Metal boride nanoparticles for diagnosis and treatment of cancer

Abstract

The invention provides a metal boride nano particle for diagnosing and treating cancer, the metal boride nano particle has dual functions of diagnosing and treating tumor, the surface of the metal boride nano particle is modified with an antibody and a biological probe or is coated with a biological cell membrane, and the antibody or the probe has specificity of being combined with a receiver of a specific tumor cell.

Description

Technical Field

[0001] The present invention relates to a nanoparticle, and more particularly to a metal boride nanoparticle for diagnosing and treating cancer. Background Art

[0002] The theoretical principle of neutron capture therapy (NCT) for treating cancer has been successfully demonstrated clinically. Utilizing the strong neutron absorption ability of boron-10 atoms and gallium-157 atoms, after a boron-10 atom absorbs a neutron, it becomes unstable boron-11, and then rapidly undergoes nuclear fission to generate high-energy α-particles and 7Li-particles, which can kill cancer cells within a range of 10 μm to 15 μm nearby. After a gallium-157 atom absorbs a neutron, it becomes unstable gallium-158, and the unstable gallium-158 will release γ-rays, causing damage to the protein and DNA structures of cancer cells within a range of several centimeters over a relatively long distance around, thereby killing cancer cells. The therapeutic effect of neutron capture therapy depends on the accumulation amount of boron-10 atoms in the tumor (which must be greater than 20 - 35 μg 10B / gram of tumor tissue) and the 10B ratio of the tumor to the blood (which must be greater than 3.0). For effective gallium neutron capture therapy, it is necessary to accumulate more than 50 - 200 μg 157Gd / g of tumor tissue at the tumor site to effectively kill cancer cells. So far, most neutron capture therapies have used small molecules containing boron atoms (such as: p-boronophenylanaline, BPA) as neutron capture reagents. Small molecule boron-containing drugs lack the function of actively targeting tumors, and the ratio of boron atoms they contain is too small or the number of gallium-157 atoms is too small to accumulate at the tumor site to reach the threshold for effective treatment. There is no successful case of simultaneously combining effective boron neutron capture therapy and gallium neutron capture therapy. Here, "effective" means that the number of boron atoms and gallium-157 atoms accumulated in the tumor tissue simultaneously exceeds the threshold values mentioned above. Therefore, there are disadvantages such as the therapeutic effect not meeting expectations and many side effects.

[0003] On the other hand, regarding the treatment of cancer tumors by near-infrared light photodynamic therapy and near-infrared light photothermal therapy, most of the existing technologies use inorganic nanoparticles as photosensitizers to absorb near-infrared light to generate reactive oxygen species (ROS) or heat energy, thereby killing tumor cells. The near-infrared light wavelengths used are usually between 800 nm and 1550 nm. Since the near-infrared light wavelengths used in the existing technologies are not long enough, the penetration depth into biological tissues is limited, resulting in the inability to be used for treating deep tumors or the treatment effect being poor.

[0004] Based on the above, a metal boride nanoparticle is developed, which has the function of diagnosing and treating tumors. It can effectively accumulate a sufficient amount of boron-10 atoms in tumor tissues, and can absorb long-wavelength mid-infrared light (wavelength between 2000 nm and 7000 nm) that can effectively penetrate biological tissues, thereby generating reactive oxygen species (ROS) or heat energy to kill tumor cancer cells, and has the ability to actively target specific tumors or tissues, which is an important topic to be studied currently. Summary of the Invention

[0005] The present invention provides a metal boride nanoparticle, which has the function of diagnosing and treating tumors. It can effectively accumulate a sufficient amount of boron-10 atoms or gallium-157 atoms in tumor tissues, and can absorb long-wavelength mid-infrared light (wavelength between 2000 nm and 7000 nm) that can effectively penetrate biological tissues, thereby generating reactive oxygen species (ROS) or heat energy to kill tumor cancer cells, and has the ability to actively target specific tumors or tissues.

[0006] The present invention provides a metal boride nanoparticle, which has the function of diagnosing and treating tumors. The surface of the metal boride nanoparticle is modified with an antibody, a biological probe, or coated with a biological cell membrane. The antibody or biological probe has the specificity to bind to the receptor on the cell membrane surface of specific tumor cells, thus having the ability to actively target specific tumors or tissues.

[0007] In an embodiment of the present invention, the biological cell membrane includes a red blood cell membrane.

[0008] In an embodiment of the present invention, the metal boride nanoparticle binds to the receptor on the cell membrane surface of specific tumor cells through an antibody or a biological probe to actively target tumor tissues.

[0009] In an embodiment of the present invention, the receptor includes a folate receptor, a fibroblast activation protein receptor (FAPI), an epidermal growth factor receptor (EGFR), or a vascular endothelial growth factor receptor (VEGFR).

[0010] In an embodiment of the present invention, the tumor includes but is not limited to melanoma, brain tumor, lung tumor, or head and neck tumor.

[0011] In an embodiment of the present invention, after the metal boride nanoparticle is irradiated with a neutron beam, high-energy α-particles and 7Li particles or γ-rays are generated.

[0012] In an embodiment of the present invention, after the metal boride nanoparticle is irradiated with near-infrared light or mid-infrared light, reactive oxygen species (ROS) or heat energy is generated to kill tumor cancer cells, and the irradiation wavelength λ is between 2000 nm and 7000 nm.

[0013] In one embodiment of the present invention, the metal boride nanoparticles are doped with a metal element that can emit near-infrared fluorescence. After being excited by near-infrared light (800 nm to 1100 nm), they emit light in the range of 1100 nm to 2000 nm in the near-infrared region. The wavelength of the near-infrared light is 800 nm to 1100 nm.

[0014] In one embodiment of the present invention, the metal element includes Gd, Eu, Er, Ho, Yb, Pr, Cu, Cr, Ni, or a combination thereof.

[0015] In one embodiment of the present invention, based on the total moles of metal in the metal boride nanoparticles, the molar content ratio of the metal element that can emit fluorescence ranges from 0% to 100%.

[0016] In one embodiment of the present invention, the metal boride nanoparticles utilize the emitted near-infrared fluorescence and are applied to near-infrared fluorescence images as a tool for diagnosing the location and size of tumors. Additionally, magnetic metal boride nanoparticles can also be used as a contrast agent for magnetic resonance imaging (MRI); and the metal boride nanoparticles, due to containing high atomic number metal elements, can also be used as a contrast agent for computer tomography (CT).

[0017] In one embodiment of the present invention, the particle size of the metal boride nanoparticles is 5 nm to 300 nm.

[0018] In one embodiment of the present invention, metal boride nanoparticles enriched with isotope boron-10 (10B% ≥ 20%) are prepared by the Microwave arcing method.

[0019] In one embodiment of the present invention, based on the molar ratio of boron element in the metal boride nanoparticles, the content of isotope boron-10 is 20% to 100%.

[0020] In one embodiment of the present invention, the antibody includes, but is not limited to, one of anti-EGFR antibody, anti-VEGF antibody, or TCR-like antibody.

[0021] In one embodiment of the present invention, the biological probe includes, but is not limited to, biological probes based on folic acid, TAT polypeptide, fibroblast activation protein inhibitor (FAPI), RGD polypeptide, or heparin (HEP) polysaccharide.

[0022] Based on the above, the present invention provides a metal boride nanoparticle, which has the function of diagnosing and treating tumors. It is surface-modified with antibodies, biological probes or coated with biological cell membranes, and serves as a neutron capture reagent with active tumor targeting function. The metal boride nanoparticles of the present invention can also be used as photosensitizers for near-infrared light and / or mid-infrared light photodynamic therapy and photothermal therapy, and can generate ROS or heat energy after irradiation with near-infrared light and / or mid-infrared light for treating deep tumors. On the other hand, the metal boride nanoparticles of the present invention are doped with metal elements that emit fluorescence in the near-infrared region, and can emit long-wavelength near-infrared light (1100-2000nm) fluorescence after irradiation with near-infrared light (800-1100nm), and can be applied to near-infrared fluorescence as a tool for diagnosing the location and size of tumors. In addition, magnetic metal boride nanoparticles can also be used as contrast reagents for magnetic resonance imaging (MRI); and metal boride nanoparticles can also be used as contrast reagents for computer tomography (CT) because they contain high atomic number metal elements. The metal boride nanoparticles of the present invention have a high content of boron-10 atoms, can effectively accumulate a sufficient amount of boron-10 atoms in tumor tissues, and at the same time have the ability to actively target specific tumors or tissues. Detailed Description of the Invention

[0023] Hereinafter, embodiments of the present invention will be described in detail. However, these embodiments are illustrative, and the disclosure of the present invention is not limited thereto.

[0024] In this article, a range represented by "a numerical value to another numerical value" is a summary representation method to avoid listing all the numerical values in the range in the specification one by one. Therefore, the description of a specific numerical range covers any numerical value within the range and the smaller numerical range defined by any numerical value within the range, as if the arbitrary numerical value and the smaller numerical range are written out in the specification.

[0025] The present invention provides a metal boride nanoparticle, which has the function of diagnosing and treating tumors. The surface of the metal boride nanoparticle is modified with antibodies, biological probes or coated with biological cell membranes, and the antibodies or biological probes have specificity for binding to the cell membrane surface receptors of specific tumor cells.

[0026] In this embodiment, the antibody or bioprobe surface-modified on the metal boride nanoparticles has specificity in binding to the cell membrane surface receptors of specific tumor cells. The antibody may include, for example, anti-EGFR antibody, anti-VEGF antibody or TCR-like antibody. The bioprobe may include, for example, bioprobes based on folic acid, TAT polypeptide, fibroblast activation protein inhibitor (FAPI), RGD polypeptide or heparin (HEP) polysaccharide. The receptor may include folate receptor, fibroblast activation protein inhibitor FAPI, epidermal growth factor receptor EGFR antibody or vascular endothelial growth factor receptor VEGFR antibody. Antibodies or bioprobes that can bind to receptors of different tumor cells can also be used to modify the surface of the metal boride nanoparticles. Since the antibody or bioprobe surface-modified on the metal boride nanoparticles has specificity in binding to the receptors of specific tumor cells, the metal boride nanoparticles can bind to the receptors of specific tumor cells through the antibody or bioprobe to actively target tumor tissues, enabling the metal boride nanoparticles to be used as neutron capture reagents with active tumor targeting function or photosensitizers for near-infrared and mid-infrared photodynamic therapy / photothermal therapy. The tumor cells or tumor tissues mentioned here include but are not limited to melanoma, brain tumor, lung tumor or head and neck tumor. Depending on the different antibodies or bioprobes surface-modified on the metal boride nanoparticles, they can also bind to the receptors of other different types of tumor cells to actively target other different types of tumor tissues.

[0027] In this embodiment, the method for surface-modifying antibodies or bioprobes on metal boride nanoparticles is, for example, to couple a carbonate group with an amino group to form an amide group using N,N'-dicyclohexylcarbodiimide (abbreviated as DCC). As shown in the following formula (1), first, the metal boride nanoparticles are coated with a polymer containing carbonate groups, and then DCC is used to couple the carbonate groups on the polymer with the amino groups on the antibody or bioprobe molecules, or the metal boride nanoparticles are coated with a polymer containing amino groups, and then DCC is used to couple the amino groups on the polymer with the carbonate groups on the antibody or bioprobe molecules.

[0028]

[0029] Here, R1 and R2 represent hydrocarbon chains (alkyl chains) with different arbitrary chemical structures.

[0030] In this embodiment, the metal boride nanoparticles can also be coated with a biological cell membrane, which may include a red blood cell membrane. Since the metal boride nanoparticles are coated with a biological cell membrane, they can be used as neutron capture reagents with active tumor targeting function or photosensitizers for near-infrared and mid-infrared photodynamic therapy. The method of coating metal boride nanoparticles with a biological cell membrane is described below, taking the red blood cell membrane as an illustrative example, but the present invention is not limited thereto. First, membrane vesicles are derived from red blood cells, and then the vesicles are fused to the surface of the metal boride nanoparticles. More specifically, purified red blood cells are treated with low osmotic pressure to remove their intracellular contents. Thereafter, the resulting red blood cell ghosts are extruded through a porous membrane to generate red blood cell membrane-derived vesicles. The mechanical force provided by the extrusion process can promote the fusion of the red blood cell membrane vesicles with the metal boride nanoparticles, thereby coating the metal boride nanoparticles with the red blood cell membrane.

[0031] In this embodiment, the metal boride nanoparticles can generate reactive oxygen species (ROS) after irradiation with near-infrared light and / or mid-infrared light, and the irradiation wavelength λ is between 2000 nm and 7000 nm. More specifically, the metal boride nanoparticles not only have the active tumor targeting function described above, but can also be used as photosensitizers for near-infrared and / or mid-infrared photodynamic therapy and photothermal therapy, generating ROS or heat energy to kill cancer cells and treat deep tumor cancers. In this way, the problem of the lack of photosensitizers that can absorb long-wavelength near-infrared and mid-infrared light to generate reactive oxygen-containing free radicals and heat energy in existing photodynamic therapy and photothermal therapy can be solved.

[0032] In this embodiment, the metal boride nanoparticles are doped with a metal element that emits fluorescence in the near-infrared region. After being excited by irradiation with near-infrared light (800 nm to 1100 nm), they can emit light in the near-infrared region of 1100 nm to 2000 nm. In this way, they can be used as a diagnostic tool for the presence of deep tumors. The metal element may include, but is not limited to, Gd, Eu, Er, Ho, Yb, Pr, Cu, Cr, or Ni, and the molar content ratio of the near-infrared light-emitting metal element is between 0% and 100% based on the total moles of the metal in the metal boride nanoparticles. The meaning of 0% is that the metal boride nanoparticles do not contain a metal element that can emit fluorescence, but only contain other metal elements that do not emit fluorescence.

[0033] In the present embodiment, metal boride nanoparticles capable of fluorescing in the near-infrared light region can be used as non-invasive fluorescence diagnostic tools, and metal boride nanoparticles containing magnetic metal ions can be used as magnetic resonance imaging (MRI) contrast agents, while all metal boride nanoparticles can be used as contrast agents for computed tomography (CT).

[0034] In the present embodiment, the particle size of the metal boride nanoparticles can range from 5 nm to 300 nm. The precursor of the metal boride nanoparticles can include boric acid enriched with the isotope boron-10. The metal ion salts and the boric acid powder enriched with the isotope boron-10 are ground evenly and then prepared by the microwave arcing method. The microwave arc generates a plasma atmosphere with a temperature exceeding 1000 °C, which is used for the decomposition of the organometallic precursor and the recombination of high-energy atoms and clusters. Calculated based on the molar ratio of boron element in the metal boride nanoparticles, the content of isotope boron-10 can reach between 20% and 100%. In this way, a very large number of boron-10 atoms can be contained in a very small nanoparticle volume, effectively solving the drawback in the prior art that the number of boron-10 atoms in small molecule drugs is too small to accumulate a sufficient amount of boron-10 atoms in tumor tissues.

[0035] In summary, the metal boride nanoparticles of the present invention have the dual functions of diagnosing and treating tumors, are surface-modified with antibodies, biological probes or coated with biological cell membranes, and the antibodies or biological probes have the specificity to bind to the receptors of specific tumor cells. In addition, the metal boride nanoparticles enriched with boron-10 of the present invention are prepared by the Microwave arcing method, and the molar content of the isotope boron-10 accounts for more than 20% of the total boron element. In this way, the metal boride nanoparticles of the present invention can be used as neutron capture reagents with active tumor targeting functions, and can effectively accumulate a sufficient amount of boron-10 atoms in tumor tissues. On the other hand, the metal boride nanoparticles of the present invention are doped with metal elements that can emit fluorescence in the near-infrared light region (1100 nm to 2000 nm). After being excited by irradiating near-infrared light (800 nm to 1100 nm), they can emit light in the 1100 nm to 2000 nm wavelength band of the near-infrared light region. In this way, they can be used as diagnostic tools for the presence of deep tumors, and can also generate reactive oxygen species (ROS) or heat energy after being irradiated with mid-infrared light (2000 nm to 7000 nm) to kill tumor cancer cells. In addition, the metal boride nanoparticles containing magnetic metal ions can be used as magnetic resonance imaging (MRI) contrast reagents, and all metal boride nanoparticles can be used as computed tomography (CT) contrast reagents. Therefore, the disadvantages of the traditional neutron capture therapy, such as many side effects and inability to image and track the distribution of nano-drug particles in vivo with bioimaging techniques, can be effectively solved.

Claims

1. A metal boride nanoparticle, characterized in that, It has the function of diagnosing and treating tumors. The surface of the metal boride nanoparticles is modified with antibodies, biological probes or coated with biological cell membranes, and the antibodies or the biological probes have specificity for binding to the cell membrane surface receptors of tumor cells.

2. The metal boride nanoparticles according to claim 1, wherein The biological cell membrane includes red blood cell membranes.

3. The metal boride nanoparticles according to claim 1, characterized in that, The metal boride nanoparticles bind to the receptors of the tumor cells through the antibodies or the biological probes to actively target tumor tissues.

4. The metal boride nanoparticles according to claim 3, characterized in that, The receptors include folic acid receptors, fibroblast activation protein receptors FAPI, epidermal growth factor receptors EGFR or vascular endothelial growth factor receptors VEGFR.

5. The metal boride nanoparticles according to claim 1, characterized in that, The tumors include melanoma, brain tumors, lung tumors or head and neck tumors.

6. The metal boride nanoparticles according to claim 1, wherein After the metal boride nanoparticles are irradiated with neutron beams, high-energy α-particles and 7Li particles, γ-rays or a combination thereof are generated.

7. The metal boride nanoparticles according to claim 1, wherein The metal boride nanoparticles generate reactive oxygen species, heat energy or a combination thereof after being irradiated with near-infrared light or mid-infrared light, and the wavelength λ of the irradiated light is between 2000 nm and 7000 nm.

8. The metal boride nanoparticles according to claim 1, characterized in that, The metal boride nanoparticles are doped with metal elements that can emit near-infrared fluorescence. After being excited by near-infrared light irradiation, they emit light in the range of 1100 nm to 2000 nm in the near-infrared region, and the wavelength of the irradiated near-infrared light is 800 nm to 1100 nm.

9. The metal boride nanoparticles according to claim 8, characterized in that The metal elements include Gd, Eu, Er, Ho, Yb, Pr, Cu, Cr, Ni or a combination thereof.

10. The metal boride nanoparticles according to claim 8, characterized in that, Based on the total moles of the metals in the metal boride nanoparticles, the molar content ratio of the metal elements ranges from 0% to 100%.

11. The metal boride nanoparticles according to claim 1, wherein The particle size of the metal boride nanoparticles is 5 nm to 300 nm.

12. The metal boride nanoparticles according to claim 1, wherein The metal boride nanoparticles are prepared by the microwave arc method.

13. The metal boride nanoparticles according to claim 1, characterized in that, Based on the molar ratio of boron elements in the metal boride nanoparticles, the content of isotope boron-10 is 20% to 100%.

14. The metal boride nanoparticles according to claim 1, characterized in that, The antibodies include anti-EGFR antibodies, anti-VEGF antibodies or TCR-like antibodies.

15. The metal boride nanoparticles according to claim 1, wherein The biological probes include biological probes based on folic acid, TAT polypeptide, tumor fibroblast activation protein inhibitor, RGD polypeptide or heparin polysaccharide.

Images