新型叶酸－金属配合物自组装纳米管作为纳米药物和多功能药物载体的抗肿瘤作用研究

Despite numerous studies have reported that nanotechnology applied in drug delivery and cancer treatments perform great potential prospects, there were rare researches about nanoparticles acted as a nanomedicine and simultaneous drug carrier for biomedical application. In our study, we develop new strategies to construct a multifunctional metal-folic acid complex nanotubes (FCNTs) as a kind of nanomedicine and a target drug delivery system through self-assembled, which is largely different from the traditional folate-decorated nanoparticles only for drug delivery. The novel nanotube is expected to achieve following major functions: (1) the nanotube itself has high anti-tumor activity; (2) it can effectively load chemotherapeutic agents and delivery into the target tumor cells through folate-receptor as a drug carrier; (3) the metal-folic complex would exhibit magnetothermal effect under the external magnetic field. The preliminary results demonstrated that nickel folic acid complex nanotubes with homogeneous tublar morphology can be obtained through coordination of Ni(II) with biological ligand folic acid via self-assembled construction. The materials not only express high inhibition effect on the tumor cells in vitro, but also can be served as a target drug delivery system after loading the anticancer drug inside the hollow cavity. For further investigations, we will establish a simple and controllable synthesis of folic acid complex nanomedicine which could be extended to different types of metal, bridging groups and surface modifiers. After loading with small molecular drugs, combining chemotherapy with the magnetothermal effect, the synergistic anti-tumor activity in vitro and in vivo of the nanotubes drug system are evaluated to screen the optimal candidate. The pharmacokinetics and biodistribution studies of the candidate in vivo are also assessed to acquire a suitable nanomedicine for further clinic.

纳米技术应用于药物的输送和治疗前景广泛，但纳米颗粒作为药物直接用于肿瘤治疗并兼作药物载体鲜有报道。本项目中，有别于传统的叶酸修饰的各类药物载体，我们以发现新型纳米药物和实现靶向递药为双重目标，构建集多种功效于一体的生物基叶酸－金属配合物纳米管，期望在其自身具备抗肿瘤活性的同时，能协同磁热效应和叶酸受体介导的靶向递药功能，高效输送小分子药物，联合发挥多机制抗肿瘤作用。前期实验证实，经分子组装直接构筑的叶酸－镍配合物纳米管，不仅表现出较强的体外肿瘤细胞抑制活性，还能实现对装载药物的靶向递送。我们将进一步从化学组成上拓展纳米管种类，实现可控合成。考察磁热效应和叶酸靶向递药，继而在进行小分子药物装载后，研究载药体系的体、内外抗肿瘤活性，筛选出活性较好的载药系统开展初步的动物体内药代动力学和组织分布测试，以综合评价该载药体系的多功能协同抗肿瘤作用，为全面开发此类新型配合物抗肿瘤纳米材料提供新思路。

纳米技术应用于药物输送和治疗前景广泛，但纳米材料作为药物直接用于肿瘤治疗并兼作药物载体却鲜有报道。本项目根据前期研究成果，对通过分子组装直接构筑的叶酸－镍配合物纳米管的活性进行了研究，发现其自身不仅具备较强的体、内外抗肿瘤活性，同时还能协同叶酸受体介导的靶向递药功能，高效输送小分子药物，实现了联合发挥多机制抗肿瘤的作用。此后，我们从化学组成上拓展了纳米管种类，实现了可控合成，并对叶酸－钴配合物纳米管体内外的抗肿瘤活性进行了探究，同样得到了较好的结果。药理结果显示，叶酸-镍/钴配合物纳米管不仅表现出较强的体内外肿瘤细胞抑制活性，同时对正常细胞和组织无明显毒副作用。进一步的体内分布和药代动实验结果显示，纳米管在给药后分布较快，体内清除时间适中，肿瘤部位滞留时间较长。在保持原有抗肿瘤活性基础上，对此类叶酸－金属配合物纳米管进行了表面亲水性修饰，一定程度上改善了其溶解性和分散性。该工作为发现一类生物基金属纳米抗肿瘤药物奠定了理论和实验基础。