WO2017157063A1 - 一种用于治疗癌症的复合纳米载药材料及其制备方法 - Google Patents
一种用于治疗癌症的复合纳米载药材料及其制备方法 Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
Definitions
- the invention relates to the field of medicine, in particular to a composite nano drug-loading material for treating cancer and a preparation method thereof.
- Cancer is the number one killer of human health. Chemotherapy drugs can effectively control and kill cancer cells in human tissues, which is an important cancer treatment.
- the 5-year survival rate of patients with early cancer after regular treatment is 70% to 95%, and the 5-year survival rate after regular treatment for advanced patients is only 10% to 30%.
- observing the therapeutic effect requires the absorption of the imaging agent by the human body and then using the corresponding imaging device for examination, which also has the problem of imaging agent targeting, and the problem that the drug effect cannot be tracked in time.
- the present invention aims to provide a composite nano drug-loading material for treating cancer and a preparation method thereof, aiming at solving the poor targeting of existing drug-loading materials, and having a large side effect on normal cells. Keep track of the effects of medications in a timely manner.
- a composite nano drug-loading material for treating cancer wherein the composite nano drug-loading material takes UCNPs as a core,
- the surface of the core is covered with a porous material, an anticancer drug is loaded in the pores, a basic manganese compound is deposited on the surface of the porous material, and one or more capture molecules or recognition molecules are labeled on the surface of the alkaline manganese compound.
- the composite nano drug-loading material for treating cancer wherein the porous material is one of a porous silicon material, a mesoporous silica material, a mesoporous titanium oxide, and a mesoporous carbon material.
- the composite nano drug-loading material for treating cancer wherein the basic manganese compound is MnO 2 , Mn(OH ) 2 or MnCO 3 .
- the composite nano drug-loading material for treating cancer wherein the anticancer drug is a broad-spectrum anticancer drug.
- the composite nano drug-loading material for treating cancer wherein the capture molecule or recognition molecule is one or more of an antigen, an antibody, and a specific protein.
- a method for preparing a composite nano drug-loading material for treating cancer comprises the steps of:
- UCNPs As the core, the surface of the core is covered with a porous material to obtain p-UCNPs covering the porous material;
- the p-UCNPs are immersed in the anticancer drug solution, soaked and adsorbed for 1 to 96 hours, and dried to obtain mp-UCNPs loaded with anticancer drugs;
- the method for preparing a composite nano drug-loading material for treating cancer wherein when the porous material is a porous silicon material, the step B specifically comprises: baking the water glass in a crucible at 120-500 ° C. -24h, a solid powder is obtained; the solid powder is washed with water, dried and placed in 0 In .03mol/L CTAB solution, stir in a water bath of 30-80 ° C, add UCNPs particles, stir for 1-8h, cool to room temperature, add 0 .1-6 mol/L HCl, the pH of the solution was adjusted to 6-9; filtered, washed, dried, and the obtained sample was incubated at 300-600 ° C for 1-8 h to obtain p-UCNPs covering the porous silicon material.
- the step D specifically comprises: removing 250 ⁇ L of mp-UCNPs loaded with anticancer drugs.
- the step D specifically comprises: removing 250 ⁇ L of mp-UCNPs loaded with anticancer drugs.
- the step D specifically comprises: removing 1 mL of mp-UCNPs loaded with anticancer drugs.
- the step D specifically comprises: removing 1 mL of mp-UCNPs loaded with anticancer drugs.
- Into a 5 mL centrifuge tube add 500 ⁇ L of 0.1 mol/L MnCl 2 solution, then add 1 mL of 0.1 mol/L Na 2 CO 3 solution dropwise under stirring. After 30 minutes, centrifuge and separate with deionized water. The supernatant was removed to obtain mmp-UCNPs in which MnCO 3 was the outer shell.
- the composite nano drug-loading material of the present invention After the composite nano drug-loading material of the present invention is injected into the body, it can bind to cancer cells and be swallowed by cancer cells under the action of immobilized capture molecules or recognition molecules on the surface. After entering the cancer cells, the alkaline manganese compound is decomposed by the acid due to the acidity in the cancer cells, and the anticancer drug enclosed in the porous material is released to kill the cancer cells.
- the free manganese ion is a nuclear magnetic resonance imaging agent, and the tumor tissue can be located by magnetic resonance imaging in time; the UCNPs covering the porous material can be up-converted to illuminate the tumor tissue by infrared laser irradiation. Among them, the up-conversion luminescence technology can avoid the background fluorescence of biological tissues and has high sensitivity.
- the present invention provides a composite nano drug-loading material for treating cancer and a preparation method thereof.
- a composite nano drug-loading material for treating cancer and a preparation method thereof.
- the invention provides a composite nano drug-loading material for treating cancer and a preparation method thereof, wherein the composite nano drug-loading material adopts UCNPs as a core, a nuclear surface is covered with a porous material, an anti-cancer drug is loaded in the pore, and the porous A basic manganese compound is deposited on the surface of the material, and the alkaline manganese compound is surface-labeled with one or more capture molecules or recognition molecules.
- the invention adopts rare earth upconversion nano materials (UCNPs) as a core, a surface covered with a porous material, an anticancer drug (such as doxorubicin) loaded in the pores, and then a basic manganese compound (such as dioxide dioxide) is deposited on the surface of the porous material.
- UCNPs rare earth upconversion nano materials
- an anticancer drug such as doxorubicin
- a basic manganese compound such as dioxide dioxide
- Manganese, manganese hydroxide or manganese carbonate to block anticancer drugs.
- the alkaline manganese compound is surface-labeled with one or more capture molecules or recognition molecules (such as antigens, antibodies or specific proteins), which can specifically recognize lung cancer, liver cancer, gastric cancer, esophageal cancer, rectal cancer, colon cancer, breast cancer.
- One or more kinds of cancer cells such as pancreatic cancer, bone cancer, prostate cancer, bladder cancer, and skin cancer.
- the composite nano drug-loading material of the invention can bind to the cancer cells and be swallowed by the cancer cells under the action of specific antigens, antibodies or specific proteins immobilized on the surface.
- the alkaline manganese compound dissolves due to the acidic environment in the cancer cell, and the anticancer drug enclosed in the porous material is released to kill the cancer cell.
- the specificity of a specific antigen, antibody or specific protein is not 100%, a small amount of nano drug-loaded particles will always enter normal cells, causing human damage.
- the composite nano drug-loading material of the invention has weak acidity in normal cells, and the alkaline manganese compound is difficult to dissolve, so the anticancer drug is not released or released slowly, and the damage of the drug to normal cells is greatly reduced (the side effect is small).
- the free manganese ion is a nuclear magnetic resonance imaging agent, and the tumor tissue can be located by magnetic resonance imaging.
- UCNPs covering porous materials can be imaged by up-conversion luminescence by infrared laser irradiation. Among them, the up-conversion luminescence technology can avoid the background fluorescence of biological tissues and has high sensitivity.
- the composite nano drug-loading material of the invention can also leave a nuclear magnetic resonance imaging agent and an up-converting fluorescent imaging agent in the apoptotic cancer cells while carrying the drug to kill the cancer cells, so as to conveniently track the drug treatment effect in time.
- the composite nano drug-loading material of the invention combines two modes of specific recognition and chemical recognition to identify tumor cells, has high targeting, greatly reduces the toxic effect of anticancer drugs on normal cells, thereby reducing the toxic side effects of chemotherapy to lowest.
- the tumor cells after the action of the drug, the tumor cells also have a magnetic resonance imaging agent and an infrared up-converting fluorescent imaging agent, which facilitates tracking and observation of the therapeutic effect, and timely adjusts or maintains the treatment plan.
- the composite nano drug-loading material of the invention can recognize and kill a variety of common tumor cells (lung cancer, liver cancer, stomach cancer, esophageal cancer, rectal cancer, colon cancer, breast cancer, pancreatic cancer, bone cancer, prostate cancer, bladder cancer, Skin cancer, etc.), and can reduce the toxicity to normal cells, good targeting, and both up-conversion fluorescence recognition function and nuclear magnetic imaging function, easy to fully track the drug effect. Can be suitable for killing early, middle and late cancer cells.
- the rare earth upconverting nano material has a particle diameter of 20 to 60 nm. That is, in the present invention, UCNPs having a particle diameter of 20 to 60 nm are preferred as a core to enhance the recognition function of UCNPs.
- the porous material is one of a porous silicon material, a mesoporous silica material, mesoporous titania, mesoporous carbon and the like. That is, the UCNPs are preferably coated with a porous silicon material, a mesoporous silica material, a mesoporous titania or a mesoporous carbon material to better support the anticancer drug.
- the anticancer drug is a broad-spectrum anticancer drug
- the broad-spectrum anticancer drug may be doxorubicin, etoposide, cyclophosphamide and fluorouracil, topotecan, paclitaxel, oxali
- the above anticancer drugs are effective in killing cancer cells.
- the basic manganese compound is MnO 2 , Mn( OH ) 2 or MnCO 3 . Due to the acidic environment of the cancer cells, the above-mentioned basic manganese compound of the present invention can be dissolved by the cancer cells after entering the cancer cells, so that the anticancer drug enclosed in the porous material is released and kills the cancer cells. However, the acidity in normal cells is weak, and the above-mentioned basic manganese compound is difficult to dissolve, so that the anticancer drug is not released or released slowly, and the damage of the anticancer drug to normal cells is greatly reduced.
- the capture molecule or recognition molecule is one or more of an antigen, an antibody, and a specific protein.
- the specific antigen, antibody or specific protein of the invention can specifically recognize lung cancer, liver cancer, gastric cancer, esophageal cancer, rectal cancer, colon cancer, breast cancer, pancreatic cancer, bone cancer, prostate cancer, bladder cancer, skin cancer and the like. Or a variety of cancer cells, and can be swallowed by cancer cells.
- the present invention further provides a method for preparing a composite nano drug-loading material for treating cancer according to any one of the above, wherein the method comprises the steps of:
- UCNPs As the core, the surface of the core is covered with a porous material, and p-UCNPs covering the porous material are obtained, which are recorded as p-UCNPs;
- P-UCNPs are immersed in anticancer drug solution, soaked and adsorbed for 1 ⁇ 96h, and dried to obtain p-UCNPs loaded with anticancer drugs, which are recorded as mp-UCNPs;
- the composite nano drug-loading material prepared by the above method can also leave a nuclear magnetic resonance imaging agent and an up-converting fluorescent imaging agent in the apoptotic cancer cells while carrying the drug to kill the cancer cells, so as to conveniently track the drug treatment effect in time. .
- the composite nano drug-loading material of the invention enters the normal cells even if a small amount of the label is unsuccessful, and the basic manganese compound is difficult to decompose due to the weak acidity in the normal cells, so the anticancer drug is not released or released slowly, and the drug is greatly reduced. Damage to normal cells reduces the side effects of chemotherapy. Since the basic manganese compound does not decompose, or the decomposition is very slow, it does not provide sufficient MRI contrast agent Mn 2+ , and does not release the fluorescent up-conversion core material, so even if the nanocomposite drug substance is recognized incorrectly and enters normal cells, It is not recognized as a tumor cell during MRI imaging and up-conversion fluorescence imaging, greatly reducing the risk of over-treatment.
- the composite nano drug-loading material of the invention combines two modes of specific recognition and chemical recognition to identify tumor cells, has high targeting, greatly reduces the toxic effect of anticancer drugs on normal cells, thereby reducing the toxic side effects of chemotherapy to lowest.
- the tumor cells after the action of the drug, the tumor cells also have a magnetic resonance imaging agent and an infrared up-converting fluorescent imaging agent, which facilitates tracking and observation of the therapeutic effect, and timely adjusts or maintains the treatment plan.
- the step A is to prepare rare earth upconverting nano materials (UCNPs) by hydrothermal method, and preferably, the rare earth upconversion nano materials (UCNPs) having a particle diameter of 20-60 nm are prepared by a hydrothermal method.
- UCNPs rare earth upconverting nano materials
- a detailed preparation method of the rare earth upconversion nanomaterial has been described in the prior art and will not be described herein.
- the porous material of the present invention may be, but not limited to, one of a porous silicon material, a mesoporous silica material, mesoporous titania (TiO 2 ), mesoporous carbon and the like.
- the step B specifically comprises: baking the water glass in a crucible at 120-500 ° C for 1-24 h to obtain a solid powder; washing the solid powder with water, drying After being placed in a 0.03 mol/L CTAB solution, stirring in a water bath at 30-80 ° C, adding UCNPs particles, stirring for 1-8 h, cooling to room temperature, adding 0.1-mol/L HCl dropwise. The pH of the solution was adjusted to 6-9; filtered, washed, and dried to obtain a sample which was incubated at 300-600 ° C for 1-8 h to obtain p-UCNPs covering the porous silicon material.
- the step B may specifically include: dissolving the polyethylene oxide ether polymer surfactant with N,N-dimethylformamide (DMF) And a mixed solution of HCl aqueous solution, then add UCNPs particles, and add a certain amount of tetraethyl orthosilicate (TEOS) under stirring After stirring the reaction at 1-90 ° C for 1-48 h, it was centrifuged and dried to obtain a white solid product which was p-UCNPs covering the porous silicon material.
- DMF N,N-dimethylformamide
- TEOS tetraethyl orthosilicate
- the step B specifically includes: adding a UCNPs particle by using a surfactant in the presence of a glycol or a polyhydric alcohol such as glycerol or butanediol, and stirring. Under the conditions, a sodium silicate solution was added to synthesize p-UCNPs covering the mesoporous silica material.
- the step B specifically includes: adding UCNPs particles in the completely dissolved sodium silicate and cationic surfactant solution, and synthesizing the mesoporous silica under stirring The p-UCNPs of the material.
- the step B specifically includes: n-butyl titanate as a precursor, isopropanol, ethylene glycol or glycerol or butanediol as a solvent. , cetyltrimethylammonium bromide (CTAB) or sodium hexadecylsulfonate or polyepoxyethylene ether, polyepoxypropylene ether as a template, synthesis of mesoporous TiO 2 by sol-gel process p-UCNPs.
- CTAB cetyltrimethylammonium bromide
- the p-UCNPs covering the porous material are immersed in the anticancer drug solution, soaked and adsorbed for 1 to 96 hours, and dried to obtain mp-UCNPs loaded with the anticancer drug.
- Step D the alkaline manganese compound as MnO 2, Mn (OH) 2 or MnCO 3.
- the step D specifically includes: removing 250 ⁇ L of mp-UCNPs (concentration of 1 mg/mL) loaded with anticancer drugs into a 2 mL centrifuge tube.
- the mmp-UCNPs in which Mn(OH) 2 is the outer shell are obtained.
- the step D specifically includes: removing 1 mL of mp-UCNPs (concentration of 2 mg/mL) loaded with anticancer drugs into a 5 mL centrifuge tube, and then Add 500 ⁇ L 0.1mol / L MnCl 2 solution, followed by the dropwise added under stirring 1mL 0 .1 mol / L Na 2 CO 3 solution, after centrifuged 30min, rinsed with deionized water, the supernatant was removed, to obtain MnCO 3 is the mmp-UCNPs of the outer shell.
- mp-UCNPs concentration of 2 mg/mL
- a capture molecule or a recognition molecule is labeled on the surface of the basic manganese compound of mmp-UCNPs to obtain a composite nano drug-loading material. That is, the specific antigen, antibody or specific protein is labeled on the surface of the basic manganese compound to specifically recognize and kill a variety of common tumor cells (lung cancer, liver cancer, stomach cancer, esophageal cancer, rectal cancer, colon cancer, breast cancer, pancreas Cancer, bone cancer, prostate cancer, bladder cancer, skin cancer, etc.).
- the common antigen-antibody recognition technology is utilized, and the characteristics of the basic manganese compound can be dissolved by the tumor cells, and only the alkaline manganese compound is dissolved, and the anticancer drug can be released to function.
- the alkaline manganese compound is hardly dissolved, and the anticancer drug is not released or released slowly, which can greatly reduce the damage of the drug to normal cells, and the side effect is small.
- the present invention provides a composite nano drug-loading material for treating cancer, and a preparation method thereof, wherein the composite nano drug-loading material has UCNPs as a core, and the surface of the core is covered with a porous material, and the pores are covered.
- Loaded with an anticancer drug a layer of basic manganese compound is deposited on the surface of the porous material, and the alkaline manganese compound is surface-labeled with one or more capture molecules or recognition molecules.
- the invention utilizes the common antigen-antibody recognition technology, and then utilizes the characteristics that the tumor cells can dissolve the basic manganese compound, and only after the alkaline manganese compound is dissolved, the anticancer drug can be released to function.
- the invention combines the up-conversion luminescence fluorescence imaging technology and the nuclear magnetic resonance technology to realize the dual-function imaging mode of the tumor tissue, improve the recognition accuracy of the tumor tissue, and accurately observe the treatment effect at any time.
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Abstract
一种用于治疗癌症的复合纳米载药材料及其制备方法，其中，所述复合纳米载药材料以UCNPs为核，核表面覆盖一层多孔材料，孔内负载抗癌药物，多孔材料表面沉积一层碱性锰化合物，碱性锰化合物表面标记一种或多种捕获分子或识别分子。
Description
本发明涉及医药领域，尤其涉及一种用于治疗癌症的复合纳米载药材料及其制备方法。
癌症是威胁人类健康的第一杀手。化疗药物可以高效率的控制和杀灭人体组织内的癌细胞，是一种重要的癌症治疗手段。
然而，现有化疗药物由于靶向性较差，不可避免的对正常细胞造成伤害，导致病人身体抵抗力严重下降，从而降低了病人的生存率。据统计，早期癌症病人正规治疗后5年生存率为70%〜95%，晚期病人正规治疗后的5年生存率只有10%〜30%。同时，观察治疗效果需要通过人体吸收成像剂后再采用相应的成像设备进行检查，这也存在成像剂靶向性问题，以及无法及时追踪用药效果等问题。
因此，现有技术还有待于改进和发展。
鉴于上述现有技术的不足，本发明的目的在于提供一种用于治疗癌症的复合纳米载药材料及其制备方法，旨在解决现有载药材料靶向性差、对正常细胞副作用大及无法及时追踪用药效果的问题。
本发明的技术方案如下：
一种用于治疗癌症的复合纳米载药材料，其中，所述复合纳米载药材料以UCNPs为核，
核表面覆盖一层多孔材料，孔内负载抗癌药物，多孔材料表面沉积一层碱性锰化合物，碱性锰化合物表面标记一种或多种捕获分子或识别分子。
所述的用于治疗癌症的复合纳米载药材料，其中，所述多孔材料为多孔硅材料、介孔氧化硅材料、介孔二氧化钛、介孔碳材料中的一种。
所述的用于治疗癌症的复合纳米载药材料，其中，所述碱性锰化合物为MnO2、Mn(OH
)2或MnCO3。
所述的治疗癌症的复合纳米载药材料，其中，所述抗癌药物为广谱抗癌药物。
所述的用于治疗癌症的复合纳米载药材料，其中，所述捕获分子或识别分子为抗原、抗体和特异性蛋白中的一种或多种。
一种如上任一所述的用于治疗癌症的复合纳米载药材料的制备方法，其中，包括步骤：
A、采用水热法制备UCNPs；
B、以UCNPs为核，核表面覆盖一层多孔材料，得到覆盖多孔材料的p-UCNPs；
C、将p-UCNPs浸入抗癌药物溶液，浸泡吸附1~96h，干燥，得到负载抗癌药物的mp-UCNPs；
D、在mp-UCNPs表面沉积一层碱性锰化合物，得到碱性锰化合物为外壳的mmp-UCNPs；
E、在mmp-UCNPs的碱性锰化合物表面标记捕获分子或识别分子，得到复合纳米载药材料。
所述的用于治疗癌症的复合纳米载药材料的制备方法，其中，所述多孔材料为多孔硅材料时，所述步骤B具体包括：将水玻璃在坩锅中于120-500℃焙烧1-24h，得到固体粉末；将所述固体粉末水洗，烘干后放到0
.03mol/L的CTAB 溶液中，在30-80℃的水浴中搅拌，同时加入UCNPs粒子，搅拌1-8h，冷却至室温，滴加0
.1-6mol/L的HCl，将溶液的pH值调至6-9；过滤，洗涤，干燥，得到的样品在300-600℃保温1-8h，即得到覆盖多孔硅材料的p-UCNPs。
所述的用于治疗癌症的复合纳米载药材料的制备方法，其中，所述碱性锰化合物为MnO2时，所述步骤D具体包括：将负载抗癌药物的mp-UCNPs移取250μL加到2mL的离心管中，再加入250μL
0 .1mol/L pH=6的2-（N-吗啉代）乙磺酸缓冲溶液，加入250μL 10 mmol/L
KMnO4进行混合；溶液30min后变成布朗胶体，经过离心分离用去离子水清洗，除去上清液，即得到MnO2为外壳的mmp-UCNPs。
所述的用于治疗癌症的复合纳米载药材料的制备方法，其中，所述碱性锰化合物为Mn( OH
)2时，所述步骤D具体包括：将负载抗癌药物的mp-UCNPs移取 250 μL加到2mL的离心管中，再加入250μL 0 .1mol/L
pH=8 .0的磷酸盐缓冲溶液，加入250μL 10mmol/L
KMnO4进行混合；30min后经过离心分离，用去离子水清洗，除去上清液，即得到Mn( OH
)2为外壳的mmp-UCNPs。
所述的用于治疗癌症的复合纳米载药材料的制备方法，其中，所述碱性锰化合物为MnCO3时，所述步骤D具体包括：将负载抗癌药物的mp-UCNPs移取1mL加到5mL的离心管中，再加入500μL
0 .1mol/L MnCl2溶液，然后在搅拌条件下逐滴加入1mL 0 .1mol/L
Na2CO3溶液，30min后经过离心分离，用去离子水清洗，除去上清液，即得到MnCO3为外壳的mmp-UCNPs。
有益效果：本发明的复合纳米载药材料注入体内后，在其表面固定的捕获分子或识别分子作用下，可以与癌细胞结合并被癌细胞吞噬。进入癌细胞后，由于癌细胞内的酸性强，碱性锰化合物被酸分解，封闭在多孔材料内的抗癌药物被释放出来，杀灭癌细胞。另外，碱性锰化合物溶解后，游离出的锰离子是核磁共振成像剂，可以及时通过核磁共振成像定位肿瘤组织；覆盖多孔材料的UCNPs可以通过红外激光照射进行上转换发光定位肿瘤组织。其中上转换发光技术可避免生物组织的背景荧光，灵敏度高。
本发明提供一种用于治疗癌症的复合纳米载药材料及其制备方法，为使本发明的目的、技术方案及效果更加清楚、明确，以下对本发明进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明提供一种用于治疗癌症的复合纳米载药材料及其制备方法，其中，所述复合纳米载药材料以UCNPs为核，核表面覆盖一层多孔材料，孔内负载抗癌药物，多孔材料表面沉积一层碱性锰化合物，碱性锰化合物表面标记一种或多种捕获分子或识别分子。本发明以稀土上转换纳米材料（UCNPs）为核，表面覆盖一层多孔材料，孔内负载抗癌药物（如阿霉素），然后在多孔材料表面沉积一层碱性锰化合物（如二氧化锰、氢氧化锰或碳酸锰），以封闭抗癌药物。碱性锰化合物表面标记一种或多种捕获分子或识别分子（如抗原、抗体或特异性蛋白），其作用是可以特异识别肺癌、肝癌、胃癌、食管癌、直肠癌、结肠癌、乳腺癌、胰腺癌、骨癌、前列腺癌、膀胱癌、皮肤癌等一种或多种癌细胞。本发明复合纳米载药材料注入体内后，在其表面固定的特异性抗原、抗体或特异性蛋白作用下，可以与癌细胞结合并被癌细胞吞噬。进入细胞后，由于癌细胞内的酸性环境，碱性锰化合物溶解，封闭在多孔材料内的抗癌药物被释放出来，杀灭癌细胞。通常，由于特异性抗原、抗体或特异性蛋白的特异性并非100%，总会有少量纳米载药颗粒进入正常细胞内，造成人体损伤。本发明的复合纳米载药材料，由于正常细胞内酸性较弱，碱性锰化合物难以溶解，因而抗癌药物不释放或释放缓慢，大大降低药物对正常细胞的伤害（副作用小）。碱性锰化合物溶解后，游离出的锰离子是核磁共振成像剂，可以通过核磁共振成像定位肿瘤组织。覆盖多孔材料的UCNPs可以通过红外激光照射进行上转换发光定位肿瘤组织。其中上转换发光技术可避免生物组织的背景荧光，灵敏度高。本发明的复合纳米载药材料，在载药杀灭癌细胞的同时，还能在凋亡的癌细胞内留下核磁共振成像剂和上转换荧光成像剂，方便及时跟踪药物治疗效果。本发明的复合纳米载药材料，结合了特异性识别和化学识别两种识别肿瘤细胞的模式，靶向性高，大大降低抗癌药物对正常细胞的毒害作用，从而把化疗的毒副作用降到最低。同时，药物作用之后，肿瘤细胞内还有同时具有核磁共振成像剂和红外上转换荧光成像剂，方便对治疗效果跟踪观察，及时调整或维持治疗方案。
本发明的复合纳米载药材料可以识别多种常见肿瘤细胞并杀灭之（肺癌、肝癌、胃癌、食管癌、直肠癌、结肠癌、乳腺癌、胰腺癌、骨癌、前列腺癌、膀胱癌、皮肤癌等），而且可以降低对正常细胞的毒性，靶向性好，同时兼具上转换荧光识别功能和核磁成像功能，便于全面追踪用药效果。可以适合杀灭早、中、晚各期癌细胞。
进一步地，所述稀土上转换纳米材料的粒径为20-60nm。即本发明优选粒径为20-60nm的UCNPs为核，以提高UCNPs的识别功能。
进一步地，所述多孔材料为多孔硅材料、介孔氧化硅材料、介孔二氧化钛、介孔碳等材料中的一种。即本发明优选在UCNPs核表面覆盖一层多孔硅材料、介孔氧化硅材料、介孔二氧化钛或介孔碳材料，以较好的负载抗癌药物。
进一步地，所述抗癌药物为广谱抗癌药物，例如，广谱抗癌药物可以为阿霉素、依托泊苷、环磷酰胺和氟脲嘧啶、托泊替康、紫杉醇、奥沙利铂、顺氯氨铂、多柔比星等中的一种或多种组合。上述抗癌药物均能有效杀灭癌细胞。
进一步地，所述碱性锰化合物为MnO2、Mn( OH
)2或MnCO3。由于癌细胞的酸性环境，本发明上述碱性锰化合物进入癌细胞后，能被癌细胞溶解，从而使得封闭在多孔材料内的抗癌药物被释放出来，杀灭癌细胞。而正常细胞内酸性较弱，上述碱性锰化合物难以溶解，因而抗癌药物不释放或释放缓慢，大大降低抗癌药物对正常细胞的伤害。
进一步地，所述捕获分子或识别分子为抗原、抗体和特异性蛋白中的一种或多种。本发明该特异性抗原、抗体或特异性蛋白可以特异识别肺癌、肝癌、胃癌、食管癌、直肠癌、结肠癌、乳腺癌、胰腺癌、骨癌、前列腺癌、膀胱癌、皮肤癌等一种或多种癌细胞，并可以被癌细胞吞噬。
基于上述复合纳米载药材料，本发明还提供一种如上任一所述的用于治疗癌症的复合纳米载药材料的制备方法，其中，包括步骤：
A、采用水热法制备UCNPs；
B、以UCNPs为核，核表面覆盖一层多孔材料，得到覆盖多孔材料的p-UCNPs，记为p-UCNPs；
C、将p-UCNPs浸入抗癌药物溶液，浸泡吸附1~96h，干燥，得到负载抗癌药物的p-UCNPs，记为mp-UCNPs；
D、在mp-UCNPs表面沉积一层碱性锰化合物，得到碱性锰化合物为外壳的mp-UCNPs，记为mmp-UCNPs；
E、在mmp-UCNPs的碱性锰化合物表面标记捕获分子或识别分子，得到复合纳米载药材料。
通过上述方法制得的复合纳米载药材料，在载药杀灭癌细胞的同时，还能在凋亡的癌细胞内留下核磁共振成像剂和上转换荧光成像剂，方便及时跟踪药物治疗效果。
本发明的复合纳米载药材料，即便有少量标记不成功，进入到了正常细胞内，由于正常细胞内酸性较弱，碱性锰化合物难以分解，因而抗癌药物不释放或释放缓慢，大大降低药物对正常细胞的伤害，降低化疗的毒副作用。由于碱性锰化合物不分解，或者分解非常缓慢，不能提供足够的MRI造影剂Mn2+，也不会释放荧光上转换内核材料，所以即便纳米复合载药材料识别错误，进入到正常细胞，也不会在MRI成像、上转换荧光成像过程中被识别为肿瘤细胞，大大降低过度治疗的风险。
本发明的复合纳米载药材料，结合了特异性识别和化学识别两种识别肿瘤细胞的模式，靶向性高，大大降低抗癌药物对正常细胞的毒害作用，从而把化疗的毒副作用降到最低。
同时，药物作用之后，肿瘤细胞内还有同时具有核磁共振成像剂和红外上转换荧光成像剂，方便对治疗效果跟踪观察，及时调整或维持治疗方案。
具体地，所述步骤A为，采用水热法制备稀土上转换纳米材料（UCNPs），优选地，采用水热法制备粒径为20-60nm的稀土上转换纳米材料（UCNPs）。现有技术已记载稀土上转换纳米材料的详细制备方法，在此不进行赘述。
步骤B中，本发明所述多孔材料可以为但不限于多孔硅材料、介孔氧化硅材料、介孔二氧化钛（TiO2）、介孔碳等材料中的一种。具体地，所述多孔材料为多孔硅材料时，所述步骤B具体包括：将水玻璃在坩锅中于120-500℃焙烧1-24h，得到固体粉末；将所述固体粉末水洗，烘干后放到0
.03mol/L的CTAB溶液中，在30-80℃的水浴中搅拌，同时加入UCNPs粒子，搅拌1-8h，冷却至室温，滴加0
.1-6mol/L的HCl，将溶液的pH值调至6-9；过滤，洗涤，干燥，得到样品在300-600℃保温1-8h，即得到覆盖多孔硅材料的p-UCNPs。
具体地，所述多孔材料为多孔硅材料时，所述步骤B也可以具体包括：把聚环氧乙烯醚聚合物表面活性剂溶于用N，N-二甲基甲酰胺( DMF
)和HCl水溶液的混合溶液中，然后加入UCNPs粒子，搅拌条件下加入一定量的正硅酸乙酯( TEOS
)，于20-90℃下搅拌反应1-48h后，离心，干燥，得白色固体产物即为覆盖多孔硅材料的p-UCNPs。
具体地，所述多孔材料为介孔氧化硅材料时，所述步骤B具体包括：用表面活性剂并在乙二醇或丙三醇或丁二醇等多元醇存在下，加入UCNPs粒子，搅拌条件下加入硅酸钠溶液，合成覆盖介孔氧化硅材料的p-UCNPs。
具体地，所述多孔材料为介孔氧化硅材料时，所述步骤B具体包括：在完全溶解的硅酸钠和阳离子表面活性剂溶液中，加入UCNPs粒子，搅拌条件下合成覆盖介孔氧化硅材料的p-UCNPs。
具体地，所述多孔材料为介孔TiO2材料时，所述步骤B具体包括：以钛酸正丁酯为前驱体，异丙醇、乙二醇或丙三醇或丁二醇等为溶剂，十六烷基三甲基溴化铵(
CTAB )或十六烷基磺酸钠或聚环氧乙烯醚、聚环氧丙烯醚为模板剂，通过溶胶-凝胶过程合成覆盖介孔TiO2的p-UCNPs。
具体地，所述步骤C为，将覆盖多孔材料的p-UCNPs浸入抗癌药物溶液，浸泡吸附1~96h，干燥，得到负载抗癌药物的mp-UCNPs。
步骤D中，所述碱性锰化合物为MnO2、Mn( OH
)2或MnCO3。具体地，所述碱性锰化合物为MnO2时，所述步骤D具体包括：将负载抗癌药物的mp-UCNPs（浓度为1mg/mL）移取250μL加到2mL的离心管中，再加入250μL
0 .1mol/L pH=6的2-（N-吗啉代）乙磺酸缓冲溶液，加入250μL 10mmol/L
KMnO4进行混合；溶液30min后变成布朗胶体，经过离心分离，用去离子水清洗，除去上清液，即得到MnO2为外壳的mmp-UCNPs。
具体地，所述碱性锰化合物为Mn( OH
)2时，所述步骤D具体包括：将负载抗癌药物的mp-UCNPs（浓度为1mg/mL）移取 250
μL加到2mL的离心管中，再加入250μL 0 .1mol/L pH=8 .0 的磷酸盐缓冲溶液，加入250μL 10 mmol/L
KMnO4 进行混合；30min后经过离心分离，用去离子水清洗，除去上清液，即得到Mn(OH
)2为外壳的mmp-UCNPs。
具体地，所述碱性锰化合物为MnCO3时，所述步骤D具体包括：将负载抗癌药物的mp-UCNPs（浓度为2mg/mL）移取1mL加到5
mL的离心管中，再加入500μL 0.1mol/L MnCl2溶液，然后在搅拌条件下逐滴加入1mL 0 .1 mol/L
Na2CO3溶液，30min后经过离心分离，用去离子水清洗，除去上清液，即得到MnCO3为外壳的mmp-UCNPs。
步骤E为，在mmp-UCNPs的碱性锰化合物表面标记捕获分子或识别分子，得到复合纳米载药材料。即在碱性锰化合物表面标记特异性抗原、抗体或特异性蛋白，以特异识别多种常见肿瘤细胞并杀灭之（肺癌、肝癌、胃癌、食管癌、直肠癌、结肠癌、乳腺癌、胰腺癌、骨癌、前列腺癌、膀胱癌、皮肤癌等）。
与现有技术相比，本发明的显著改善有两点：
a
.在特异性识别技术方面，利用普通的抗原抗体识别技术，再利用肿瘤细胞能溶解碱性锰化合物的特性，只有碱性锰化合物被溶解之后，抗癌药物才能释放出来发挥作用。正常细胞中碱性锰化合物几乎不溶解，抗癌药物不释放或释放缓慢，可大大降低药物对正常细胞的伤害，副作用小。
b
.结合上转换发光荧光成像技术和核磁共振技术，实现对肿瘤组织的双功能成像模式，提高对肿瘤组织的识别准确率，随时准确观察治疗效果。
综上所述，本发明提供的一种用于治疗癌症的复合纳米载药材料及其制备方法，其中，所述复合纳米载药材料以UCNPs为核，核表面覆盖一层多孔材料，孔内负载抗癌药物，多孔材料表面沉积一层碱性锰化合物，碱性锰化合物表面标记一种或多种捕获分子或识别分子。本发明利用普通的抗原抗体识别技术，再利用肿瘤细胞能溶解碱性锰化合物的特性，只有碱性锰化合物被溶解之后，抗癌药物才能释放出来发挥作用。正常细胞中碱性锰化合物几乎不溶解，抗癌药物不释放或释放缓慢，可大大降低药物对正常细胞的伤害，副作用小。另外，本发明结合上转换发光荧光成像技术和核磁共振技术，实现对肿瘤组织的双功能成像模式，提高对肿瘤组织的识别准确率，随时准确观察治疗效果。
应当理解的是，本发明的应用不限于上述的举例，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (10)
- 一种用于治疗癌症的复合纳米载药材料，其特征在于，所述复合纳米载药材料以 UCNPs为核，核表面覆盖一层多孔材料，孔内负载抗癌药物，多孔材料表面沉积一层碱性锰化合物，碱性锰化合物表面标记一种或多种捕获分子或识别分子。
- 根据权利要求1所述的用于治疗癌症的复合纳米载药材料，其特征在于，所述多孔材料为多孔硅材料、介孔氧化硅材料、介孔二氧化钛、介孔碳材料中的一种。
- 根据权利要求1所述的用于治疗癌症的复合纳米载药材料，其特征在于，所述碱性锰化合物为MnO2、Mn(OH )2或MnCO3。
- 根据权利要求1所述的治疗癌症的复合纳米载药材料，其特征在于，所述抗癌药物为广谱抗癌药物。
- 根据权利要求1所述的用于治疗癌症的复合纳米载药材料，其特征在于，所述捕获分子或识别分子为抗原、抗体和特异性蛋白中的一种或多种。
- 一种如权利要求1~5任一所述的用于治疗癌症的复合纳米载药材料的制备方法，其特征在于，包括步骤：A、采用水热法制备UCNPs；B、以UCNPs为核，核表面覆盖一层多孔材料，得到覆盖多孔材料的p-UCNPs；C、将p-UCNPs浸入抗癌药物溶液，浸泡吸附1~96h ，干燥，得到负载抗癌药物的mp-UCNPs；D、在mp-UCNPs表面沉积一层碱性锰化合物，得到碱性锰化合物为外壳的mmp-UCNPs；E、在mmp-UCNPs的碱性锰化合物表面标记捕获分子或识别分子，得到复合纳米载药材料。
- 根据权利要求6所述的用于治疗癌症的复合纳米载药材料的制备方法，其特征在于，所述多孔材料为多孔硅材料时，所述步骤B具体包括：将水玻璃在坩锅中于120-500℃焙烧1-24h，得到固体粉末；将所述固体粉末水洗，烘干后放到0 .03mol/L的CTAB 溶液中，在30-80℃的水浴中搅拌，同时加入UCNPs粒子，搅拌1-8h，冷却至室温，滴加0 .1-6mol/L的HCl，将溶液的pH值调至6-9；过滤，洗涤，干燥，得到的样品在300-600℃保温1-8h，即得到覆盖多孔硅材料的p-UCNPs。
- 根据权利要求6所述的用于治疗癌症的复合纳米载药材料的制备方法，其特征在于，所述碱性锰化合物为MnO2时，所述步骤D具体包括：将负载抗癌药物的mp-UCNPs移取250μL加到2mL的离心管中，再加入250μL 0 .1mol/L pH=6的2-（N-吗啉代）乙磺酸缓冲溶液，加入250μL 10 mmol/L KMnO4进行混合；溶液30min后变成布朗胶体，经过离心分离，用去离子水清洗，除去上清液，即得到MnO2为外壳的mmp-UCNPs。
- 根据权利要求6所述的用于治疗癌症的复合纳米载药材料的制备方法，其特征在于，所述碱性锰化合物为Mn( OH )2时，所述步骤D具体包括：将负载抗癌药物的mp-UCNPs移取250μL加到2mL的离心管中，再加入250μL 0 .1mol/L pH=8 .0的磷酸盐缓冲溶液，加入250μL10mmol/L KMnO4进行混合；30min后经过离心分离，用去离子水清洗，除去上清液，即得到Mn(OH )2为外壳的mmp-UCNPs。
- 根据权利要求6所述的用于治疗癌症的复合纳米载药材料的制备方法，其特征在于，所述碱性锰化合物为MnCO3时，所述步骤D具体包括：将负载抗癌药物的mp-UCNPs移取1mL加到5mL的离心管中，再加入500μL 0 .1mol/L MnCl2溶液，然后在搅拌条件下逐滴加入1mL 0 .1mol/L Na2CO3溶液，30min后经过离心分离，用去离子水清洗，除去上清液，即得到MnCO3为外壳的mmp-UCNPs。
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