days, 20 days, 40 days, and 90 days after implantation. The brain tissue, liver tissue, spleen tissue, heart tissue, lung tissue, kidney tissue, and subcutaneous tissue were dissected and combined. 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 conventional procedures to assess the safety of magnesium alloy implantation. Dissolve the other half of each organ and tissue in aqua regia, and then measure the content of magnesium in each organ. At the same time, blood samples were collected for blood biochemical and hematological testing. By measuring the content of magnesium in different organs of mice, there is no significant difference compared with mice without magnesium alloy rods, indicating that the release of ions produced by the degradation of magnesium alloys will not interfere with the physiological behavior of normal organs. At the same time, the histological examination of the main organs further confirmed that the implantation of the magnesium alloy rod has no obvious side effects on the 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 prove the excellent biological safety and biodegradability of magnesium alloys.

The above-mentioned embodiments are only preferred embodiments for fully explaining the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or alterations 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

An implantable metal is used as an accurate and high-efficiency magnetothermal treatment reagent for tumors.
The application according to claim 1, wherein the implantable metal includes one or more of magnesium alloy, titanium alloy, aluminum alloy, cobalt-chromium alloy, and medical stainless steel.
The application according to claim 2, wherein the magnesium alloy includes Mg-Al, Mg-Zn, Mg-RE, Mg-Mn, Mg-Ca, Mg-Zn, Mg-Li, Mg-Sr , One or more of Mg-Sc.
The application according to claim 1, wherein the shape of the implantable metal is rod-shaped, sheet-shaped, ring-shaped or spherical.
The application according to claim 4, wherein the diameter of the implantable metal is 0.1 mm to 5 cm.
The application according to claim 4, wherein when the shape of the implantable metal is rod-shaped, the length of the implantable metal is 0.3mm-10cm.
The application according to claim 1, wherein the magnetothermal treatment is eddy current heating of the implantable metal by a high-frequency induction heating device.
The application according to claim 7, characterized in that the high-frequency induction heating device is used to provide an alternating magnetic field, the alternating magnetic field intensity of which is 0.1-10×10 9 A·m -1 ·s -1 , and its effect The time is 1～120min.
The application according to claim 1, wherein 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, with a strength of 0.5 to 3.0×10 9 Treated in an alternating magnetic field of A·m -1 ·s -1 for 10 to 30 minutes.
A tumor magnetothermal treatment reagent is characterized in that the tumor magnetothermal treatment reagent comprises implantable metal.