载阿霉素GoldMag金磁复合微粒用于肝癌靶向治疗研究
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摘要
恶性肿瘤是严重威胁人类身体健康的重大疾病。化疗是目前常用的治疗方法。传统的给药途径使得药物在全身均匀分布,缺乏对肿瘤特异性作用。因此,在杀死肿瘤细胞的同时,也对正常组织细胞产生严重的毒副作用,从而使化疗药物的临床应用受到限制。磁导靶向给药是通过静脉将吸附或包裹于磁性载体的抗癌药物注射体内,在外磁场的诱导作用下,靶向定位于肿瘤区域；持续缓慢释放抗癌药物,从而使药物在肿瘤部位保持较高的浓度而降低其它组织和器官的药物浓度,最终达到改变药物在体内的组织分布,提高治疗指数,降低药物的毒副作用的目的。本课题研究了GoldMag金磁复合微粒体外载药、释药规律和机理及其载药后联合磁场对细胞的毒性作用；用巯基化的聚乙二醇(PEG-SH)对GoldMag金磁复合微粒进行了表面功能化修饰,并对修饰后的金磁复合微粒进行了表征；同时探讨了修饰后的金磁复合微粒(PGMNs)体外载载药释药规律和机理及其对细胞的毒性作用；以正常大鼠为材料,通过检测组织和血浆中阿霉素及铁元素的含量,探讨了载阿霉素PEG修饰的金磁复合微粒(DOX-PGMNs)在外磁场作用下在动物体内的分布,并评价它在动物体内的靶向性。最后又研究了DOX-PGMNs在外磁场作用下对H22肿瘤模型小鼠的治疗效果。结果表明：
1.在最优的载药条件下,市售GoldMag金磁复合微粒对阿霉素的最大载药率为10.2%。MTT法分析GoldMag金磁复合微粒对HepG2细胞毒性的实验结果显示：在金磁复合微粒浓度为2.0 mg／ml的条件下,细胞的存活率大于92%。载阿霉素金磁复合微粒的半数致死剂量(IC50=0.731μg／ml)大于阿霉素组(IC50=0.522μg／ml)(P<0.05)。载阿霉素金磁复合微粒联合磁场作用对细胞的抑制作用(IC50=0.42μg／ml)比单纯阿霉素(IC50=0.522μg／ml)显著增强。
2.由于酸处理的纳米金磁微粒在溶液中不稳定,我们对其表面进行了聚乙二醇(PEG)修饰。修饰后的金磁复合微粒(PGMNs)粒径约为50 nm；分散性有了很大的改善,在PBS中能稳定存在,具有良好的分散性；修饰后的GoldMag金磁复合微粒的饱和磁化强度为34 emu／g。在最佳的载药条件下,PGMNs对阿霉素的最大载药率为10.8%。细胞毒性结果显示,在2.0 mg／ml的浓度条件下,细胞的存活率大于89%。
3.PGMNs在动物体内靶向性实验结果表明：给药0.5,1,2和4小时后,载阿霉素PEG修饰的金磁复合微粒联合磁场组(DOX-PGMNs-M)的实验动物肝脏中药物的浓度(60.7±8.14,53.6±4.89,44.8±6.41和38.4±2.58 ng／g)显著高于无磁场组(40.8±9.96,31.9±7.01,28±6.11和20.7±5.78 ng／g)(P<0.05)。组织学分析显示在肝脏的靶区有大量的粒子聚集。
4. DOX-PGMNs联合磁场治疗H22肿瘤模型小鼠的效果显示：DOX-PGMNs-M组,DOX-PGMNs组,DOX组和对照组的动物存活时间分别为72.7±9.95,66.1±13.5,31.3±3.31和25.8±10.1天。治疗后33天,它们的相对肿瘤体积分别为5.46,9.21,14.8和24.3。与对照组相比,DOX-PGMNs联合磁场能够显著抑制肿瘤组织的生长。
GoldMag金磁复合微粒作为新型磁性化疗药物载体,在外加磁场作用下,具有明显的靶向性。载阿霉素PEG修饰的金磁复合微粒联合磁场作用可以有效提高肿瘤组织内化疗药物浓度,降低化疗药物毒副反应,显著抑制肿瘤组织的生长。
本研究将为GoldMag金磁复合微粒用作化疗药物载体,靶向输送药物治疗肝癌提供一定的理论基础。
Cancer remains one of the leading causes of death in most parts of the world and chemotherapy is the common treatment. The main reason for failure of chemotherapy is the poor accessibility of antineoplastic agents to the tumor, requiring higher doses, and the nonselective nature of these agents causes severe toxicity. The magnetically targeted-drug delivery system (MT-DDS) involves binding anticancer drug to biocompatible magnetic particles, injecting into the blood stream and using an external magnetic field to pull them out of suspension in the target region. The drug can be enriched and released at the specific region and enriched at the specific region, reducing their systemic distribution as well as the possibility of administering lower but more accurately targeted doses of the drug in the treatments. This local therapy could improve the efficiency of the treatment, reducing systemic toxicity. In this project, the kinetics of doxorubicin(DOX) adsorption on GoldMag nanoparticles surface and drug release were investigated firstly. The cytotoxicity assay of GoldMag nanoparticles and GoldMag nanoparticles loaded with doxorubicin combined with the permanent magnetic fields to the human hepatocellular liver carcinoma cell line (HepG2) in vitro were also tested. Then we modified GoldMag (Fe3O4/Au) nanoparticles with PEG5000-thiol (PEG-SH)(PGMNs) and investigated the kinetics of absorption and release of DOX of PGMNs in vitro. The biodistribution of DOX-loaded PGMNs combined with external magnetic field were also investigated in vivo. Additionally the therapeutic efficiency of DOX-loaded PGMNs combined with external magnetic field of DOX-loaded PGMNs was investigated. The results showed that:
1. The content of drug adsorbed on the GoldMag nanoparticle surface increased rapidly within 30 min and the maximum drug loading rate is about 10.2%.The cell viability remained more than 92% by using of GoldMag nanoparticles at the concentration as high of 2.0 mg/ml, suggesting the good biocompatibility of the nanoparticles. IC50 (0.731μg/ml) of the Dox-GoldMag group were higher than those (0.522μg/ml) of the Dox group (P<0. 05). However, the Dox-GoldMag group combined with the magnetic fields had obviously increased the inhibition rate for HepG2 cell line and IC50 was lower than Dox group (0.421μg/ml).
2. The PEG modified GoldMag nanoparticles (PGMNs) have saturated magnetization of 34 emu/g with a size range of 50 nm. The maximum quantity of doxorubicin (DOX) loaded on the particles is about 107.78mg/g (10.8%). The PGMNs loaded with DOX (DOX-loaded PGMNs) exhibited a controlled drug release within 4 h and then the drug slowly, sustained release to 96 h. The cell viability remained more than 92% incubated in cell culture medium RPMI-1640 contained PGMNs at the concentration as high as 2.0 mg/ml, suggesting the biocompatibility of the nanoparticles.
3. The results of the biodistribution of DOX-loaded PGMNs applied permanent magnetic in vivo indicated that the concentration of DOX in the liver exposed to magnetic field group (60.7±8.14,53.6±4.89,44.8±6.41 and 38.4±2.58 ng/g) were much higher than those of no magnetic field applied group (40.8±9.96,31.9±7.01,28±6.11 and 20.7±5.78 ng/g) at 0.5,1,2 and 4 h (P<0.05), respectively. Histological studies suggested a larger particle concentration in the targeted area of liver in comparison to the no exposed to magnetic field and control.
4. The results of therapeutic efficiency of DOX-loaded PGMNs combined with external magnetic field showed that DOX-PGMNs and DOX-PGMNs-M groups (M represent magnetic field) displayed more tumor suppression than DOX group. The relative tumor volumes of DOX-PGMNs-M, DOX-PGMNs, DOX and Control were 5.46,9.21,14.8 and 24.3 respectively in H22 cell-bearing mice on the 33rd day. The life span of H22 cell-bearing mice treated with DOX-PGMNs-M, DOX-PGMNs, DOX and control were 74.8±9.95,66.1±13.5, and 31.3±3.31 and 25.8±10.1 days, respectively. Histological studies suggested a larger amount necrotic cells in the targeted area of liver in comparison to the no exposed to magnetic field and control.
Summary, GoldMag nanoparticles, as a new targeting drug delivery carrier, were capable of carrying drug for targeting therapeutic purposes due to its novel property. DOX-loaded PGMNs combined with external magnetic can significantly increase the level of drug concentration in specific site and reducing their systemic distribution as well as the possibility of administering lower but more accurately targeted doses of the drug in the treatments. This local therapy system could improve the therapeutic efficiency, reducing systemic toxicity. Our study will provide basis for GoldMag nanoparticles used to drug targeting delivery carrier.
1.在最优的载药条件下,市售GoldMag金磁复合微粒对阿霉素的最大载药率为10.2%。MTT法分析GoldMag金磁复合微粒对HepG2细胞毒性的实验结果显示：在金磁复合微粒浓度为2.0 mg／ml的条件下,细胞的存活率大于92%。载阿霉素金磁复合微粒的半数致死剂量(IC50=0.731μg／ml)大于阿霉素组(IC50=0.522μg／ml)(P<0.05)。载阿霉素金磁复合微粒联合磁场作用对细胞的抑制作用(IC50=0.42μg／ml)比单纯阿霉素(IC50=0.522μg／ml)显著增强。
2.由于酸处理的纳米金磁微粒在溶液中不稳定,我们对其表面进行了聚乙二醇(PEG)修饰。修饰后的金磁复合微粒(PGMNs)粒径约为50 nm；分散性有了很大的改善,在PBS中能稳定存在,具有良好的分散性；修饰后的GoldMag金磁复合微粒的饱和磁化强度为34 emu／g。在最佳的载药条件下,PGMNs对阿霉素的最大载药率为10.8%。细胞毒性结果显示,在2.0 mg／ml的浓度条件下,细胞的存活率大于89%。
3.PGMNs在动物体内靶向性实验结果表明：给药0.5,1,2和4小时后,载阿霉素PEG修饰的金磁复合微粒联合磁场组(DOX-PGMNs-M)的实验动物肝脏中药物的浓度(60.7±8.14,53.6±4.89,44.8±6.41和38.4±2.58 ng／g)显著高于无磁场组(40.8±9.96,31.9±7.01,28±6.11和20.7±5.78 ng／g)(P<0.05)。组织学分析显示在肝脏的靶区有大量的粒子聚集。
4. DOX-PGMNs联合磁场治疗H22肿瘤模型小鼠的效果显示：DOX-PGMNs-M组,DOX-PGMNs组,DOX组和对照组的动物存活时间分别为72.7±9.95,66.1±13.5,31.3±3.31和25.8±10.1天。治疗后33天,它们的相对肿瘤体积分别为5.46,9.21,14.8和24.3。与对照组相比,DOX-PGMNs联合磁场能够显著抑制肿瘤组织的生长。
GoldMag金磁复合微粒作为新型磁性化疗药物载体,在外加磁场作用下,具有明显的靶向性。载阿霉素PEG修饰的金磁复合微粒联合磁场作用可以有效提高肿瘤组织内化疗药物浓度,降低化疗药物毒副反应,显著抑制肿瘤组织的生长。
本研究将为GoldMag金磁复合微粒用作化疗药物载体,靶向输送药物治疗肝癌提供一定的理论基础。
Cancer remains one of the leading causes of death in most parts of the world and chemotherapy is the common treatment. The main reason for failure of chemotherapy is the poor accessibility of antineoplastic agents to the tumor, requiring higher doses, and the nonselective nature of these agents causes severe toxicity. The magnetically targeted-drug delivery system (MT-DDS) involves binding anticancer drug to biocompatible magnetic particles, injecting into the blood stream and using an external magnetic field to pull them out of suspension in the target region. The drug can be enriched and released at the specific region and enriched at the specific region, reducing their systemic distribution as well as the possibility of administering lower but more accurately targeted doses of the drug in the treatments. This local therapy could improve the efficiency of the treatment, reducing systemic toxicity. In this project, the kinetics of doxorubicin(DOX) adsorption on GoldMag nanoparticles surface and drug release were investigated firstly. The cytotoxicity assay of GoldMag nanoparticles and GoldMag nanoparticles loaded with doxorubicin combined with the permanent magnetic fields to the human hepatocellular liver carcinoma cell line (HepG2) in vitro were also tested. Then we modified GoldMag (Fe3O4/Au) nanoparticles with PEG5000-thiol (PEG-SH)(PGMNs) and investigated the kinetics of absorption and release of DOX of PGMNs in vitro. The biodistribution of DOX-loaded PGMNs combined with external magnetic field were also investigated in vivo. Additionally the therapeutic efficiency of DOX-loaded PGMNs combined with external magnetic field of DOX-loaded PGMNs was investigated. The results showed that:
1. The content of drug adsorbed on the GoldMag nanoparticle surface increased rapidly within 30 min and the maximum drug loading rate is about 10.2%.The cell viability remained more than 92% by using of GoldMag nanoparticles at the concentration as high of 2.0 mg/ml, suggesting the good biocompatibility of the nanoparticles. IC50 (0.731μg/ml) of the Dox-GoldMag group were higher than those (0.522μg/ml) of the Dox group (P<0. 05). However, the Dox-GoldMag group combined with the magnetic fields had obviously increased the inhibition rate for HepG2 cell line and IC50 was lower than Dox group (0.421μg/ml).
2. The PEG modified GoldMag nanoparticles (PGMNs) have saturated magnetization of 34 emu/g with a size range of 50 nm. The maximum quantity of doxorubicin (DOX) loaded on the particles is about 107.78mg/g (10.8%). The PGMNs loaded with DOX (DOX-loaded PGMNs) exhibited a controlled drug release within 4 h and then the drug slowly, sustained release to 96 h. The cell viability remained more than 92% incubated in cell culture medium RPMI-1640 contained PGMNs at the concentration as high as 2.0 mg/ml, suggesting the biocompatibility of the nanoparticles.
3. The results of the biodistribution of DOX-loaded PGMNs applied permanent magnetic in vivo indicated that the concentration of DOX in the liver exposed to magnetic field group (60.7±8.14,53.6±4.89,44.8±6.41 and 38.4±2.58 ng/g) were much higher than those of no magnetic field applied group (40.8±9.96,31.9±7.01,28±6.11 and 20.7±5.78 ng/g) at 0.5,1,2 and 4 h (P<0.05), respectively. Histological studies suggested a larger particle concentration in the targeted area of liver in comparison to the no exposed to magnetic field and control.
4. The results of therapeutic efficiency of DOX-loaded PGMNs combined with external magnetic field showed that DOX-PGMNs and DOX-PGMNs-M groups (M represent magnetic field) displayed more tumor suppression than DOX group. The relative tumor volumes of DOX-PGMNs-M, DOX-PGMNs, DOX and Control were 5.46,9.21,14.8 and 24.3 respectively in H22 cell-bearing mice on the 33rd day. The life span of H22 cell-bearing mice treated with DOX-PGMNs-M, DOX-PGMNs, DOX and control were 74.8±9.95,66.1±13.5, and 31.3±3.31 and 25.8±10.1 days, respectively. Histological studies suggested a larger amount necrotic cells in the targeted area of liver in comparison to the no exposed to magnetic field and control.
Summary, GoldMag nanoparticles, as a new targeting drug delivery carrier, were capable of carrying drug for targeting therapeutic purposes due to its novel property. DOX-loaded PGMNs combined with external magnetic can significantly increase the level of drug concentration in specific site and reducing their systemic distribution as well as the possibility of administering lower but more accurately targeted doses of the drug in the treatments. This local therapy system could improve the therapeutic efficiency, reducing systemic toxicity. Our study will provide basis for GoldMag nanoparticles used to drug targeting delivery carrier.
引文
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