技术领域technical field
本发明涉及生物医药技术领域，具体涉及主动靶向抗肿瘤纳米药物及其制备方法和应用。The invention relates to the technical field of biomedicine, in particular to an active targeting anti-tumor nano-medicine and a preparation method and application thereof.
背景技术Background technique
恶性肿瘤是一种以局部表现为主的全身系统性疾病，严重威胁着人类的健康。近年来，恶性肿瘤的发病率逐渐增高。随着有关恶性肿瘤知识的普及、危险因素的干预和普查的广范开展，早期检出率不断提高，加上各种治疗手段的进步，病死率有所下降。但如何使病人获得最合适的，即效果好，副反应小的治疗仍然是肿瘤科医生所不懈追求的目标。传统的手术、化疗、放疗等治疗手段都有其一定的局限性，新兴的内分泌治疗、靶向治疗、生物治疗等不断地显示出其优越性。Malignant tumor is a systemic disease with local manifestations, which seriously threatens human health. In recent years, the incidence of malignant tumors has gradually increased. With the popularization of knowledge about malignant tumors, the intervention of risk factors, and the extensive development of general surveys, the early detection rate has been continuously improved, coupled with the progress of various treatment methods, the mortality rate has decreased. But how to make patients get the most suitable treatment, that is, good effect and less side effects, is still the unremitting goal of oncologists. Traditional treatment methods such as surgery, chemotherapy, and radiotherapy have certain limitations, while emerging endocrine therapy, targeted therapy, and biological therapy continue to show their superiority.
纳米科学是一门涵盖多学科跨领域的前沿交叉学科，近年来飞速发展，其与医学的交叉碰撞产生了令人瞩目的成果，如白蛋白紫杉醇、脂质体阿霉素等纳米载药体系明显提高了化疗药物的抗肿瘤疗效，降低了毒副作用，临床意义重大，经济、社会效益显著。白蛋白结合型紫杉醇是唯一应用白蛋白纳米技术构建的靶向化疗药物，利用独特的纳米技术使疏水性紫杉醇与白蛋白结合，无需使用有毒溶剂。在血液中以两种形式存在:游离型紫杉醇(5％-10％)和白蛋白结合型紫杉醇(90-95％)，游离型紫杉醇体积很小，能够以被动转运的方式穿过血管内皮细胞间隙到达肿瘤细胞，导致其凋亡。白蛋白结合型紫杉醇利用白蛋白在体内的天然转运机制(gp60-caveolin-1-SPARC)，以主动转运的方式穿过血管内皮细胞进入肿瘤间质，使紫杉醇更多分布于肿瘤组织，达到更高的肿瘤细胞内浓度。(曲妥珠单抗)是一种重组DNA衍生的人源化单克隆抗体，特异性地作用于人表皮生长因子受体-2(HER2)的细胞外部位。通过抑制HER2下游的信号通路从而抑制HER2过度表达的肿瘤细胞的增殖。纳米药物靶向治疗肿瘤领域正不断朝着更精准更多重靶向的方向发展。本研究即受此思路启发，充分拓展内涵，在现有科技水平上，首次将与两种临床上市药物进行药物重组，构建一种精准且双重靶向HER2(+)恶性肿瘤细胞、组织的主动靶向纳米载药体系。预期获得相比重组药物中每一单一组分更有的抗肿瘤作用。Nanoscience is a cutting-edge interdisciplinary subject covering multiple disciplines and cross-fields. It has developed rapidly in recent years. Its cross-collision with medicine has produced remarkable results, such as nano-drug delivery systems such as nab-paclitaxel and liposomal doxorubicin. The anti-tumor curative effect of the chemotherapy drugs is obviously improved, the toxic and side effects are reduced, the clinical significance is great, and the economic and social benefits are remarkable. nab-paclitaxel It is the only targeted chemotherapy drug constructed using albumin nanotechnology. It uses unique nanotechnology to combine hydrophobic paclitaxel with albumin without the use of toxic solvents. Exist in two forms in blood: free paclitaxel (5%-10%) and albumin-bound paclitaxel (90-95%), free paclitaxel is small in size and can pass through vascular endothelial cells in a passive transport mode The gaps reach tumor cells, leading to their apoptosis. Nab-paclitaxel uses the natural transport mechanism of albumin (gp60-caveolin-1-SPARC) in the body to actively transport through the vascular endothelial cells into the tumor stroma, so that paclitaxel is more distributed in the tumor tissue and achieves a more stable effect. high concentrations in tumor cells. (trastuzumab) is a recombinant DNA-derived humanized monoclonal antibody that specifically acts on the extracellular site of human epidermal growth factor receptor-2 (HER2). Inhibits the proliferation of tumor cells overexpressing HER2 by inhibiting the signaling pathway downstream of HER2. The field of nano-drug targeted therapy for tumors is constantly developing in the direction of more precise and multiple targeting. Inspired by this idea, this study fully expands the connotation. On the existing level of technology, it is the first time to and Two clinically marketed drugs were recombined to construct an active targeting nano-drug delivery system that is precise and dual-targeted to HER2(+) malignant tumor cells and tissues. It is expected to obtain a greater antitumor effect than that of each single component in the recombinant drug.
发明内容Contents of the invention
解决的技术问题：本发明的目的在于秉承精准医学的理念，提供一种靶向HER2(+)肿瘤细胞的主动靶向抗肿瘤纳米药物及其制备方法和应用，其中组分对HER2(+)肿瘤细胞具有靶向作用，且能通过抑制HER2下游信号通路来发挥抗肿瘤作用，组分具有对紫杉醇高载药性能、EPR被动靶向肿瘤组织等特点，将广谱的抗肿瘤药物双重靶向输送至肿瘤组织、细胞。二者协同可实施精准有力的双重打击，同时减少对正常组织、细胞的毒副作用。Technical problem to be solved: the purpose of the present invention is to uphold the concept of precision medicine, to provide an active targeting anti-tumor nano drug targeting HER2(+) tumor cells and its preparation method and application, wherein The components have a targeting effect on HER2(+) tumor cells, and can exert anti-tumor effects by inhibiting the downstream signaling pathway of HER2, The components have the characteristics of high drug-loading performance for paclitaxel, EPR passively targeting tumor tissue, etc., and can deliver broad-spectrum anti-tumor drugs to tumor tissue and cells. The synergy of the two can implement a precise and powerful double strike while reducing the toxic side effects on normal tissues and cells.
技术方案：主动靶向抗肿瘤纳米药物的制备方法，步骤为：按比例，取5mg/mL白蛋白结合型紫杉醇0.5mL加入1mL PBS中，再加入5.75×10-7g/mL NHS100μL，以10rpm速度反应30min后，加入2.3×10-7g/mL EDC10μL及0.2mg/mLAnti-ErbB 2单克隆抗体20μL，4℃层析柜中以10rpm反应24小时后收集反应物，高速离心机以10000rpm离心45min后收集沉淀，用1mLPBS重悬得偶联化合物。Technical solution: The preparation method of actively targeting anti-tumor nano-drugs, the steps are: take 0.5 mL of 5 mg/mL nab-paclitaxel in proportion and add it to 1 mL PBS, then add 5.75×10-7 g/mL NHS 100 μL, at 10 rpm After speed reaction for 30 minutes, add 10 μL of 2.3×10-7 g/mL EDC and 20 μL of 0.2 mg/mL Anti-ErbB 2 monoclonal antibody, react in a chromatography cabinet at 4°C at 10 rpm for 24 hours, collect the reactants, and centrifuge at 10,000 rpm in a high-speed centrifuge After 45 min, the precipitate was collected and resuspended with 1 mL of LPBS to obtain the coupled compound.
上述制备方法所获得的偶联化合物。The coupling compound obtained by the above preparation method.
上述偶联化合物在制备主动靶向抗肿瘤纳米药物中的应用。Application of the above coupling compound in the preparation of active targeting anti-tumor nano-medicine.
上述的肿瘤指实体肿瘤。The aforementioned tumors refer to solid tumors.
有益效果：实验研究表明，通过使用重组新一代主动靶向抗肿瘤纳米药物，在细胞水平可以观察到对HER2(+)肿瘤细胞相比两种独立组分较高的毒性、凋亡率及细胞周期阻滞效果。动物水平上可以观察到其对荷瘤裸鼠更高的肿瘤抑制率及更小的毒副作用。Beneficial Effects: Experimental studies have shown that by using recombinant A new generation of active targeting anti-tumor nano-drugs can be observed at the cellular level with higher toxicity, apoptosis rate and cell cycle arrest effect on HER2(+) tumor cells than the two independent components. At the animal level, it can be observed that it has a higher tumor inhibition rate and less toxic side effects on tumor-bearing nude mice.
附图说明Description of drawings
图1为本发明药物合成和作用机制示意图，其中①：重组主动靶向抗肿瘤纳米药物结构示意图：白蛋白结合型紫杉醇是唯一应用白蛋白纳米技术构建的靶向化疗药物，利用独特的纳米技术使疏水性紫杉醇与白蛋白结合，无需使用有毒溶剂。在血液中以两种形式存在:游离型紫杉醇(5％-10％)和白蛋白结合型紫杉醇(90-95％)，游离型紫杉醇体积很小，能够以被动转运的方式穿过血管内皮细胞间隙到达肿瘤细胞，导致其凋亡。白蛋白结合型紫杉醇利用白蛋白在体内的天然转运机制(gp60-caveolin-1-SPARC)，以主动转运的方式穿过血管内皮细胞进入肿瘤间质，使紫杉醇更多分布于肿瘤组织，达到更高的肿瘤细胞内浓度。(曲妥珠单抗)是一种重组DNA衍生的人源化单克隆抗体，特异性地作用于人表皮生长因子受体-2(HER2)的细胞外部位。通过抑制HER2下游的信号通路从而抑制HER2过度表达的肿瘤细胞的增殖。②、③：与通过EDC/NHS法“一步法”反应生成偶联物，通过尾静脉注射重组主动靶向抗肿瘤纳米药物至荷瘤裸鼠模型中，综合对Her2过表达乳腺癌细胞的靶向作用以及纳米制剂紫杉醇高载药性能、EPR被动靶向肿瘤组织等特点，将广谱的抗肿瘤药物主动靶向性的输送到HER2(+)肿瘤细胞中、实施精准有力的双重打击，减少对正常细胞的毒副作用。Figure 1 is a schematic diagram of the synthesis and action mechanism of the drug of the present invention, wherein ①: recombination Schematic diagram of active targeting anti-tumor nanomedicine: nab-paclitaxel It is the only targeted chemotherapy drug constructed using albumin nanotechnology. It uses unique nanotechnology to combine hydrophobic paclitaxel with albumin without the use of toxic solvents. Exist in two forms in blood: free paclitaxel (5%-10%) and albumin-bound paclitaxel (90-95%), free paclitaxel is small in size and can pass through vascular endothelial cells in a passive transport mode The gaps reach tumor cells, leading to their apoptosis. Nab-paclitaxel uses the natural transport mechanism of albumin (gp60-caveolin-1-SPARC) in the body to actively transport through the vascular endothelial cells into the tumor stroma, so that paclitaxel is more distributed in the tumor tissue and achieves a more stable effect. high concentrations in tumor cells. (trastuzumab) is a recombinant DNA-derived humanized monoclonal antibody that specifically acts on the extracellular site of human epidermal growth factor receptor-2 (HER2). Inhibits the proliferation of tumor cells overexpressing HER2 by inhibiting the signaling pathway downstream of HER2. ②, ③: and The conjugate is generated by the "one-step" reaction of the EDC/NHS method and reconstituted by tail vein injection Active targeting of anti-tumor nano-drugs into tumor-bearing nude mouse models, comprehensive Targeting of Her2 overexpressing breast cancer cells and The nano-preparation paclitaxel has the characteristics of high drug-loading performance and EPR passive targeting of tumor tissues. It actively targets and delivers broad-spectrum anti-tumor drugs to HER2 (+) tumor cells, and implements precise and powerful double strikes to reduce damage to normal cells. toxic side effects.
图2为本发明药物电镜照片。Fig. 2 is electron micrograph of medicine of the present invention.
具体实施方式detailed description
本发明提供了重组新一代主动靶向抗肿瘤纳米药物及其制备方法，将(白蛋白结合型紫杉醇)与(曲妥珠单抗)两种临床上市药物通过EDC/NHS法进行“一步法”偶联构建药物传输系统，本发明主要运用于实体肿瘤，如HER2(+)乳腺癌、胃癌等。本发明的新一代主动靶向抗肿瘤纳米药物可以制成静脉注射的冻干粉制剂。综合对HER2(+)肿瘤细胞的靶向作用以及纳米制剂紫杉醇高载药性能、EPR被动靶向肿瘤组织等特点，将广谱的抗肿瘤药物双重靶向输送至肿瘤组织、细胞实施精准有力的双重打击，同时减少对正常组织、细胞的毒副作用。总之，本发明将两种临床上市药物进行重组，制备步骤简单，开发成本低，生物相容性高，在现代肿瘤靶向治疗中具有重要的价值。The present invention provides recombinant A new generation of actively targeting anti-tumor nano-drugs and their preparation methods will (albumin-bound paclitaxel) and (Trastuzumab) Two clinically marketed drugs are coupled through the EDC/NHS method to construct a drug delivery system in a "one-step method". The present invention is mainly used in solid tumors, such as HER2 (+) breast cancer, gastric cancer, etc. The new generation active targeting anti-tumor nano-medicine of the present invention can be made into freeze-dried powder preparation for intravenous injection. comprehensive Targeting of HER2(+) tumor cells and The nano-preparation paclitaxel has the characteristics of high drug-loading performance and EPR passive targeting of tumor tissues. It can deliver broad-spectrum anti-tumor drugs to tumor tissues and cells to carry out precise and powerful double strikes, while reducing toxic and side effects on normal tissues and cells. . In a word, the present invention recombines two clinically marketed drugs, has simple preparation steps, low development cost and high biocompatibility, and has important value in modern tumor targeted therapy.
实施例1Example 1
(1)重组新一代主动靶向抗肿瘤纳米药物及其制备方法(1) Reorganization A new generation of active targeting anti-tumor nano drug and its preparation method
利用中的白蛋白组分与中的氨基或羧基末端通过EDC/NHS法将二者进行一步法偶联。具体步骤：取1mL(5mg/mL，货号：6109342)加入1mL PBS中，再加入100μL NHS(5.75×10-7g/mL)以10rpm速度反应30min后，加入10μL EDC(2.3×10-7g/mL)及10μL Anti-ErbB2单克隆抗体(0.2mg/mL，货号ab2428)，4℃层析柜中以10rpm反应24小时后收集反应物，高速离心机以10000rpm离心45min后收集沉淀，用1mLPBS重悬，分装保存。并通过动态光散射(DLS)检测其水和粒径、透射电镜检测观察复合物的粒径大小。结果显示所制得的药物具有良好的稳定性，粒径大小约为130±30nm(如图2所示)use The albumin fraction in The amino or carboxyl terminus of the two were coupled in one step by EDC/NHS method. Specific steps: take Add 1mL (5mg/mL, product number: 6109342) to 1mL PBS, then add 100μL NHS (5.75×10-7 g/mL) and react at 10rpm for 30min, then add 10μL EDC (2.3×10-7 g/mL) and 10μL Anti-ErbB2 monoclonal antibody (0.2mg/mL, Cat. No. ab2428), react in a chromatographic cabinet at 4°C at 10 rpm for 24 hours, collect the reactant, centrifuge at 10,000 rpm for 45 min, collect the precipitate, resuspend in 1 mL of PBS, and store in aliquots. The water and particle size were detected by dynamic light scattering (DLS), and the particle size of the complex was observed by transmission electron microscopy. The result shows that the prepared medicine has good stability, and the particle size is about 130 ± 30nm (as shown in Figure 2)
(2)体外对肿瘤细胞作用的实验研究(2) Experimental research on the effect on tumor cells in vitro
通过CCK-8检测重组药物对HER2(+)乳腺癌及胃癌细胞抑制率的影响、AnnexinⅤ/PI双染法经流式细胞仪检测细胞凋亡情况、DAPI染料观察细胞核形态变化，上述结果显示重组药物相比单一组分具有更高的体外杀伤力。主要实验结果摘要如下：CCK-8法检测得出PTX、处理乳腺癌SK-BR-3细胞48H后得出其IC50分别为0.04、0.02、0.004ug/ml,上述三种剂型药物取紫杉醇等效浓度处理SK-BR-3细胞48H后其晚期凋亡率分别为6.2％、11.4％、18.2％。CCK-8 was used to detect the effect of recombinant drugs on the inhibitory rate of HER2(+) breast cancer and gastric cancer cells, AnnexinⅤ/PI double staining method was used to detect cell apoptosis by flow cytometry, and DAPI dye was used to observe the changes in the nucleus morphology. Drugs have higher in vitro lethality than single components. The main experimental results are summarized as follows: CCK-8 method detected PTX, After treating breast cancer SK-BR-3 cells for 48 hours, the IC50 values were 0.04, 0.02, and 0.004 ug/ml, and the late apoptosis rate of the above three dosage forms of SK-BR-3 cells was treated with the equivalent concentration of paclitaxel for 48 hours. They were 6.2%, 11.4%, and 18.2%, respectively.
(3)体内抗肿瘤作用的实验研究(3) Experimental study of anti-tumor effect in vivo
建立HER2(+)乳腺癌及胃癌裸鼠移植瘤原位接种模型并观察裸鼠生存曲线及肿瘤抑制率，近红外染料预染药物并通过小动物活体成像观察其在裸鼠体内分布情况。结果表明，重组药物具有比单一组分更大的体内肿瘤抑制率，且能改善裸鼠的生存质量、延长生存期。小动物活体成像表明重组药物在肿瘤部位具有更高的蓄积性，提示重组药物较高的靶向性。The orthotopic inoculation model of HER2(+) breast cancer and gastric cancer nude mice was established, and the survival curve and tumor inhibition rate of nude mice were observed. The drug was pre-stained with near-infrared dyes, and its distribution in nude mice was observed through small animal live imaging. The results show that the recombinant drug has a greater tumor inhibition rate in vivo than the single component, and can improve the quality of life and prolong the survival period of nude mice. In vivo imaging of small animals showed that recombinant drugs had higher accumulation in tumor sites, suggesting higher targeting of recombinant drugs.
综上所述：我们经过实验研究，构建了新一代主动靶向抗肿瘤纳米药物及其制备方法，对细胞和动物的实验表明，该药物相比单一组分抗肿瘤效应更显著，因此，这种技术可望用于临床恶性肿瘤的综合治疗。本发明将大大加快新药开发的速度，对肿瘤精准治疗具有重要的价值。To sum up: After experimental research, we have constructed a new generation of active targeting anti-tumor nano-medicine and its preparation method. Experiments on cells and animals have shown that the drug has a more significant anti-tumor effect than a single component. Therefore, this This technique is expected to be used in the comprehensive treatment of clinical malignant tumors. The invention will greatly speed up the development of new drugs, and has important value for the precise treatment of tumors.
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| CN201610825608.7ACN106310291A (en) | 2016-09-14 | 2016-09-14 | Actively targeted antitumor nano-medicine, method for preparing same and application of actively targeted antitumor nano-medicine |
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