WO2016074334A1 - 一种利用微纳材料特异性破坏肿瘤血管实现肿瘤靶向治疗的方法 - Google Patents

一种利用微纳材料特异性破坏肿瘤血管实现肿瘤靶向治疗的方法 Download PDF

Info

Publication number
WO2016074334A1
WO2016074334A1 PCT/CN2015/000390 CN2015000390W WO2016074334A1 WO 2016074334 A1 WO2016074334 A1 WO 2016074334A1 CN 2015000390 W CN2015000390 W CN 2015000390W WO 2016074334 A1 WO2016074334 A1 WO 2016074334A1
Authority
WO
WIPO (PCT)
Prior art keywords
micro
nano material
tumor
cancer
magnetic
Prior art date
Application number
PCT/CN2015/000390
Other languages
English (en)
French (fr)
Inventor
王春儒
甄明明
邹头君
舒春英
李雪
Original Assignee
北京福纳康生物技术有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京福纳康生物技术有限公司 filed Critical 北京福纳康生物技术有限公司
Publication of WO2016074334A1 publication Critical patent/WO2016074334A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations

Definitions

  • the invention belongs to the field of medicine, and particularly relates to a method for achieving targeted tumor therapy by specifically destroying tumor blood vessels based on micro-nano materials.
  • Tumor cell-targeted therapies utilize specific antigens or receptors on the surface of tumor cells for targeting, although they enhance local tumors to some extent.
  • the concentration within the tissue but because these macromolecular substances are required to reach the tumor cell target area, it still needs to pass through the vascular endothelial cell barrier, and this process is relatively slow.
  • people gradually realize that the use of tumor blood vessels as a target has great advantages, and can accumulate rapidly and at a high concentration in the target site after administration.
  • the normal vascular growth cycle is one year, and the growth cycle of tumor blood vessels is 4 days.
  • EPR effect enhanced permeability and retention effect
  • tumor treatment methods that specifically destroy tumor blood vessels can be designed for tumor blood vessel specificity, similar to vascular disrupting agents (VDAs).
  • VDAs vascular disrupting agents
  • most of the existing tumor vascular blockers have serious side effects.
  • Ib/Bc, CA-1P and MPC-6827 have reported cardiovascular adverse reactions such as hypertension and tachycardia. Speed, slow arrhythmia, atrial fibrillation, myocardial infarction, these adverse reactions limit its clinical use.
  • One of the objects of the present invention is to provide a new use of micro-nano materials.
  • micro/nano material provided by the present invention is its application as a tumor vascular blocker drug for targeted cancer therapy.
  • the micro/nano material of the present invention has all of the following properties: (1) having good dispersibility and proper water solubility, enabling it to be injected into a living body via a vein and carried to a tumor blood vessel, and can be metabolized by the body; (2) The particle size is between 10 and 500 nm, which can be tightly retained in the pores of the tumor blood vessel wall by the EPR effect and the high blood pressure in the tumor; (3) in close contact with the tumor vascular endothelial cells, The electromagnetic wave is driven to produce specific physical damage to the surrounding tumor vascular endothelial cells, which ultimately leads to tumor necrosis. (4) The surface has a certain electronegativity, so that it does not produce non-specific adsorption with the normal cells and normal tissue. Sex, can selectively destroy tumor blood vessels; (5) driven by electromagnetic waves, the micro-nano material produces mechanical motion, deformation, volume expansion.
  • the micro-nano material is driven by electromagnetic waves (such as radio waves, microwaves, infrared rays, visible light, ultraviolet rays, X-rays, and gamma rays) to produce physical changes that destroy tumor endothelial cells, and such changes directly affect tumor vascular endothelial cells. .
  • electromagnetic waves such as radio waves, microwaves, infrared rays, visible light, ultraviolet rays, X-rays, and gamma rays
  • the mechanism of the micro-nano material of the present invention for destroying tumor vascular endothelial cells may be as follows: after the micro-nano material having a size in the range of 10-500 nm enters the living body through the vein, the EPR effect can be specifically retained in the void of the inner wall of the tumor blood vessel. Because the pressure of the tumor blood vessels is higher than the normal blood vessels, the material can be closer to the tumor vascular endothelial cells. At this time, under the electromagnetic wave, the physical changes produced by the micro-nano materials will have a strong destructive effect, directly destroying the surrounding tumors. Vascular endothelial cells eventually reach the role of blocking the nutrient supply of tumor tissues, but have no toxic side effects on normal tissues.
  • the micro/nano material of the present invention has a size in the range of 10-500 nm and has a remarkable EPR effect.
  • micro-nano material and the matching radiation source capable of generating electromagnetic waves are used together to cause physical destruction under the action of electromagnetic waves, and directly act on the tumor endothelial cells.
  • the action of the electromagnetic wave in the present invention mainly causes the following changes in the micro/nano material: physical physical effects such as physical mechanical action, deformation, volume expansion, and the like.
  • micro-nano material which satisfies the properties of the present invention in principle and which can undergo the above physical changes under the action of electromagnetic waves can achieve the purpose of the tumor-targeted therapy of the present invention.
  • the micro-nano material described in the present invention may specifically be a magnetic micro-nano material or a micro-nano material which is deformed under the action of electromagnetic waves.
  • the preferred electromagnetic wave form is a radio frequency or an alternating magnetic field or the like.
  • the magnetic micro/nano material can produce mechanical motion under alternating magnetic or radio frequency driving. Its forms of motion include: vibration, swing, translation, rotation, and so on. This mechanical action can be used to selectively destroy tumor vascular endothelial cells.
  • the magnetic micro-nano material needs to further have the following properties: the magnetic micro-nano material has a rough surface topography or a sharp angular structure, so that it is in an alternating magnetic field/RF drive. It can produce a strong mechanical action when moving down.
  • the surface having a rough surface topography or a sharp edge structure such as a triangle, a quadrangle, a spindle, a star, a sawtooth, etc., forming a polyhedron such as a triangular prism, a cube, a hexagon, or a truncated octahedral truncated polyhedron
  • the structure may also be a sphere having a rough surface.
  • the magnetic micro-nano material of the present invention is obtained by water-soluble and electronegative modification of a host magnetic metal material.
  • the main magnetic metal material includes, in principle, all micro-nano particles which are mechanically driven by an alternating magnetic field (including radio frequency), and may be a single metal magnetic material, a composite metal magnetic material, or a metal organic complex.
  • Magnetic material typical materials such as: magnetic metal oxide M x O y , magnetic metal composite oxide M x A y O z , magnetic metal fluoride M x F y , magnetic metal composite fluoride M x A y F z , Magnetic metal oxyfluoride M x O y F, magnetic metal sulfide M x S y , magnetic metal sulfur oxide M x O y S, or alloy M x A y , metal organic complex magnetic material such as carbonyl iron, ferrocene Iron and other structures.
  • the main magnetic metal material of the present invention may specifically be Fe 3 O 4 , Fe(CO) 5 , MnFe 2 O 4 , NaGdF 4 , GdF 3 , GdOF, Gd 2 O 3 , GdFe 2 O 4 , NaMnF 3 , Mn 3 .
  • Magnetic substance such as O 4 .
  • the magnetic host material comprises at least one or any combination of the above.
  • the host material may also be used as a core to form a magnetic core-shell structure such as Fe 3 O 4 @Au, NaGdF 4 @NaYF 4 or the like.
  • the above-mentioned main magnetic metal material can also be multi-functionalized by doping other metal elements, such as ferrite as the core, and Fe 3 O 4 @Au core-shell magnetic structural metal particles having a metal outer shell, combined with gold light.
  • the functions of acoustic imaging and CT angiography can realize the real-time diagnosis of the therapeutic effect; for example, NaGdF 4 is used as the main material, and the sensitizer (Yb) and the activator (Er, Tm, Ho) are prepared to obtain the up-converting luminescent material.
  • the use of its fluorescent properties can be used for the integration of high-sensitivity diagnosis and treatment.
  • the host magnetic metal material in the present invention can be prepared by conventional synthetic methods such as coprecipitation, thermal decomposition, microemulsion, hydrothermal and chemical reduction.
  • the magnetic micro-nano material used in the present invention needs to have good dispersibility and water solubility, can be injected into the living body through the vein, and exerts a therapeutic effect as the blood circulates and transports to the tumor blood vessel.
  • the above-described host magnetic metal material can usually be water-soluble modified to make it more biocompatible.
  • Commonly used water-soluble modification methods include: organic small molecule modification, mainly using a coupling agent (such as ethanol, organic carboxylic acid, thiol or silane, etc.) and a surfactant (such as oleic acid, dodecylamine or carboxymethyl)
  • organic cellulose modification such as natural biomacromolecules, synthetic polymers, and composite modification of the two
  • inorganic nanomaterial modification commonly used SiO 2 , Au and Ag modification.
  • the above modification methods can be modified in accordance with the methods disclosed in the prior art.
  • the water-soluble modified magnetic micro-nano material can also obtain a rough and sharp surface structure by other techniques.
  • Common techniques include etching technology (RF plasma, laser etching, etc.), chemical vapor deposition, stencil method, and sol-gelation.
  • Glue method water-soluble method and corrosion metal method.
  • the modified layer may be subjected to a certain roughness treatment or further coated or grown with a water-soluble coating having a rough or sharp surface by the above technique.
  • the magnetic micro-nano material used in the present invention should have a certain electronegativity, and the electronegativity modification method includes directly introducing an electronegative functional group such as a hydroxyl group, a carboxyl group and an amino acid through a covalent bond on the surface of the host magnetic metal material.
  • an electronegative functional group such as a hydroxyl group, a carboxyl group and an amino acid
  • Non-covalently coated such as a hydroxylated silica layer, a carboxylated carbon film, a peptide chain, etc., may also be carried out by a carrier having an electronegative property.
  • the material is not easily phagocytized by cells or adsorbed by normal tissues and blood vessels, and even if it is contacted, it is rapidly bounced off, so that it does not produce non-specific adsorption with normal cells and the inner wall of blood vessels of normal tissues, and on the other hand, the nanomaterial is avoided.
  • Intravascular aggregation and embolization makes it difficult to adsorb to normal tissues or blood vessel walls, and avoids damage to normal cells and tissues when the magnetic micro-nano materials rotate.
  • the micro/nano material according to the present invention may also be a micro-nano material which is deformed under the action of electromagnetic waves, such as a thermally deformable micro-nano material, a photo-induced micro-nano material or the like.
  • the thermally deformable micro-nano material according to the present invention is a structure in which a thermo-deformable material is introduced into a micro-nano material, so that the shape of the material is abrupt when the external temperature changes, wherein the micro-nano material may be magnetic micro- Nanomaterials and/or micro-nano materials that generate heat under the action of electromagnetic waves (eg, metal micro-nano particles, etc.).
  • Typical molecules include polyurethane materials, heat sensitive gels (gel swelling at elevated temperatures, increased volume), and the like.
  • the heating method of the thermally deformable micro-nano material can be realized by the magnetocaloric effect, that is, the magnetic particles are used as the inner core, and the heat generation under the alternating magnetic field causes the thermo-induced deformation phenomenon, such as the heat-sensitive gel wrapped with Fe 3 O 4 as the core.
  • Prepared thermodeformable material It is also possible to cause thermal deformation phenomenon by heating the metal particles under laser light, such as preparing a thermotropic material by using Au nanoparticles as a core.
  • the photodeformable micro/nano material of the invention introduces photoisomerization, photoionization or photo-cyclization groups into the skeleton structure of the micro-nano material, so that under the external illumination condition, the whole material A mutation occurs in size and shape.
  • Typical molecules such as photo-cis-isomerized azobenzene molecules, photodissociated triphenylmethane, photo-expanded polypropylene/(ethylene/octene) copolymer, photosensitive gel (lighting) Phase transition occurs) and so on.
  • Preferred forms of ambient light are infrared light, visible light, ultraviolet light, and the like.
  • the micro-nano material used in the present invention does not directly kill the tumor cells, but directly destroys the tumor blood vessels, and indirectly cuts off the nutritional supply of the tumor cells. This method is for normal blood vessels and cells. The killing effect is small.
  • Another object of the present invention is to provide a pharmaceutical kit for treating a tumor.
  • the kit of parts provided by the present invention consists of the above-described micro-nano material and means for providing a radiation source capable of generating electromagnetic waves.
  • Another object of the present invention is to provide a method of tumor targeted therapy.
  • the method for tumor targeted therapy utilizes the micro-nano material to be specifically enriched by the EPR effect and retained in the pores of the tumor blood vessel, and directly destroys the tumor vascular endothelium driven by electromagnetic waves.
  • the cells in turn, block the tumor blood vessels, cut off the nutritional supply of the tumor tissue, and achieve the purpose of targeted treatment of the tumor.
  • the method for treating tumors provided by the invention comprises the following steps:
  • Electromagnetic wave irradiation is performed on the tumor site of the living body after the injection.
  • the "effective amount” as used in the present invention means an amount sufficient to efficiently deliver an active ingredient for treating a disease to an organism when administered to the living body micro-nanomaterial by the method of the present invention.
  • the organism described in the present invention refers to a mammal including a human.
  • the irradiation time according to the present invention is irradiated for 1-30 min after intravenous injection of the micro-nano material for 0-1 h.
  • the injection dose is 1-20 mg/kg.
  • the electromagnetic wave may be specifically provided by an energy source such as radio waves, microwaves, infrared rays, visible rays, ultraviolet rays, X rays, and gamma rays.
  • an energy source such as radio waves, microwaves, infrared rays, visible rays, ultraviolet rays, X rays, and gamma rays.
  • the preferred injection method of the above tumor treatment method is intravenous injection, which directly functions in the blood without permeation, and the amount of the medicament used is small and the curative effect is high.
  • the micro/nano material used in the invention can specifically block tumor vascular treatment of tumor, and utilizes the difference between tumor tissue blood vessels and normal blood vessels, and thus has broad spectrum and is applicable to all solid tumors, including: liver cancer, lung cancer, colorectal Cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, laryngeal cancer, liver cancer, cholangiocarcinoma, cervical cancer, uterine cancer, testicular cancer, meningioma , skin cancer, melanoma, sarcoma (such as fibrosarcoma, mucinous sarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma).
  • liver cancer including: liver cancer, lung cancer, colorectal Cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer,
  • the micro/nano material used in the present invention treats tumors by specifically blocking tumor blood vessels, and the whole process takes place within 1-2 hours, and has the effect of rapidly treating tumors.
  • the tumor treatment method of the invention aims at the difference of tumor blood vessels and normal blood vessels, specifically destroys tumor blood vessels, and truly achieves the purpose of targeted treatment of tumors. And the treatment effect on advanced cancer and metastatic cancer is particularly remarkable.
  • the method for treating tumors has the following advantages: (1) having broad spectrum; (2) administering by intravenous injection, directly acting on the tumor blood vessel wall through blood circulation, Simple drug mode and low dose; (3) Highly targeted, for the structural difference of tumor blood vessels than normal blood vessels, can selectively destroy tumor blood vessels; almost no damage to normal tissues; (4) fast and effective, generally 1-2h (5)
  • the treatment is not limited to the location and depth of the tumor, and has a therapeutic effect on advanced tumors; (6) there is no problem of drug resistance; (7) the material is easy to obtain and the cost is low.
  • Example 1 is a TEM photograph of a water-soluble modified magnetic nanomaterial in Example 1.
  • Example 2 is a high resolution TEM photograph and a selected area electron diffraction photograph of the water-soluble modified magnetic nanomaterial in Example 1.
  • Example 3 is a particle size distribution of the water-soluble modified magnetic nanomaterial in Example 1 in an aqueous solution.
  • Example 4 is a photograph of a tumor treated with water-soluble modified magnetic nanomaterials in Example 1.
  • Fig. 5 is a magnetic resonance imaging photograph of a tumor site before and after injection of a water-soluble modified magnetic nanomaterial in Example 1.
  • Figure 6 is a scanning electron micrograph of the tumor vascular environment after treatment with water-soluble modified magnetic nanomaterials for 24 hours.
  • Example 7 is a TEM photograph of a water-soluble modified magnetic nanomaterial in Example 2.
  • Figure 8 is a photograph of a tumor treated with a water-soluble modified magnetic nanomaterial in Example 2.
  • Example 9 is a scanning electron micrograph of a tumor vascular environment after treatment with a water-soluble modified magnetic nanomaterial in Example 2 for 24 hours.
  • Example 1 Magnetic micro-nano material with NaGdF 4 as the main magnetic metal material is used for tumor vascular blocker
  • the following examples are exemplified by the conventional up-converting magnetic nanoparticles.
  • the nanomaterials having all of the properties of the present invention are NaGdF 4 :Yb, Er citric acid-modified water-soluble nanoparticles.
  • the preparation method thereof is referred to the literature (Adv. Mater. 2010, 22, 3266; J. Am. Chem. Soc., 2013, 135, 18920; Journal of Fluorine Chemistry 144 (2012) 157). Since citric acid has a water-soluble functional group and is electronegative after ionization in water, the above-mentioned NaGdF 4 :Yb,Er citric acid-modified water-soluble nanoparticles are also electronegative in water.
  • Figure 1 is a TEM photograph of the up-conversion material, the particle size is about 60-70 nm, the surface of the material is rough and not smooth;
  • Figure 2 is a selected area electron diffraction image with obvious lattice lines and diffraction points. The DLS test showed a more uniform size distribution in the aqueous solution (as shown in Figure 3).
  • mice inoculated with H22 hepatoma cell line were aspirated, and the supernatant was counted by centrifugation, and 50 ⁇ L of a cell suspension having a cell concentration of 10 7 /mL was inoculated subcutaneously into the right thigh of each mouse. After 5-7 days of growth, the tumor size was about 5 mm.
  • the above-mentioned up-converting material aqueous solution (dose of 20 mg/kg) was injected into the tumor-bearing mice by a tail vein for 10-30 min, and a pulsed radio frequency was applied to the tumor site for 30 min.
  • the frequency of the radio frequency used was 200 MHz, and the output power was 100 W.
  • the tumor site was found to be necrotic (shown in Figure 4).
  • the results of magnetic resonance imaging showed (as shown in Figure 5) that the tumor necrosis site covered the entire tumor site.
  • the environment of the tumor was observed by environmental scanning electron microscopy (as shown in Fig. 6). After 24 hours of treatment, the inner wall of the tumor blood vessel was severely damaged. It shows that the mechanical damage caused by the rotation of magnetic micro/nano materials under alternating magnetic field can significantly destroy tumor blood vessels and achieve the purpose of treating cancer quickly, efficiently and safely.
  • Example 2 Magnetic micro-nano material with Gd 2 O 3 as main magnetic metal material for tumor vascular blocker
  • the magnetic material having all of the properties described in the present invention used in the present embodiment is commercially available as Gd 2 O 3 as a host material (CAS No. 12064-62-9), and is obtained by water-soluble coating of SiO 2 .
  • a TEM photograph of the Gd 2 O 3 @SiO 2 material has a particle diameter of about 70 nm, and the surface of the material has many angular structures.
  • 150 ⁇ l of a Gd 2 O 3 @SiO 2 aqueous solution having a concentration of 20 mg/ml was injected into the tumor-bearing mice via a tail vein, and injected at a frequency of 11 MHz after 15 minutes to 30 minutes.
  • the tumor treatment method provided by the invention has therapeutic effects on various tumors, does not require minimally invasive surgery, and effectively avoids tumor metastasis by cutting off tumor blood vessels, and is a broad spectrum, highly targeted, fast and safe. Non-invasive and effective tumor treatment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Magnetic Treatment Devices (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种微纳材料在制备肿瘤靶向治疗药物中的应用。所述微纳材料具备下述所有性质：(1)具有水分散性和水溶性，使其能够经由静脉注入到生物体内并被运载至肿瘤血管，并且可被机体代谢；(2)颗粒尺寸介于10-500nm之间，可通过EPR效应和肿瘤血管内的高压使其紧密地滞留在肿瘤血管内壁的孔隙处；(3)在与肿瘤血管内皮细胞紧密接触时，在电磁波的驱动下对周围肿瘤血管内皮细胞产生特异性地物理破坏作用，最终导致肿瘤坏死；(4)表面带有电负性，使其与正常细胞及正常组织的血管内壁不产生非特异吸附性，能高选择性破坏肿瘤血管；(5)在电磁波的驱动下，所述微纳材料产生机械运动、形变、体积膨胀。

Description

一种利用微纳材料特异性破坏肿瘤血管实现肿瘤靶向治疗的方法 技术领域
本发明属于医药领域，具体涉及一种基于微纳材料通过特异性破坏肿瘤血管实现靶向性肿瘤治疗的方法。
背景技术
近年来癌症的发病率和死亡率均呈上升趋势，已对人类健康和生命构成严重的威胁，癌症调查报告显示2007年全球约有760万人死于癌症，到2020年全球每年的癌症死亡人数将增加一倍。传统的三大治疗手段手术、放疗、化疗均有一些局限性，因此目前亟需解决的难点问题是获得快速、高效、毒副作用小的肿瘤靶向治疗方法。
肿瘤的靶向治疗技术针对明确靶点向肿瘤区域精确的投递药物，肿瘤细胞靶向治疗是利用肿瘤细胞表面的特异性抗原或受体作为靶向，虽然其在某种程度上提高了局部肿瘤组织内的浓度，但由于这些大分子物质要到达肿瘤细胞靶区，仍然需要通过血管内皮细胞屏障，而这一过程是相对缓慢的。随着癌症研究的日益进展，人们逐渐认识到，将肿瘤血管作为靶点具有很大的优势，在给药后可以迅速高浓度地积聚在靶标部位。正常的血管生长周期是一年，而肿瘤血管的生长周期为4天，快速生长周期导致肿瘤血管内皮细胞间隙较大、结构不完整，形成纳米级孔隙，使得血液循环中的大分子物质容易渗透进入肿瘤组织并长期滞留，此现象被称为实体瘤的“高渗透性滞留效应”(enhanced permeability and retention effect，简称EPR效应)。
基于正常血管和肿瘤血管的差异，针对肿瘤血管特殊性，可以设计特异性地将肿瘤血管破坏的肿瘤治疗方法，类似于肿瘤血管阻断剂(vascular disrupting,agents,VDAs)。但是，现有的大部分肿瘤血管阻断剂有比较严重的副作用，例如齐布司他、CA-1P和MPC-6827等Ⅰ/Ⅱ期临床试验均报道有心血管不良反应如高血压、心动过速、缓慢性心律失常、心房颤动、心肌梗死，这些不良反应限制了其在临床上的推广使用。
发明公开
本发明的目的之一是提供一种微纳材料的新用途。
本发明所提供的微纳材料的新用途是其作为肿瘤血管阻断剂药物进行靶向癌症治疗的应用。
本发明所述的微纳材料具备下述所有性质：(1)具有良好的分散性和适当的水溶性，使其能够经由静脉注入到生物体内并被运载至肿瘤血管，并且可被机体代谢；(2)颗粒尺寸介于10-500nm之间，可以通过EPR效应和肿瘤血管内的高压使其紧密地滞留在肿瘤血管内壁的孔隙处；(3)在与肿瘤血管内皮细胞紧密接触时，在电磁波的驱动下对周围肿瘤血管内皮细胞产生特异性地物理破坏作用，最终导致肿瘤坏死；(4)表面带有一定电负性，使其与正常细胞及正常组织的血管内壁不产生非特异吸附性，能高选择性破坏肿瘤血管；(5)在电磁波的驱动下，所述微纳材料产生机械运动、形变、体积膨胀。
所述的微纳材料在电磁波(如无线电波、微波、红外线、可见光、紫外线、X射线和伽马射线)驱动下产生具有破坏肿瘤内皮细胞的物理变化，这种变化直接作用于肿瘤血管内皮细胞。
本发明所述的微纳材料破坏肿瘤血管内皮细胞的机理可能如下：尺寸在10-500nm范围内的微纳材料经静脉进入生物体内后，通过EPR效应可以特异性地滞留于肿瘤血管内壁的空隙处，并且由于肿瘤血管的压力高于正常的血管，材料可以更紧密地贴近肿瘤血管内皮细胞，此时在电磁波驱动下，微纳材料产生的物理变化会产生强力破坏作用，直接破坏周围的肿瘤血管内皮细胞，最终达到阻断肿瘤组织营养供给的作用，而对正常组织没有毒副作用。
本发明所述的微纳材料尺寸在10-500nm范围内，具有显著的EPR效应。
所述的微纳材料和与其相匹配的能产生电磁波的辐射源配套使用，使其在电磁波驱动下产生物理破坏作用，直接作用于肿瘤内皮细胞。
本发明中电磁波的作用主要导致微纳材料发生以下变化：产生物理机械作用、发生变形、体积膨胀等物理破坏作用。
因此，原则上满足本发明所述性质且能在电磁波作用下发生上述物理变化的微纳材料均能实现本发明所述的肿瘤靶向治疗的目的。
本发明中所述的微纳材料具体可为磁性微纳材料或在电磁波作用下发生形变的微纳材料。
当所述微纳材料为磁性微纳材料时，优选的电磁波形式为射频或者交变磁场等。所述磁性微纳材料在交变磁场或射频驱动下可以产生机械运动。其运动形式包括：振动、摆动、平动、转动等。该种机械作用，可以用于选择性破坏肿瘤血管内皮细胞。
为了达到更好的对肿瘤血管的破坏作用，所述磁性微纳材料还需进一步具备如下性质：磁性微纳材料具有粗糙的表面形貌或者锋利的棱角结构，使得其在交变磁场/射频驱动下运动时能够产生强力的机械作用。
所述具有粗糙表面形貌或者锋利的棱角结构，如表面为三角形、四边形、纺锤形、星形、锯齿等形状，形成如三棱体、立方体、六方体等多面体或者截角八面体截角多面体结构，还可以是具有粗糙表面的球体。
本发明所述的磁性微纳材料是由主体磁性金属材料经过水溶性和电负性修饰得到的。
所述主体磁性金属材料原则上包括一切在交变磁场(包括射频)驱动下产生机械运动的微纳颗粒，可以是单金属磁性材料，也可以是复合金属磁性材料，还可以是金属有机配合物磁性材料，典型的材料例如：磁性金属氧化物MxOy、磁性金属复合氧化物MxAyOz、磁性金属氟化物MxFy、磁性金属复合氟化物MxAyFz、磁性金属氟氧化物MxOyF、磁性金属硫化物MxSy、磁性金属硫氧化物MxOyS、或者合金MxAy、金属有机配合物磁性材料如羰基铁、二茂铁等结构。(M、A均代表金属元素；其中M＝Fe，Gd，Mn，Tb，Dy等磁性金属，A为任意与M形成稳定结构的金属元素(A与M可以同为磁性金属元素)。
本发明所述主体磁性金属材料具体可为Fe3O4，Fe(CO)5，MnFe2O4、NaGdF4、GdF3、GdOF、Gd2O3、GdFe2O4、NaMnF3，Mn3O4等磁性物质。
所述磁性主体材料至少包含上述一种或任意几种的组合物。亦可以将主体材料作为核芯，形成磁性核壳结构，例如Fe3O4@Au，NaGdF4@NaYF4等等。
上述的主体磁性金属材料亦可以通过掺杂其他的金属元素实现多功能 化，如以铁氧体为核心，得到具有金属外壳的Fe3O4@Au核壳磁性结构金属颗粒，结合金的光声成像及CT造影的功能实现对治疗效果的实时诊断；再例如以NaGdF4为主体材料，掺入敏化剂(Yb)以及激活剂(Er、Tm、Ho)等制备得到上转换发光材料，利用其荧光性质可以用于高敏度诊疗一体化。
本发明中所述主体磁性金属材料可通过目前常见的合成方法，如共沉淀法、热分解法、微乳液法、水热法和化学还原法等制备得到。
本发明所使用的磁性微纳材料需具备良好的分散性和水溶性，能够经由静脉注入到生物体内，并随着血液循环输送至肿瘤血管处发挥治疗作用。为实现此目的，通常可对上述主体磁性金属材料进行水溶性修饰，使其更具生物相容性。常用的水溶性修饰方法包括：有机小分子修饰，主要是用偶联剂(如乙醇、有机羧酸、硫醇或硅烷等)和表面活性剂(如油酸、十二烷基胺或羧甲基纤维素钠等)修饰；有机高分子修饰，如天然生物大分子、合成高分子以及两者的复合修饰；无机纳米材料修饰，常用的有SiO2、Au和Ag修饰。上述修饰方法均可按照现有技术公开的方法进行修饰。
水溶性修饰后的磁性微纳材料也可以借助其他技术进一步得到粗糙锋利的表面结构，常用的技术包括刻蚀技术(射频等离子体、激光刻蚀等)、化学气相沉积法、模版法、溶胶凝胶法、水溶法和腐蚀金属法等。可以直接通过上述技术对修饰层进行一定粗糙度的处理或者进一步涂覆或生长一层具有粗糙或锋利表面的水溶性涂层。
本发明所使用的磁性微纳材料应带有一定的电负性，电负性修饰方法包括直接在上述主体磁性金属材料表面通过共价键引入电负性官能团，如羟基、羧基和氨基酸等，亦可以通过带有电负性的载体进行非共价作用包覆，如羟基化的二氧化硅层、羧基化的碳膜、肽链等。使得材料不易被细胞吞噬或被正常组织及血管吸附，即使接触也会被迅速弹开，使其与正常细胞及正常组织的血管内壁等不产生非特异吸附性，一方面避免所述纳米材料在血管内聚集栓塞，另一方面也使其不易吸附于正常组织或血管壁，避免磁性微纳材料发生转动时对正常细胞和组织的伤害。
当然为了简化修饰的步骤，也可以通过选择合适的修饰方法，同步实 现对主体磁性金属材料的水溶化修饰和负电修饰。
本发明所述的微纳材料还可为在电磁波作用下发生形变的微纳材料，例如热致变形微纳材料、光致变形微纳材料等。
本发明所述的热致变形微纳材料是将具有热致变形材料引入微纳材料的骨架结构中，使其在外界温度改变时，材料形状发生突变，其中，微纳材料具体可为磁性微纳材料和/或在电磁波作用下产热的微纳材料(如：金属微纳颗粒等)。典型的分子包括聚氨酯材料、热敏性凝胶(升高温度时，凝胶溶胀，体积增加)等。
热致变形微纳材料的加热方式可以利用磁热效应实现，即用磁性颗粒作为内核，其在交变磁场下产热导致热致变形现象的发生，如以Fe3O4为核心包裹热敏性凝胶制备的热致变形材料。亦可以通过金属颗粒在激光下升温导致热致变形现象，如以Au纳米颗粒为核心制备热致变形材料等。
本发明所述的光致变形微纳材料是将光致异构化、光致离子化或者光致环化基团引入到微纳材料的骨架结构中，使其在外界光照条件下，整体材料在尺寸和形状上发生突变。典型分子如具有光致顺反异构化的偶氮苯分子，光致解离化的三苯基甲烷，光致膨胀的聚丙烯/(乙烯/辛烯)共聚物，光敏性凝胶(光照下发生相转变)等。优选的外界光照(电磁波)的形式为红外光、可见光和紫外光等。
本发明所使用的微纳材料与用于常规肿瘤治疗的材料相比，不是通过直接杀死肿瘤细胞，而是直接摧毁肿瘤血管，间接切断肿瘤细胞的营养供给，这种方法对正常血管及细胞的杀伤作用小。
本发明的目的之二是提供一种用于治疗肿瘤的药物套装。
本发明所提供的药物套装由上述微纳材料和提供与其相匹配的能产生电磁波的辐射源的装置组成。
关于上述辐射源，本领域技术人员可以根据现有技术的教导，依据形成所述微纳材料中主体材料对不同辐射能量的吸收性质，做出合理的选择。
本发明的目的之二是提供一种肿瘤靶向治疗的方法。
本发明所提供的肿瘤靶向治疗的方法利用微纳材料通过EPR效应特异性富集并滞留在肿瘤血管孔隙处，在电磁波驱动下直接破坏肿瘤血管内皮 细胞，进而阻断肿瘤血管，切断肿瘤组织营养供给，实现靶向治疗肿瘤的目的。
本发明所提供的肿瘤治疗方法，包括下述步骤：
1)向需要治疗的荷瘤生物体注射有效剂量的微纳材料；
2)注射后对所述生物体的肿瘤部位进行电磁波辐照。
本发明中所述的“有效剂量”是指当通过本发明的方法给予生物体微纳材料时，足以向生物体有效传递用于治疗疾病的活性成分的量。
本发明中所述的生物体是指包括人在内的哺乳动物。
本发明所述的辐照时间为静脉注射微纳米材料0-1h后辐照1-30min。注射剂量为1-20mg/kg。
所述电磁波具体可由下述能量源提供：无线电波、微波、红外线、可见光、紫外线、X射线和伽马射线。
上述肿瘤治疗方法优选的注射方式为静脉注射，直接在血液中发挥作用，无需渗透，所用的药剂量小，疗效高。
本发明所使用的微纳材料能特异性地阻断肿瘤血管治疗肿瘤，是利用肿瘤组织血管与正常血管的差异，因而具有广谱性，适用于一切实体肿瘤，包括：肝癌、肺癌、结肠直肠癌、肾癌、胰腺癌、骨癌、乳腺癌、卵巢癌、前列腺癌、食管癌、胃癌、口腔癌、鼻癌、喉癌、肝癌、胆管癌、宫颈癌、子宫癌、睾丸癌、脑膜瘤、皮肤癌、黑色素瘤、肉瘤(如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤)等。
本发明所使用的微纳材料通过特异性地阻断肿瘤血管治疗肿瘤，整个过程发生在1-2个小时内，具有快速治疗肿瘤的效果。
本发明所述的肿瘤治疗方法针对肿瘤血管与正常血管的差异性，专一性地破坏肿瘤血管，真正达到靶向治疗肿瘤的目的。并且对于晚期癌症以及转移癌的治疗效果特别显著。
由于上述治疗方法对肿瘤的杀伤是纯物理性损伤，因此也不存在抗药性的问题；
综上所述，本发明提供的肿瘤治疗方法具有以下优点：(1)具有广谱性；(2)通过静脉注射给药，经血液循环直接作用于肿瘤血管壁，给 药方式简单、剂量低；(3)高度靶向性，针对肿瘤血管比正常血管的结构差异性，可以选择性破坏肿瘤血管；对正常组织几乎无伤害；(4)快速有效，一般1-2h内有明显效果；(5)治疗不受限于肿瘤的位置及深度，并且对晚期肿瘤亦具有治疗效果；(6)不存在耐药性问题；(7)材料易得，成本低。
附图说明
图1为实施例1中水溶性修饰的磁性纳米材料的TEM照片。
图2为实施例1中水溶性修饰的磁性纳米材料高分辨TEM照片及选区电子衍射照片。
图3为实施例1中水溶性修饰的磁性纳米材料在水溶液中的粒径分布。
图4为实施例1中水溶性修饰的磁性纳米材料治疗肿瘤的照片。
图5为实施例1中注射水溶性修饰的磁性纳米材料前后，肿瘤部位的磁共振成像照片。
图6为使用水溶性修饰的磁性纳米材料治疗24h后，肿瘤血管环境扫描电镜照片。
图7为实施例2中水溶性修饰的磁性纳米材料的TEM照片。
图8为实施例2中水溶性修饰的磁性纳米材料治疗肿瘤的照片。
图9为实施例2中使用水溶性修饰的磁性纳米材料治疗24h后，肿瘤血管环境扫描电镜照片。
实施发明的最佳方式
下面通过具体实施例对本发明进行说明，但本发明并不局限于此。
下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。
实施例1、以NaGdF4为主体磁性金属材料的磁性微纳材料用于肿瘤血管阻断剂
1、材料制备：
下述实施例以常见的上转换磁性纳米颗粒为例，具备本发明全部所述性质的纳米材料为NaGdF4:Yb,Er柠檬酸修饰的水溶性纳米颗粒。其制备方法参照文献(Adv.Mater.2010,22,3266；J.Am.Chem.Soc.,2013,135,18920；Journal of Fluorine Chemistry 144(2012)157)。由于柠檬酸带有水溶性官能团，在水中电离后显负电性，所以上述NaGdF4:Yb,Er柠檬酸修饰的水溶性纳米颗粒也会在水中呈电负性。
图1为该上转换材料的TEM照片，粒径在60-70nm左右，该材料表面粗糙不光滑；图2为选区电子衍射图像，具有明显的晶格线及衍射点。DLS测试显示其在水溶液中具有较均一的尺寸分布(如图3所示)。
2、建立荷瘤鼠动物模型：
抽取腹腔接种H22肝癌细胞株的小鼠腹水，离心去上清液计数，接种细胞浓度为107/mL的细胞悬浮液50μL于每只小鼠右侧大腿皮下。待生长5-7天后，肿瘤大小在5mm左右进行实验。
3、活体实验：
通过尾静脉注射上述上转换材料水溶液(剂量为20mg/kg)200μL于荷瘤鼠体内10-30min后对肿瘤部位施加脉冲射频30min，所用射频的频率为200MHz，输出功率100W。撤离射频1h后发现肿瘤部位明显坏死(图4所示)，通过磁共振成像结果显示(如图5所示)，肿瘤坏死部位覆盖整个肿瘤部位。进一步使用环境扫描电镜观察肿瘤血管情况(如图6所示)，治疗24h后，肿瘤血管内壁被严重地破坏。说明磁性微纳材料在交变磁场下的转动产生的机械破坏作用可以显著地破坏肿瘤血管，达到快速高效且安全的治疗癌症的目的。
实施例2、以Gd2O3为主体磁性金属材料的磁性微纳材料用于肿瘤血管阻断剂
本实施例所采用的具备本发明全部所述性质的磁性材料以市售Gd2O3为主体材料(CAS号12064-62-9)，经SiO2水溶性包覆得到。如图7所示，Gd2O3@SiO2材料的TEM照片，粒径在70nm左右，该材料表面具有很多棱角结构。按照实施例1中所述的活体实验方法，经尾静脉注射浓度为20mg/ml的Gd2O3@SiO2水溶液150μl于荷瘤鼠体内，注射15min-30 min后在频率为11MHz的射频下辐照30min，治疗1h后如图8所示，肿瘤部位明显坏死，利用环境扫描电镜观察肿瘤血管，可以发现肿瘤血管严重受损(图9)，综上所述，所述的Gd2O3@SiO2在11MHz的射频下具有特异性阻断肿瘤血管的作用。
工业应用
本发明提供的肿瘤治疗方法对多种肿瘤均有治疗效果，无需进行微创手术，并且通过切断肿瘤血管，有效的避免了肿瘤的转移，是一种广谱、高度靶向性、快速、安全无创的高效肿瘤治疗方法。

Claims (13)

  1. 一种微纳材料在制备肿瘤靶向治疗药物中的应用；
    其中，所述微纳材料具备下述所有性质：(1)具有水分散性和水溶性，使其能够经由静脉注入到生物体内并被运载至肿瘤血管，并且可被机体代谢；(2)颗粒尺寸介于10-500nm之间，可通过EPR效应和肿瘤血管内的高压使其紧密地滞留在肿瘤血管内壁的孔隙处；(3)在与肿瘤血管内皮细胞紧密接触时，在电磁波的驱动下对周围肿瘤血管内皮细胞产生特异性地物理破坏作用，最终导致肿瘤坏死；(4)表面带有电负性，使其与正常细胞及正常组织的血管内壁不产生非特异吸附性，能选择性破坏肿瘤血管；(5)在电磁波的驱动下，所述微纳材料产生机械运动、形变、体积膨胀。
  2. 根据权利要求1所述的应用，其特征在于：所述微纳材料具有磁性，为磁性微纳材料；
    所述磁性微纳材料是由主体磁性金属材料经过水溶性和电负性修饰得到；所述主体磁性金属材料包括一切在电磁波驱动下产生机械运动的微纳颗粒；所述电磁波为交变磁场和/或射频。
  3. 根据权利要求2所述的应用，其特征在于：所述磁性微纳材料还具备如下性质：所述的磁性微纳材料具有粗糙的表面形貌或者锋利的棱角结构。
  4. 根据权利要求2或3所述的应用，其特征在于：所述主体磁性金属材料选自下述至少一种材料或是以下述至少一种材料为核芯结构：磁性金属氧化物MxOy、磁性金属复合氧化物MxAyOz、磁性金属氟化物MxFy、磁性金属复合氟化物MxAyFz、磁性金属氟氧化物MxOyF、磁性金属硫化物MxSy、磁性金属硫氧化物MxOyS、或者合金MxAy、金属有机配合物磁性材料羰基铁或者二茂铁，其中M、A均代表金属元素。
  5. 根据权利要求4所述的应用，其特征在于：所述M代表Fe、Gd、Mn、Tb或Dy，A为任意与M形成稳定结构的金属元素，其中A与M可以同为磁性金属元素。
  6. 根据权利要求4或5所述的应用，其特征在于：所述主体磁性金属材料选自下述至少一种材料或是以下述至少一种材料为核芯结构：Fe3O4， Fe(CO)5，MnFe2O4、NaGdF4、GdF3、GdOF、Gd2O3、GdFe2O4、NaMnF3和Mn3O4。
  7. 根据权利要求1所述的应用，其特征在于：所述微纳材料为在电磁波作用下发生形变的微纳材料。
  8. 根据权利要求7所述的应用，其特征在于：所述发生形变的微纳材料为热致变形微纳材料或光致变形微纳材料；
    所述热致变形微纳材料是将具有热致变形材料引入微纳材料的骨架结构中，使其在外界温度改变时，材料形状发生突变；
    所述光致变形微纳材料是将光致异构化、光致离子化或者光致环化基团引入到微纳材料的骨架结构中，使其在外界光照条件下，整体材料在尺寸和形状上发生突变。
  9. 根据权利要求8所述的应用，其特征在于：所述热致变形微纳材料中的热致变形材料为聚氨酯材料和/或热敏性凝胶，微纳材料为磁性微纳材料和/或在电磁波作用下产热的微纳材料；
    所述光致变形微纳材料中的光致异构化、光致离子化或者光致环化基团来自光致顺反异构化的偶氮苯分子、光致解离化的三苯基甲烷、光致膨胀的聚丙烯/(乙烯/辛烯)共聚物或光敏性凝胶。
  10. 一种用于治疗肿瘤的药物套装，由权利要求1-9中任一项所述的微纳材料和提供与其相匹配的能产生电磁波辐射源的装置组成。
  11. 一种肿瘤的治疗方法，包括下述步骤：
    1)向需要治疗的荷瘤生物体注射给予有效剂量的权利要求1-9中任一项所述的微纳材料；
    2)注射后对所述生物体的肿瘤部位进行电磁波辐照。
  12. 根据权利要求11所述的治疗方法，其特征在于：所述的生物体是指包括人在内的哺乳动物。
  13. 根据权利要求10所述的药物套装或根据权利要求11或12所述的治疗方法，其特征在于：所述肿瘤为实体肿瘤；所述实体肿瘤，包括：肝癌、肺癌、结肠直肠癌、肾癌、胰腺癌、骨癌、乳腺癌、卵巢癌、前列腺癌、食管癌、胃癌、口腔癌、鼻癌、喉癌、肝癌、胆管癌、宫颈癌、子宫癌、睾丸癌、脑膜瘤、皮肤癌、黑色素瘤、肉瘤。
PCT/CN2015/000390 2014-11-11 2015-06-05 一种利用微纳材料特异性破坏肿瘤血管实现肿瘤靶向治疗的方法 WO2016074334A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410643728.6 2014-11-11
CN201410643728.6A CN105641695B (zh) 2014-11-11 2014-11-11 一种利用磁性微纳材料在交变磁场或射频驱动下破坏肿瘤血管的靶向抗癌药物

Publications (1)

Publication Number Publication Date
WO2016074334A1 true WO2016074334A1 (zh) 2016-05-19

Family

ID=55953648

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/000390 WO2016074334A1 (zh) 2014-11-11 2015-06-05 一种利用微纳材料特异性破坏肿瘤血管实现肿瘤靶向治疗的方法

Country Status (2)

Country Link
CN (1) CN105641695B (zh)
WO (1) WO2016074334A1 (zh)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107789635B (zh) * 2016-09-05 2021-01-01 中国科学院化学研究所 T2造影剂及其制备方法和用途
CN109045475B (zh) * 2018-09-11 2021-11-02 同济大学 用于杀伤肿瘤细胞的振动磁场装置
CN113519459B (zh) * 2021-06-11 2022-03-25 中国科学院合肥物质科学研究院 一种采用调节肝细胞ros水平的磁场发生装置在调节人/鼠肝细胞氧化应激中的应用
CN115554400A (zh) * 2021-06-30 2023-01-03 香港城市大学深圳研究院 高机械强度可降解的磁控微型机器人及其制备方法和应用
CN116270530A (zh) * 2023-04-08 2023-06-23 哈尔滨工业大学 一种子母式微纳机器人

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103623407A (zh) * 2013-12-01 2014-03-12 中国科学院上海硅酸盐研究所 一种集辅助肿瘤热疗与放疗功能于一体的纳米协同治疗剂
CN104127872A (zh) * 2014-07-29 2014-11-05 中国科学院化学研究所 金属富勒烯单晶纳米颗粒在制备特异性肿瘤血管阻断剂中的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104127873B (zh) * 2014-07-29 2016-05-18 北京福纳康生物技术有限公司 一种由纳米材料和外加辐射源组成的实现肿瘤血管阻断的肿瘤治疗药物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103623407A (zh) * 2013-12-01 2014-03-12 中国科学院上海硅酸盐研究所 一种集辅助肿瘤热疗与放疗功能于一体的纳米协同治疗剂
CN104127872A (zh) * 2014-07-29 2014-11-05 中国科学院化学研究所 金属富勒烯单晶纳米颗粒在制备特异性肿瘤血管阻断剂中的应用

Also Published As

Publication number Publication date
CN105641695A (zh) 2016-06-08
CN105641695B (zh) 2019-02-12

Similar Documents

Publication Publication Date Title
Jaque et al. Nanoparticles for photothermal therapies
WO2016074334A1 (zh) 一种利用微纳材料特异性破坏肿瘤血管实现肿瘤靶向治疗的方法
Fang et al. Nanomaterials for photohyperthermia: a review
RU2420330C2 (ru) Способ активации фотосенсибилизатора
US20200246458A1 (en) Method for treating cancer based on metallofullerene monocrystalline nanoparticles that specifically disrupt tumor blood vessels
KR20070014172A (ko) 활성 입자, 그 제조 방법 및 사용 방법
CN104127873B (zh) 一种由纳米材料和外加辐射源组成的实现肿瘤血管阻断的肿瘤治疗药物
Fu et al. MoS 2 nanosheets encapsulated in sodium alginate microcapsules as microwave embolization agents for large orthotopic transplantation tumor therapy
Maleki et al. Titanium‐based nanoarchitectures for sonodynamic therapy‐involved multimodal treatments
Wang et al. Functionalization of bismuth sulfide nanomaterials for their application in cancer theranostics
Zhang et al. Near-infrared triggered injectable ferrimagnetic chitosan thermosensitive hydrogel for photo hyperthermia and precisely controlled drug release in tumor ablation
Chen et al. Micro-nanomaterials for tumor microwave hyperthermia: design, preparation, and application
US20090226526A1 (en) Nanoparticles of a heterocrystal mineral for use as a medicament and method of producing the same
WO2021083370A1 (zh) 一种特异性激活免疫系统的纳米材料的制备和应用
Du et al. A bright future: advanced nanotechnology-assisted microwave therapy
Yang et al. Nanomedicines enhance minimally invasive therapy of pancreatic cancer
CN107982535B (zh) 一种靶向性微波控释载药纳米微球及其制备方法和应用
Zhao et al. Injectable “cocktail” hydrogel with dual‐stimuli‐responsive drug release, photothermal ablation, and drug‐antibody synergistic effect
Chao et al. Application of advanced biomaterials in photothermal therapy for malignant bone tumors
WO2016015173A1 (zh) 一种通过纳米材料和外加辐射源实现肿瘤血管阻断的肿瘤治疗方法
Yazdanpanah et al. Threatening sarcoma with combinational therapies: Magnetic hyperthermia using nanoparticles
Xie et al. Present and future of metal nanoparticles in tumor ablation therapy
Huang et al. Nanotechnology-enabled sonodynamic therapy against malignant tumors
Li et al. Semiconducting Polymers for Cancer Immunotherapy
Saha et al. MXenes in photothermal therapy

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15859752

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15859752

Country of ref document: EP

Kind code of ref document: A1