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WO2016015172A1 - 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 - Google Patents

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 Download PDF

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Publication number
WO2016015172A1
WO2016015172A1 PCT/CN2014/000722 CN2014000722W WO2016015172A1 WO 2016015172 A1 WO2016015172 A1 WO 2016015172A1 CN 2014000722 W CN2014000722 W CN 2014000722W WO 2016015172 A1 WO2016015172 A1 WO 2016015172A1
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tumor
nanomaterial
cancer
nanomaterials
energy
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French (fr)
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WO2016015172A8 (zh
WO2016015172A9 (zh
Inventor
王春儒
甄明明
王太山
舒春英
张国强
邹头君
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Beijing Fullcan Bio-Technology Co Ltd
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Beijing Fullcan Bio-Technology Co Ltd
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Priority to PCT/CN2014/000722 priority Critical patent/WO2016015172A1/zh
Priority to AU2014402251A priority patent/AU2014402251B2/en
Priority to EP14898405.7A priority patent/EP3130351A4/en
Priority to JP2017503020A priority patent/JP6582039B2/ja
Priority to CA2940611A priority patent/CA2940611C/en
Priority to US15/329,116 priority patent/US20170216436A1/en
Application filed by Beijing Fullcan Bio-Technology Co Ltd filed Critical Beijing Fullcan Bio-Technology Co Ltd
Publication of WO2016015172A1 publication Critical patent/WO2016015172A1/zh
Publication of WO2016015172A9 publication Critical patent/WO2016015172A9/zh
Publication of WO2016015172A8 publication Critical patent/WO2016015172A8/zh
Anticipated expiration legal-status Critical
Priority to US16/837,953 priority patent/US20200246458A1/en
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    • 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
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0487—Metallocenes, i.e. complexes based on a radioactive metal complexed by two cyclopentadienyl anions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A61K51/1251—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/40—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals
    • A61N1/403—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals for thermotherapy, e.g. hyperthermia
    • A61N1/406—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals for thermotherapy, e.g. hyperthermia using implantable thermoseeds or injected particles for localized hyperthermia

Definitions

  • Tumor treatment method for tumor vascular occlusion by nano material and external radiation source Tumor treatment method for tumor vascular occlusion by nano material and external radiation source
  • the invention belongs to the field of medicine, and particularly relates to a tumor treatment method for realizing tumor vascular blockage by using nano materials and an external radiation source.
  • tumor tissue is actually a complete ecosystem formed by tumor cells and tumor neovascularization. If a tumor tumor grows up rapidly, it must rely on the formation of tumor neovascularization, and the tumor blood vessel is the main transfer channel of cancer cells. Therefore, blocking or destroying the tumor blood vessels can cut off the nutrient supply of tumor tissue. Dead "tumors, on the other hand, will block the spread and metastasis of cancer cells to the greatest extent.
  • the normal vascular growth cycle is one year, usually consisting of a three-layer membrane of intima, media, and adventitia.
  • the growth cycle of tumor blood vessels is 4 days, and there is only a thin inner membrane in the structure. Due to the large gap and incomplete structure of the endothelial cells, the tumor blood vessels contain a large number of nanometer-sized pores, and the plasma can pass through. Out.
  • the tumor is rich in blood supply, and the tumor blood vessels also have blood flow and high blood pressure, which is three times the normal blood pressure.
  • VDAs tumor vascular disrupting agents
  • vascular disrupting agents are drugs for the purpose of treating cancer by selectively destroying neovascularization of malignant tumors. They target the tumor blood vessels that have been formed, and cause apoptosis of endothelial cells by rapidly changing the shape of endothelial cells or damaging endothelial cells, exposing the basement membrane, and significantly affecting Capillary blood flow, thereby disintegrating the vascular system inside the solid tumor, leading to tumor ischemia and extensive necrosis.
  • VDAs small molecule VDAs
  • a variety of small molecule VDAs have been introduced into preclinical experiments.
  • most VDAs candidates have been found to have more serious side effects, such as ibsstatin, CA-1P, and MPC-6827, etc.
  • Cardiovascular adverse reactions such as hypertension, tachycardia, bradyarrhythmia, atrial fibrillation, myocardial infarction have been reported and are dose-related, and these adverse reactions have limited their widespread clinical use.
  • Invention disclosure
  • One of the objects of the present invention is to provide a new use of nanomaterials.
  • the new use of the nanomaterial provided by the present invention is as a tumor vascular blocker drug, combined with a matching radiation source for the purpose of treating tumors.
  • the nanomaterial of the present invention has all of the following properties: (1) the surface is hydrophilic so that it can be injected into the living body via the vein and carried to the tumor blood vessel; (2) the surface is electrically negative, so that It does not produce non-specific adsorption with normal cells and the inner wall of blood vessels of normal tissues, on the one hand, avoids aggregation of the nanomaterials in blood vessels, and on the other hand, it is not easy to adsorb to normal tissues or blood vessel walls, and avoids normal cells.
  • nanomaterials have a particle size range of 50-250 nm, and the material is rigid (ie, not easily deformable), allowing it to become stuck when it is intended to pass through the pores of the tumor vessel wall; 4)
  • the nanomaterial is capable of absorbing external radiant energy and internally converting it into thermal energy, and accumulating the thermal energy, causing the morphological structure of the nano material to change drastically, thereby causing a change in the morphological structure or function of the tumor vascular endothelial cell. , eventually destroying the tumor blood vessels.
  • Possible ways for the morphological structure of the nanomaterial to change are as follows: For a nanomaterial having a single crystal/polycrystalline structure, when the accumulated temperature exceeds the phase transition temperature point of the material (40-150 ° C), the material volume is rapidly Expansion occurs; for nano-materials that are loose inside and contain bound water, the accumulated temperature exceeds 10 CTC. The water inside the evaporation produces water vapor. When the vapor pressure accumulates to a certain extent, the micro-explosion occurs beyond the binding force of the material; or the material sudden heat occurs directly. Explosion; all of the possible pathways can act on tumor blood vessels, and ultimately achieve the effect of highly effective treatment of tumors.
  • the nanomaterial of the present invention is obtained by modifying the water-soluble and electronegative properties of the host material.
  • the host material is a nano material having the ability to absorb external radiation (infrared, visible light, X-ray, alternating magnetic field, radio frequency, etc.) and accumulating heat, and may be a single metal or a non-metal material, or a composite material, typically Materials such as: fullerene nanoparticles, embedded metal fullerene nanoparticles, noble metal nanoclusters (including gold nanoclusters, silver nanoclusters, platinum nanoclusters), ferroferric oxide nanomaterials, zinc oxide nanomaterials Materials, zinc sulfide nanomaterials, Cadmium selenide nanomaterials, cadmium telluride nanomaterials, rare earth oxide nanomaterials, carbon quantum dots, carbon nanohorns, carbon nanotubes, graphene, and the like, and any combination thereof.
  • the nano material according to the present invention may specifically be Au@S i0 2 nano particles (ie, a negatively charged Si 2 layer coated with Au nanoparticles, a Zeta potential of -34 ⁇ 0. 4 eV), and a water-soluble rich Receptor nanoparticles, water-soluble metal fullerene nanoparticles, Fe 3 0 4 nanoparticles coated with a hydrophilic layer, and the like.
  • the externally radiated energy sources of the present invention include radio frequency (also known as radio waves), microwaves, infrared light, visible light, laser light, X-rays, alternating magnetic fields, and the like, and any combination thereof.
  • the energy form is as short as possible short-wave pulse radiation, such as laser pulse, electromagnetic pulse (including radio frequency pulse), etc., in order to facilitate the rapid absorption of the radiant energy by the nano material to make the temperature rise rapidly, and then before the energy is lost through heat exchange or the like. Deformation (expansion or explosion) occurs quickly, releasing energy.
  • the pulse energy source can also reduce the damage of the external radiation to the living body.
  • the nanomaterial used in the present invention needs to be water-soluble, can be injected into a living body via a vein, and exerts a therapeutic effect as blood is circulated to the tumor blood vessel.
  • the host material described above is typically water soluble to make it more biocompatible.
  • the surface of the host material is modified with one or more hydrophilic chemical groups, such as: hydroxyl group, amino group, sulfhydryl group, carboxyl group, etc., and any combination thereof; and a hydrophilic inorganic substance such as dioxide may be coated on the surface of the host material.
  • the assembly forms a form of a water-soluble supramolecular system. All of the above modification methods can be modified in accordance with the methods disclosed in the prior art.
  • the nanomaterial 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 material, or
  • the electronegative carrier is non-covalently coated, such as a hydroxylated silica layer, a carboxylated carbon film, a peptide chain, and the like.
  • the material is not easily phagocytosed by cells or adsorbed by normal tissues and blood vessels, and even if it is contacted, it is quickly bounced off, which can reduce damage to normal cells or biological tissues when the nanomaterial is deformed (expanded or exploded).
  • water-solubilization modification and negative-electrode modification of the host material can also be simultaneously achieved by selecting an appropriate modification method.
  • the size distribution of the nanomaterials used in the present invention should generally be in the range of 50-250 nm.
  • the material needs to have a certain rigidity (not easily deformed), so that it cannot pass through the nanopores between the tumor vascular endothelial cells, and can be closely adhered to the pores of the blood vessel wall by the pressure difference between the blood vessels inside and outside the tumor, so as to facilitate Nanomaterials are more effective in damaging tumor vascular endothelial cells when they are rapidly deformed (expanded or exploded).
  • 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 nanomaterials and means for providing a source of radiant energy matched thereto.
  • the drug kit can be specifically gold nanoclusters + pulsed laser; fullerene nanoparticles + pulsed laser; metal fullerene nanoclusters + radio frequency; ferroferric oxide nanoparticles + alternating magnetic field.
  • a third object of the present invention is to provide a method for treating tumors based on the above-described nanomaterials which can specifically block tumor blood vessels.
  • the method for treating tumors provided by the invention comprises the following steps:
  • the "effective dose” as used in the present invention means an amount sufficient to efficiently deliver an active ingredient for treating a disease to an organism when the biological nanomaterial is administered by the method of the present invention.
  • the organism described in the present invention refers to a mammal including a human.
  • the irradiation according to the present invention is irradiated with nanomaterials for 0-1 h and irradiated for a period of time, for example, 10 min-1 h.
  • the preferred method of injection of the above tumor treatment method is intravenous injection, which acts directly in the blood without osmosis, and the amount of the medicament used is small and the curative effect is high.
  • the nanomaterial used in the present invention treats tumor by specifically blocking tumor blood vessels, and utilizes the difference between blood vessels in the tumor tissue 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, gastric cancer, oral cancer, nasal cancer, laryngeal cancer, liver cancer, cholangiocarcinoma, cervical cancer, uterine cancer, testicular cancer, meningioma , skin cancer, melanoma, sarcoma (such as fiber Uterine sarcoma, mucinous sarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, etc.
  • liver cancer lung cancer, colorectal Cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ova
  • the nanomaterial used in the present invention is a specific nanoparticle having a size of 50-250 nm, which can be deformed after absorbing a specific wavelength of radiant energy (infrared, visible light, X-ray, alternating magnetic field, radio frequency, etc.). Or explosion).
  • a specific wavelength of radiant energy infrared, visible light, X-ray, alternating magnetic field, radio frequency, etc.
  • the nanomaterial is intravenously injected into the tumor-bearing organism and transported to the tumor via the blood.
  • the smaller size nanomaterials will enter the tumor through these voids, but the nanomaterials of suitable size and rigidity (ie, nanomaterials having the properties described in the present invention) It is trapped by these nanopores and is retained in the gaps of these tumor vascular cells for a long time due to the pressure difference between the blood vessels and the inside.
  • a suitable wavelength of radiation is applied to the vicinity of the tumor, so that the nanomaterial absorbs the radiant energy and the internal temperature rapidly rises.
  • the temperature accumulates to a certain extent, the morphology and/or structure of the nanomaterial changes (such as an explosion or The volume is exploding).
  • nanomaterials are closely contacted with blood vessel pores by intravascular and extravascular blood pressure, the rapid deformation of the nanomaterials causes damage and apoptosis of peripheral tumor vascular endothelial cells, exposing the basement membrane, thereby significantly affecting capillary blood flow and destroying the transport of tumor blood vessels.
  • the blood function causes the tumor cells to lose their nutrient supply and starve to death.
  • the nanomaterials used in the present invention are rapidly deformed (rapidly expanding or exploding) when absorbed, and if they are located in normal blood vessels or organs, since the surface electronegativity of the nanomaterials repels them away from these blood vessels and organ surfaces, Normal blood vessels or biological organs have little damage; if nanomaterials pass through the interstitial cell space located in tumor blood vessels, when the absorbed radiant energy rapidly deforms (rapid expansion or explosion), it will seriously damage nearby endothelial cells and change the morphology of peripheral tumor vascular endothelial cells. And function, leading to cell apoptosis, exposure of the basement membrane, and finally the loss of nutrients in the tumor vascular damage, rapid starvation of tumor cells.
  • the nanomaterial used in the present invention treats a tumor by specifically blocking tumor blood vessels, causing a large number of tumor cells to starve or be damaged, and the tumor cells after death are absorbed by the body, which will stimulate the body's immune response and further produce an anti-tumor effect. .
  • the nanomaterial used in the invention treats the tumor by specifically blocking the tumor blood vessel, and the administration method is intravenous injection, the medicine directly functions in the blood, does not need to penetrate, and the dosage is small, the curative effect is high, and the medicine can be delivered to the living body.
  • the whole body therefore, can not only treat primary tumors, but also treat late tumors that have spread throughout the body. Since the above treatment method is purely physical damage to the tumor, there is no problem of drug resistance;
  • the nanomaterial used in the present invention treats tumor by specifically blocking tumor vasculature, rapidly damages tumor vascular endothelial cells, induces apoptosis of tumor vascular endothelial cells, exposes basement membrane, vascular damage, and then tumor cells die due to lack of nutrition, the whole The process takes place within 2-5 hours and thus has the effect of rapidly treating the tumor.
  • the tumor treatment method provided by the invention utilizes nano materials to block tumor blood vessels with high selectivity, has strong specificity, large power, direct and rapid, and is safe and efficient, and has little damage to normal tissues, and is a promising new type of tumor treatment. method.
  • the method for treating tumors has the following advantages: (1) has broad spectrum and is effective for any solid tumor; (2) water-soluble nanomaterial directly acts on tumor blood vessel wall (endothelial cells) through blood circulation
  • the drug delivery method is simple and the targeting effect is strong; (3)
  • the therapeutic effect has a magnifying effect. Since one vascular endothelial cell supports the growth of 50-100 tumor cells, the effect of inhibiting the tumor will be multiplied after destroying the tumor blood vessel; 4)
  • the side effects are small, only for tumor blood vessels with pores, and the blood vessels of normal tissues are not easily damaged due to different structures; (5) Physical destruction of tumor blood vessels, no drug resistance problem; (6) Tumor metastasis is also dependent on blood vessels.
  • the treatment is not limited to the location of the tumor. And depth, and also have a therapeutic effect on advanced tumors; (9) protection and activation of immunity; (10) stronger town Effect.
  • FIG. 1 is a schematic diagram of nanomaterial-specific destruction of tumor vascular endothelial cells, in which black particles refer to nanomaterials that satisfy the properties of the present invention, that is, can undergo deformation (rapid expansion or explosion); green particles refer to those that do not satisfy the present invention. Nanoparticles of the nature; the purple fraction refers to the action of the nanomaterials leading to apoptosis of tumor vascular endothelial cells.
  • Figure 2 is a transmission electron micrograph of water-soluble Au@SiO 2 nanoparticles.
  • Figure 3 shows that the water-soluble Au@SiO 2 solution rapidly generates a large number of bubbles under the action of 760 nm laser, indicating that some nanoparticles have exploded.
  • Figure 4 shows the treatment of tumors after 24 cycles of laser pulse using Au@SiO 2 nanoparticles. Effect chart.
  • Figure 5 is an environmental scanning electron micrograph of tumor blood vessels that have been pulsed with Au@SiO 2 nanoparticles and laser pulses (the yellow arrow in the figure is where the tumor is damaged). The best way to implement the invention
  • nanomaterials having all of the properties described in the present invention used in the following examples are water-soluble Au@ ⁇ -based SiO 2 nanoparticles, and the preparation method thereof is referred to the literature (J. Am. Chem. Soc. 2014, 136, 7317). ; Angew. Chem. Int. Ed. 2010, 49, 3777 )
  • Example 2 is a transmission photograph of the above water-soluble Au@SiO 2 nanoparticles, the size of the particles is about 80-100 nm, and the thickness of the hydroxylated SiO 2 coating layer is about 7 nm. Since the surface of the modified SiO 2 has a hydroxyl group, the surface of the Au@SiO 2 nanoparticle is electronegative, and the Zeta potential value is determined to be -34 ⁇ 0.4 eV.
  • Example 1 Au@SiO 2 aqueous solution produced bubbles under the action of laser
  • Au@SiO 2 aqueous solution (concentration 25 mg/mL) produced a large number of bubbles under the action of 760 nm laser pulse (average power 500 mW, 16 W/cm 2 ), indicating that the laser pulse was passed through the gold nanoparticles. Under the action, heat can be generated. Because the outer layer is covered with a layer of heat-insulating SiO 2 , it does not exchange energy with the outside world. When the internal heat accumulates to a certain extent, an explosion occurs. The laser-treated sample no longer explodes.
  • Example 2 Tumor treatment and effect verification of Au@SiO 2 nanomaterials under laser irradiation
  • mice inoculated with H22 hepatoma cell line were intraperitoneally, and the supernatant was counted by centrifugation, and a cell suspension having a cell concentration of 10 7 /mL was inoculated to the right thigh of each mouse. After 5-7 days of growth, the tumor size was about 5 mm.
  • An aqueous solution of Au@SiO 2 was injected through the tail vein (concentration 25 mg/mL, where Au concentration was 10 Mg/kg) 200 ⁇ L in tumor-bearing mice.
  • the 760 nm laser pulse was applied to the tumor site for 30 min, and the imaging of tumor tissue, kidney and liver at each time point was collected.
  • Fig. 4 is a photograph of a tumor after 24 hours of treatment using the method of the present invention. After treatment, the inside of the tumor is hollow, external scab, and most of the tumor tissue is digested by the body.
  • Figure 5 shows an environmental scanning electron micrograph of tumor blood vessels after radiofrequency exposure for 2 days after treatment with Au@SiO 2 . It can be observed that after exposure to Au@SiO 2 nanomaterials and laser pulses, tumor angiogenesis has a large range of endothelial cell necrosis. The exposed vascular basement membrane indicates that the explosion impact of the Au@SiO ⁇ ft rice material under the action of laser can quickly and effectively destroy the tumor blood vessels, and finally "starved" the tumor tissue to achieve efficient and rapid treatment.
  • the tumor treatment method provided by the invention utilizes nano materials to block tumor blood vessels with high selectivity, has strong specificity, large power, direct and rapid, and is safe and efficient, and has little damage to normal tissues, and is a promising new type of tumor treatment. method.

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Abstract

本发明公开了一种纳米材料的新用途。该新用途是其在制备肿瘤血管阻断剂中的应用，所述纳米材料具备下述所有性质：（1）表面为亲水性；（2）表面带有电负性；（3）纳米材料的尺寸介于50-250nm之间，且该材料具有刚性，使其不易通过肿瘤血管壁孔洞而被卡在所述孔洞；（4）能够吸收外界辐射能量并在内部转化成为热能，同时将所述热能蓄积，使得所述纳米材料的形态结构发生剧烈变化。治疗时，将上述纳米材料注射到荷瘤生物体内，再对肿瘤部位施加辐射，使纳米材料吸收辐射能量而内部温度迅速升高，当温度蓄积到一定程度，会使纳米材料的形态结构发生改变（爆炸或体积急剧膨胀），从而导致肿瘤血管内皮细胞的形态结构或功能的改变，破坏肿瘤血管。

Description

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 技术领域
本发明属于医药领域， 具体涉及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。
背景技术
近年来癌症的发病率和死亡率均呈上升趋势， 每年全球新增癌症患者 多达 1500万人， 严重地威胁着人类的健康。 传统的三大肿瘤治疗方法即外 科手术、 放疗和化疗都是以杀伤肿瘤细胞为主要目标。 然而， 随着癌症研 究的日益进展， 人们逐渐认识到， 肿瘤组织里不仅有肿瘤细胞， 还有丰富 的肿瘤新生血管， 肿瘤组织实际上是由肿瘤细胞和肿瘤新生血管形成的一 个完整生态系统。 一个肿瘤瘤体要想快速长大， 必须依赖肿瘤新生血管的 生成， 并且肿瘤血管是癌细胞的主要转移通道， 因此， 阻断或破坏肿瘤血 管， 一方面能切断肿瘤组织的营养供给， "饿死"肿瘤， 另一方面会最大程 度地阻断癌细胞的扩散和转移。
实体瘤与正常组织相比， 在解剖学和病理学上存在很大差异。 正常的 血管生长周期是一年， 一般由内膜、 中膜和外膜三层膜组成。 而肿瘤血管 的生长周期为 4天， 结构上只有一层薄薄的内膜， 并且由于内皮细胞间隙 较大、 结构不完整， 导致肿瘤血管包含有大量纳米尺寸的小孔， 血浆能够 透过而出。 此外， 肿瘤处血运丰富， 肿瘤血管还具有血流量多， 血压高的 特点， 是正常血管压力的 3倍。
基于正常血管和肿瘤血管差异， 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 ) 。 VDAs是通过选择性地破坏恶性肿瘤新生血管 从而实现治疗癌症目的的药物， 它靶向已生成的肿瘤血管， 通过快速改变 内皮细胞形状或损伤内皮细胞引起内皮细胞凋亡， 暴露基底膜， 显著影响 毛细血管血流量， 从而瓦解实体瘤内部的血管系统， 导致肿瘤局部缺血和 大范围坏死。 该类药物中研究最多的是小分子 VDAs , 现已有多种小分子 VDAs进入临床前期实验中。 但是， 大部分 VDAs类候选药被发现有比较 严重的副作用， 例如齐布司他、 CA- 1P和 MPC-6827等 Ι / Π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， 且与剂量呈相关性， 这些不良反应限制了其在临床上的广 泛使用。 发明公开
本发明的目的之一是提供一种纳米材料的新用途。
本发明所提供的纳米材料的新用途是其作为肿瘤血管阻断剂药物， 结 合与其相匹配的辐射源实现治疗肿瘤的目的。
本发明所述的纳米材料具备下述所有性质： （1 ) 表面为亲水性， 使 其能够经由静脉注入到生物体内并被运载至肿瘤血管； （2 ) 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， 避免对正常细胞和组织的伤害； （3 ) 纳米材料 的颗粒尺寸范围介于 50-250 nm 之间， 且该材料具有刚性 （即不易变 形） ， 使其在欲通过肿瘤血管壁孔隙时能够被卡住； （4 ) 所述纳米材料 能够吸收外界辐射能量并在内部转化成为热能， 同时将所述热能蓄积， 使 得所述纳米材料的形态结构发生剧烈变化， 从而导致肿瘤血管内皮细胞的 形态结构或功能的改变， 最终破坏肿瘤血管。
所述纳米材料的形态结构发生改变的可能途径如下： 对于具有单晶 / 多晶结构的纳米材料来说， 当蓄积的温度超过材料的相变温度点 （40- 150 °C ) ， 材料体积迅速地发生膨胀； 对于内部疏松并含有结合水的纳米 材料， 蓄积的温度超过 10CTC蒸发内部的水产生水蒸气， 当蒸气压累积到 一定程度超过材料的结合力发生微型爆炸； 或者材料骤热直接发生爆炸； 所述的可能途径均可以作用于肿瘤血管， 最终达到高效治疗肿瘤的效果。
本发明所述的纳米材料是由主体材料经过水溶性和电负性修饰得到 的。 所述主体材料是具有可以吸收外界辐射 （红外线、 可见光、 X 射线、 交变磁场， 射频等） 能量并蓄积热量的纳米材料， 可以是单质金属或非金 属材料， 也可以是复合材料， 典型的材料例如： 富勒烯纳米颗粒、 内嵌金 属富勒烯纳米颗粒、 贵金属纳米团簇 （包括金纳米团簇、 银纳米团簇、 铂 纳米团簇） 、 四氧化三铁纳米材料、 氧化锌纳米材料、 硫化锌纳米材料、 硒化镉纳米材料、 碲化镉纳米材料、 稀土氧化物纳米材料、 碳量子点、 碳 纳米角、 碳纳米管、 石墨烯等及其任意组合。
本发明所述的纳米材料具体可为 Au@S i02纳米颗粒 （即荷负电的 S i02 层包覆 Au纳米颗粒的复合纳米粒子， Zeta 电势 -34±0. 4 eV) 、 水溶性富 勒烯纳米颗粒、 水溶性金属富勒烯纳米颗粒、 表面包覆亲水层的 Fe304纳米 颗粒等。
本发明所述外界辐射的能量源包括射频 （又称为无线电波） 、 微波、 红外光、 可见光、 激光、 X 射线和交变磁场等及其任意组合。 能量形式尽 可能为超短时间脉冲辐射， 例如激光脉冲、 电磁脉冲 （包括射频脉冲） 等， 以利于纳米材料快速吸收辐射能量而使温度迅速上升， 然后在未及时 通过热交换等方式散失能量前迅速发生形变 （膨胀或爆炸） ， 从而释放能 量。 脉冲能量源同时可降低外界辐射对生物体的损伤。
本发明所使用的纳米材料需具备水溶性， 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 常可对上述主体材料进行水溶性修饰， 使其更具生物相容性。 例如在主体 材料表面修饰一种或多种亲水性化学基团， 如： 羟基、 氨基、 巯基、 羧基 等及其任意组合； 还可以在主体材料表面包裹一层亲水性无机物如二氧化 硅、 或直接用亲水性生物小分子如氨基酸、 肽链等包裹主体材料， 还可以 借助具有生物相容性的载体材料负载主体材料， 如脂质体、 细胞膜等作为 载体， 亦可以通过自组装形成水溶性超分子体系等形式。 上述修饰方法均 可按照现有技术公开的方法进行修饰。
本发明所使用的纳米材料应带有一定的电负性， 电负性修饰方法包括 直接在主体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， 这样在纳米材料发生形变 （膨 胀或爆炸） 时可降低对正常细胞或生物组织的损伤。
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 现对主体材料的水溶化修饰和负电修饰。
本发明所使用的纳米材料的尺寸分布一般应该在 50-250 nm 范围内， 并且该材料需要具有一定的刚性 （不易变形） ， 使其不能穿过肿瘤血管内 皮细胞间的纳米孔隙， 且又能够利用肿瘤血管内外压力差紧紧地贴合在血 管壁的孔隙部位， 以利于纳米材料迅速发生形变 （膨胀或爆炸） 时更有效 地损伤肿瘤血管内皮细胞。
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纳米材料和提供与其相匹配的辐射能 量源的装置组成。
药物套装可具体为金纳米团簇 +脉冲激光； 富勒烯纳米颗粒 +脉冲激 光； 金属富勒烯纳米团簇 +射频； 四氧化三铁纳米颗粒 +交变磁场等。
关于上述能量源， 本领域技术人员可以根据现有技术的教导， 依据形 成所述纳米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。
本发明的目的之三是提供一种基于上述纳米材料能特异性阻断肿瘤血 管的肿瘤治疗方法。
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给予有效剂量的纳米材料；
2 ) 用与所述纳米材料相匹配的辐射能量源对所述生物体的肿瘤部位 进行辐照。
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纳 米材料时， 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。
本发明所述的辐照为静脉注射纳米材料 0-1 h 后辐照一段时间， 例如 10 min-1 h。
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。
本发明所使用的纳米材料通过特异性地阻断肿瘤血管治疗肿瘤， 是利 用肿瘤组织内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。
本发明所采用的纳米材料为尺寸在 50-250 纳米之间的特定纳米粒 子， 能够在吸收外界特定波长的辐射能量 （红外线、 可见光、 X 射线、 交 变磁场， 射频等） 后发生形变 （膨胀或爆炸） 。 使用时将纳米材料静脉注 射到荷瘤生物体内， 经血液输运至肿瘤。 由于肿瘤血管壁细胞之间存在着 大量的纳米孔隙， 尺寸较小的纳米材料将通过这些空隙进入肿瘤体内， 但 尺寸合适并具有一定刚性的纳米材料 （即具有本发明所述性质的纳米材 料） 被这些纳米孔卡住， 并因血管内外压差而使其长时间滞留于这些肿瘤 血管细胞间隙处。 这时再对肿瘤附近施加合适波长的辐射， 使纳米材料吸 收辐射能量而内部温度迅速升高， 当温度蓄积到一定程度， 使得所述纳米 材料的形态和 /或结构发生改变 （如发生爆炸或体积急剧膨胀） 。 由于纳 米材料被血管内外血压差作用密切接触肿瘤血管孔隙， 其所发生的迅速形 变导致周围肿瘤血管内皮细胞受损凋亡， 暴露基底膜， 从而显著影响毛细 血管血流量， 破坏肿瘤血管的输运血液功能， 使肿瘤细胞失去营养供给而 被饿死。
本发明所使用的纳米材料在吸收辐射能量发生迅速形变 （快速膨胀或 爆炸） 时， 如果位于正常血管或器官， 由于纳米材料表面电负性与它们相 斥而远离这些血管与器官表面， 所以对正常血管或生物器官损伤很小； 而 如果纳米材料通过位于肿瘤血管的内皮细胞间隙， 当吸收辐射能量发生迅 速形变 （快速膨胀或爆炸） 时会重伤附近的内皮细胞， 改变周围肿瘤血管 内皮细胞形态及功能， 导致细胞调亡， 暴露基膜， 最后产生肿瘤血管破损 营养物质流失， 快速饿死肿瘤细胞。
本发明所使用的纳米材料通过特异性地阻断肿瘤血管来治疗肿瘤， 导 致大量肿瘤细胞饿死或受损， 死亡后的肿瘤细胞被机体吸收， 会激发机体 的免疫反应， 进一步产生抗肿瘤效应。
本发明所使用的纳米材料通过特异性地阻断肿瘤血管治疗肿瘤， 给药 方式为静脉注射， 药物直接在血液中发挥作用， 无需渗透， 所用的药剂量 小， 疗效高， 能够送达生物体全身， 因此， 不但能够治疗原发肿瘤， 还可 治疗已在全身扩散的后期肿瘤。 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；
本发明所使用的纳米材料通过特异性地阻断肿瘤血管治疗肿瘤， 通过 迅速损伤肿瘤血管内皮细胞， 引发肿瘤血管内皮细胞凋亡， 暴露基膜， 血 管损坏， 继而肿瘤细胞因缺乏营养死亡， 整个过程发生在 2-5 个小时内， 因而具有快速治疗肿瘤的效果。
本发明提供的肿瘤治疗方法利用纳米材料高选择性地阻断肿瘤血管， 特异性强， 威力大， 直接快速， 并且安全高效， 对正常组织伤害性小， 是 一种非常具有前景的新型肿瘤治疗方法。
综上， 本发明提供的肿瘤治疗方法具有以下优点： （1 ) 具有广谱 性， 对任何实体肿瘤都有效； （2 ) 水溶化的纳米材料经血液循环直接作 用于肿瘤血管壁（内皮细胞），给药方式简单、 靶向作用强； （3 ) 治疗效果 具有放大效应， 由于一个血管内皮细胞支持 50-100 个肿瘤细胞生长， 所 以破坏肿瘤血管后， 抑制肿瘤的效果会成倍放大； （4 ) 副作用小， 只针 对具有孔隙的肿瘤血管， 而正常组织的血管由于结构不同， 不易受到损 害； （5 ) 物理破坏肿瘤血管， 没有耐药性问题； （6 ) 肿瘤转移也依赖于 血管， 故能抑制肿瘤转移与扩散； （7 ) 作用时间短， 一旦肿瘤血管出血 或阻塞阻断营养供给， 肿瘤细胞缺血发生坏死的时间不超过 2 h; (8 ) 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； （9 ) 保护和激活免疫； （10) 较强的镇痛效果。 附图说明
图 1 为纳米材料特异性破坏肿瘤血管内皮细胞示意图， 图中黑色颗粒 指代满足于本发明所述性质即可以发生形变 （快速膨胀或爆炸） 的纳米材 料； 绿色颗粒指代未满足本发明所述性质的纳米颗粒； 紫色部分指代纳米 材料发生作用后导致肿瘤血管内皮细胞凋亡。
图 2为水溶性 Au@SiO2纳米颗粒的透射电镜照片。
图 3 为水溶性 Au@SiO2溶液在 760 nm激光作用下迅速产生大量气 泡， 表明一些纳米颗粒发生了爆炸。
图 4为使用 Au@SiO2纳米颗粒进行激光脉冲作用后的肿瘤治疗 24后 效果图。
图 5为经过 Au@SiO2纳米颗粒和激光脉冲的肿瘤血管的环境扫描电镜 照片 （图中黄色箭头为肿瘤血管受损处） 。 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。
下述实施例中使用的具备本发明全部所述性质的纳米材料为水溶性 Au@^ 基化的 SiO2纳米颗粒， 其制备方法参照文献 （J. Am. Chem. Soc. 2014, 136, 7317; Angew. Chem. Int. Ed. 2010, 49, 3777 )
图 2为上述水溶性 Au@SiO2纳米颗粒的透射照片， 颗粒的尺寸约为 80- 100 nm左右， 羟基化的 SiO2包覆层的厚度为 7 nm左右。 由于所修饰的 SiO2表面带有羟基集团， 故该 Au@SiO2纳米颗粒表面具有电负性， Zeta 电势值测定为 -34±0.4 eV。 实施例 1 : Au@SiO2水溶液在激光作用下产生气泡实验
如图 3所示， Au@SiO2水溶液 （浓度 25 mg/mL ) 在 760 nm激光脉冲 (平均功率 500 mW, 16 W/cm2) 作用下产生大量的气泡， 说明通过金纳米 颗粒在激光脉冲作用下可以产生热量， 由于外部包裹一层隔热的 SiO2层， 不与外界进行快速能量交换， 当内部热量积聚到一定程度， 产生爆炸。 而 经过激光处理后的样品不再产生爆炸作用。 实施例 2: Au@SiO2纳米材料在激光作用下肿瘤治疗及效果验证
1、 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 50 于每只小鼠右侧大腿皮下。 待生长 5-7天后， 肿瘤大小在 5 mm左右进行实验。
2、 动物实验活体磁共振成像及肿瘤治疗实验：
通过尾静脉注射 Au@SiO2水溶液 （浓度 25 mg/mL , 其中 Au浓度 10 mg/kg ) 200 μL于荷瘤鼠体内。 对肿瘤部位施加 760 nm激光脉冲 30 min， 分别采集各个时间点肿瘤组织、 肾脏和肝脏的成像情况。
图 4为使用本发明方法治疗 24 h后肿瘤的照片， 经治疗后肿瘤内部中 空， 外部结痂， 大部分的肿瘤组织被机体消解。
图 5显示经过 Au@SiO2处理 2天后的肿瘤在射频作用后肿瘤血管的环 境扫描电镜照片， 可以观察到经过 Au@SiO2纳米材料和激光脉冲作用后， 肿瘤血管发生大范围内皮细胞坏死脱落， 露出血管基膜， 说明 Au@SiO^ft 米材料在激光作用下的爆炸冲击力可以快速有效地摧毁肿瘤血管， 最终"饿 死"肿瘤组织， 达到高效快速治疗的作用。 工业应用
本发明提供的肿瘤治疗方法利用纳米材料高选择性地阻断肿瘤血管， 特异性强， 威力大， 直接快速， 并且安全高效， 对正常组织伤害性小， 是 一种非常具有前景的新型肿瘤治疗方法。

Claims

权利要求
1、 一种纳米材料在制备肿瘤血管阻断剂中的应用；
所述的纳米材料具备下述所有性质： （1 ) 表面为亲水性， 使其能够 经由静脉注入到生物体内并被运载至肿瘤血管； （2 ) 表面具有电负性， 使其与正常细胞及正常组织的血管内壁产生排斥性； （3 ) 纳米材料的颗 粒尺寸范围介于 50-250 nm之间， 且该材料具有刚性， 使其在通过肿瘤血 管内壁孔隙时而被卡住， 被由于肿瘤血管内外压力差而长期滞留该处；
( 4 ) 所述纳米材料能够吸收外界辐射能量并在内部转化成为热能， 同时 将所述热能蓄积， 使得所述纳米材料的形态结构发生剧烈变化， 从而导致 肿瘤血管内皮细胞的形态结构或功能的改变。
2、 根据权利要求 1所述的应用， 其特征在于： 所述纳米材料由下述至 少一种材料经过水溶性和电负性修饰得到： 富勒烯纳米颗粒、 内嵌金属富 勒烯纳米颗粒、 贵金属纳米团簇、 四氧化三铁纳米材料、 氧化锌纳米材 料、 硫化锌纳米材料、 硒化镉纳米材料、 碲化镉纳米材料、 稀土氧化物纳 米材料、 碳量子点、 碳纳米角、 碳纳米管和石墨烯。
3、 根据权利要求 1或 2所述的应用， 其特征在于： 提供所述外界辐射 能量的能量源选自下述至少一种： 射频、 微波、 红外光、 可见光、 激光、 X射线和交变磁场。
4、 根据权利要求 1-3中任一项所述的应用， 其特征在于： 所述外界辐 射能量的能量形式为超短时间脉冲辐射， 其能量源优选： 激光脉冲、 电磁 脉冲。
5、 根据权利要求 1-4中任一项所述的应用， 其特征在于： 所述纳米材 料为荷负电的 SiO2层包覆 Au纳米颗粒形成的复合纳米粒子即 Au@SiO^ft 米颗粒、 水溶性富勒烯纳米颗粒、 水溶性金属富勒烯纳米颗粒或表面包覆 亲水层的 Fe3O4纳米颗粒。
6、 一种用于治疗肿瘤的药物套装， 由权利要求 1-5中任一项所述的纳 米材料和提供与所述纳米材料相匹配的辐射能量源的装置组成。
7、 根据权利要求 6所述的药物套装， 其特征在于： 所述纳米材料为 Au@SiO2纳米颗粒， 与其相匹配的辐射能量源为脉冲激光； 所述纳米材料 为水溶性富勒烯纳米颗粒， 与其相匹配的辐射能量源为脉冲激光； 所述纳 米材料为水溶性金属富勒烯纳米团簇， 与其相匹配的辐射能量为射频； 所 述纳米材料为表面包覆亲水层的 Fe3O4纳米颗粒， 与其相匹配的辐射源为 交变磁场。
8、 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 1-5中任一 项所述的纳米材料；
2 ) 用与所述纳米材料相匹配的辐射能量源对所述生物体的肿瘤部位 进行辐照。
9、 根据权利要求 8所述的方法， 其特征在于： 所述的生物体是指包括 人在内的哺乳动物； 所述注射的方式为静脉注射；
所述的辐照为静脉注射纳米材料 0- 1 h后辐照一段时间， 例如 10 min-
1 h。
10、 根据权利要求 1-5 中任一项所述的应用、 权利要求 6-7所述的药 物套装、 权利要求 8-9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/CN2014/000722 2014-07-29 2014-07-29 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 Ceased WO2016015172A1 (zh)

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