磁性纳米胶束在药物控制释放领域的应用研究
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摘要
本论文在合成出超顺磁性纳米粒子(SPIONs)的基础上制备了一系列磁性纳米胶束。它们是由SPIONs,聚醚类生物相容性高分子F127,F127与聚乳酸的共聚物(F127-PLA),靶向性配体(叶酸)构成。并通过红外分光光度计(FT-IR),X-射线衍射仪(XRD),振动样品磁强计(VSM),动态光散射激光仪(DLS),透射电子显微镜(TEM)和原子力显微镜(AFM)对该系列的磁性纳米胶束进行了表征。
首先,通过共沉淀法制备出SPIONs,它们在油相里能稳定分散,具有超顺磁性和较高的饱和磁化强度。
其次,通过化学接枝法将生物相容性高分子F127及F127-PLA与SPIONs相连接,该复合纳米粒子在水相可以通过自组装形成胶束。选用抗癌药物盐酸阿霉素(DOX·HCl)作为药物模型,研究其在中性,酸性及交变磁场作用下磁性胶束的体外药物释放行为。同时用Alamar blue法对系列磁性纳米胶束进行生物相容性评价,并对载药胶束对肿瘤的抑制作用的进行了材料对细胞的抗增殖评估。结果显示,磁性纳米胶束具有良好的生物相容性,当携载药物时,对肿瘤细胞生长有明显的抑制作用。
最后,针对上述磁性纳米胶束在药物输送体系中的局限性,本课题在磁性纳米胶束的基础上接枝了主动靶向配体-叶酸。这种靶向性磁性纳米胶束用于靶向给药体系中具有双重靶向性(即：叶酸靶向和磁靶向)。当其作为药物载体用肿瘤治疗时,能提高药物利用度和将药物输送到肿瘤部位的准确性。选用DOX·HCl作为药物模型研究在中性,酸性作用下磁性胶束的体外药物释放行为。并用Alamar blue法评估了载药胶束在不同条件下对肿瘤的抑制作用,细胞试验证明在有磁场作用下载药胶束对含叶酸配体的肿瘤细胞有更强的抑制作用。体内动物实验证明,该载药靶向性胶束在外加磁场的引导下,对腿部带VX2肿瘤的新西兰白兔的肿瘤部位能较精确的定位,并对肿瘤组织有较明显的治疗作用。综上所述,本论文制备的系列胶束作为药物载体在生物医学领域有着潜在的应用价值。
A Series of magnetic nanomicelles was synthesized based on the SPIONs, the biocompatible polymer-Pluronic F127 or its copolymer with poly(DL-lactic acid) (F127-PLA) and folic acid via a facile chemical conjugation method. The magnetic nanomicelles were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), vibrating sample magnetometer (VSM), dynamic light scattering measurements (DLS), transmission electron microscopy (TEM) and atomic force microscope (AFM).
Firstly, SPIONs were prepared by modified chemical co-precipitation. Their superparamagnetic behaviors and high saturation magnetization values are able to broaden their biomedical applications.
Secondly, SPIONs were chemically conjugated biocompatible Pluronic F127 and F127-PLA. The multifunctional magnetic nanoparticles formed into micelles in aqueous phase. Doxorubicin hydrochloride (DOX·HCl) was selected as a model anticancer drug to investigate the drug loading and release behaviors in the buffer solutions with different conditions. The Alamar blue assay was performed to evaluate the biocompatibility of the micelles and the antiproliferative effect of the drug-loaded micelles. The results displayed that the magnetic micelles were safe carriers and the DOX·HCl-loaded micelles suppressed the growth of the tumor cells.
Finally, the magnetic nanomicelles conjugated with folic acid as a potential platform for dual targeted (folate-mediated and magnetic-guided) drug delivery were developed to enhance the efficiency and veracity of drug delivering to tumor site. DOX·HCl was selected to investigate the drug loading and release behaviors in different conditions. The Alamar blue assay was performed to evaluate the antiproliferative effect of the drug-loaded micelles. The results displayed that the treatment efficacy of the drug would be enhanced by application of permanent magnetic field and folic acid. Additionally, The primary in vivo tumor model study, which was carried out in VX2 tumor-bearing male New Zealand white rabbits, demonstrated that the nanomicelles could be guided into tumor site more efficiently by application of permanent magnetic field, and further represented significant therapeutic efficiency to solid tumor. Therefore, the magnetic micelles possess many great potential applications in nanomedicine fields.
首先,通过共沉淀法制备出SPIONs,它们在油相里能稳定分散,具有超顺磁性和较高的饱和磁化强度。
其次,通过化学接枝法将生物相容性高分子F127及F127-PLA与SPIONs相连接,该复合纳米粒子在水相可以通过自组装形成胶束。选用抗癌药物盐酸阿霉素(DOX·HCl)作为药物模型,研究其在中性,酸性及交变磁场作用下磁性胶束的体外药物释放行为。同时用Alamar blue法对系列磁性纳米胶束进行生物相容性评价,并对载药胶束对肿瘤的抑制作用的进行了材料对细胞的抗增殖评估。结果显示,磁性纳米胶束具有良好的生物相容性,当携载药物时,对肿瘤细胞生长有明显的抑制作用。
最后,针对上述磁性纳米胶束在药物输送体系中的局限性,本课题在磁性纳米胶束的基础上接枝了主动靶向配体-叶酸。这种靶向性磁性纳米胶束用于靶向给药体系中具有双重靶向性(即：叶酸靶向和磁靶向)。当其作为药物载体用肿瘤治疗时,能提高药物利用度和将药物输送到肿瘤部位的准确性。选用DOX·HCl作为药物模型研究在中性,酸性作用下磁性胶束的体外药物释放行为。并用Alamar blue法评估了载药胶束在不同条件下对肿瘤的抑制作用,细胞试验证明在有磁场作用下载药胶束对含叶酸配体的肿瘤细胞有更强的抑制作用。体内动物实验证明,该载药靶向性胶束在外加磁场的引导下,对腿部带VX2肿瘤的新西兰白兔的肿瘤部位能较精确的定位,并对肿瘤组织有较明显的治疗作用。综上所述,本论文制备的系列胶束作为药物载体在生物医学领域有着潜在的应用价值。
A Series of magnetic nanomicelles was synthesized based on the SPIONs, the biocompatible polymer-Pluronic F127 or its copolymer with poly(DL-lactic acid) (F127-PLA) and folic acid via a facile chemical conjugation method. The magnetic nanomicelles were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), vibrating sample magnetometer (VSM), dynamic light scattering measurements (DLS), transmission electron microscopy (TEM) and atomic force microscope (AFM).
Firstly, SPIONs were prepared by modified chemical co-precipitation. Their superparamagnetic behaviors and high saturation magnetization values are able to broaden their biomedical applications.
Secondly, SPIONs were chemically conjugated biocompatible Pluronic F127 and F127-PLA. The multifunctional magnetic nanoparticles formed into micelles in aqueous phase. Doxorubicin hydrochloride (DOX·HCl) was selected as a model anticancer drug to investigate the drug loading and release behaviors in the buffer solutions with different conditions. The Alamar blue assay was performed to evaluate the biocompatibility of the micelles and the antiproliferative effect of the drug-loaded micelles. The results displayed that the magnetic micelles were safe carriers and the DOX·HCl-loaded micelles suppressed the growth of the tumor cells.
Finally, the magnetic nanomicelles conjugated with folic acid as a potential platform for dual targeted (folate-mediated and magnetic-guided) drug delivery were developed to enhance the efficiency and veracity of drug delivering to tumor site. DOX·HCl was selected to investigate the drug loading and release behaviors in different conditions. The Alamar blue assay was performed to evaluate the antiproliferative effect of the drug-loaded micelles. The results displayed that the treatment efficacy of the drug would be enhanced by application of permanent magnetic field and folic acid. Additionally, The primary in vivo tumor model study, which was carried out in VX2 tumor-bearing male New Zealand white rabbits, demonstrated that the nanomicelles could be guided into tumor site more efficiently by application of permanent magnetic field, and further represented significant therapeutic efficiency to solid tumor. Therefore, the magnetic micelles possess many great potential applications in nanomedicine fields.
引文
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