大配体铂(IV)配合物-氧化铁多功能复合纳米药物的构筑及其在肿瘤治疗中的应用

Cisplatin, carboplatin and oxaliplatin are three major classic divalent metal platinum drugs which are widely used in clinical [abbreviated as Pt(II)]. But they all have the drawbacks such as low bioavailability, significant side effects, tumor drug resistance. At present, to solve above problems, we proposed some strategies which included (1) introducing bulky ligands into platinum(IV) prodrug molecules [abbreviated as Pt(IV)], which can reduce side effects and dramatically minimize the “deactivation” effect; (2) preparation of nano-scale magnetic ferric oxide carriers for Pt(IV) drugs which can change the route of administration and overcome the drug resistance of tumor; (3) design Pt(IV) drugs which are covalently linked with another anticancer drug cantharidin for precise combination therapy; (4) multiple levels of tumor targeting and drug delivery strategies are used in combination (passive/active targeting, magnetic targeting) which can increase the concentration of drug accumulation in the tumor tissue. Taken together, the present project aims to design a new multifunctional nano-drug delivery system in which there are platinum (IV) prodrugs for delivery, combination therapy, multi-level tumor targeting for drug delivery, magnetic resonance imaging (MRI). Here, we can systematically carry out the research on reversal of ovarian cancer resistance, inhibition of tumor invasion and metastasis, which can provide a theoretical basis and data support for inorganic platinum nano-drug delivery system research.

顺铂、卡铂、奥沙利铂是临床上应用最广泛的三大经典的二价金属铂类药物[简称，铂(II)]。但它们普遍存在生物利用率低、毒副作用大、易产生肿瘤耐药性等需要克服的问题。目前，针对上述问题，本项目拟采取的策略包括：(1)合成大配体取代的四价铂前药[简称铂(IV)]，减小毒副作用，大幅降低“去活化”作用；(2)制备纳米尺度的磁性氧化铁载体用于担载铂(IV)，改变给药途径，克服肿瘤耐药性；(3)与另一种抗癌药物斑蝥素共价连接用于肿瘤联合治疗；(4)多层次肿瘤靶向给药策略联合使用(被动/主动靶向、磁靶向)，提高药物在肿瘤组织的蓄积浓度。本项目旨在获得一类新型的集铂(IV)前药传递、联合治疗、多层次肿瘤靶向给药、磁共振成像为一体的多功能纳米药物控释系统，系统开展其在卵巢癌耐药逆转、抑制肿瘤侵袭、转移等方面的研究，为无机纳米铂药载体的研究提供理论依据和数据支撑。

该项目以无机纳米铂药传递及生物应用为主题，围绕新型铂(IV)的设计与合成、无机纳米载体的构筑、药物的靶向传递及释放、联合多种治疗模式的抗肿瘤研究等开展了系统深入的研究:(1) 发展了系列无机纳米铂前药载体，如磁性氧化铁体系、二硫化钼体系、稀土上转换纳米体系等，系统研究其抗肿瘤活性及相关机制；(2)拓展了几种锰基的纳米复合体系，利用肿瘤微环境响应的特性，实现药物的可控释放及刺激响应的生物医学成像；(3)构筑超大介孔包覆的上转换纳米体系用于协同负载抗原及光敏剂，探索其作为免疫佐剂，实现了近红外光响应的光动力免疫协同治疗等。本项目发表SCI论文22篇，申请发明专利1项，参加国内国际学术会议10余次，培养研究生8名。