治疗监测一体化的pH敏感-酶控型口服结肠靶向释药系统研究

Investigation of oral colon-targeting drug delivery system for the treatment and diagnosis of colon cancer is of great significance. This study intends to construct an oral colon-targeting-theranostic drug delivery system with pH-sensitive and enzymes-responsive properties , and its application will be evaluated in experimental colon cancer. Firstly, the lanthanoid-contained (Gd3+ and Yb3+) mesoporous hydroxyapatite nanoparticles with CT and MRI imaging functions are prepared, and then the target therapy drug gefitinib and the chemotherapeutic drug 5-fluorouracil are co-loaded into the nanoparticles to achieve a combination therapeutic effect as well as real-time monitoring of the tumor. According to the characteristics of the microbial flora at colon, the guar gum is introduced as a coating agent on the surface of the drug-loaded nanoparticles as an “on-and-off switch”, which could respond to the colon glycosidase for achieving the colon-specific drug release. Besides, according to the pH characteristics of the gastrointestinal tract, a layer of methacrylic acid copolymer (Eudragit ® S100) is wrapped on the surface of the guar gum-coated nanoparticles to prevent the drug leakage in the gastrointestinal tract due to the swelling of the guar gum. In summary, a theranostic pH-sensitive and enzymes-responsive oral colon-targeting drug delivery system with CT and MRI imaging function is constructed for efficient treatment of colon cancer. The drug release profile, tumor monitoring capability, combination therapeutic effect of target therapy and chemotherapy as well as its mechanism will be evaluated in details in vitro and in vivo.

探索治疗监测一体化的口服结肠靶向释药系统对结肠癌的治疗具有重要意义。本课题拟构建一种治疗监测一体化的pH敏感-酶控型口服结肠靶向释药系统，并探索其在实验性结肠癌中的运用。首先制备掺有镧系元素（Gd3+和Yb3+）的具有CT和MRI成像功能的载体介孔羟磷灰石纳米粒，使之能够对肿瘤进行实时监测；然后联合负载分子靶向药物吉非替尼和化疗药物5-氟尿嘧啶，形成分子靶向治疗与化疗相结合的治疗监测系统。根据结肠的微生物菌群特点，本研究采用瓜尔豆胶覆盖在载药纳米粒表面形成 “门控开关”，响应结肠的糖苷酶形成酶控型的结肠靶向释药系统。最后根据胃肠道的pH特点，在纳米粒最外层包裹一层甲基丙烯酸共聚物（Eudragit® S100），防止药物在胃肠道因溶胀而发生渗漏现象。我们将在体外和体内全面研究该系统的释药特性，对肿瘤的监测，靶向药物与化疗的联合治疗作用及其机制。

我们已经成功构建了基于治疗监测一体化的pH敏感-酶控型口服结肠靶向释药系统，还根据肠道微生物菌群的特点成功构建了基于益生菌的口服药物递送系统，并且分别在体外和体内进行了系列表征。我们首先制备了掺入钆离子的介孔羟基磷灰石纳米棒以及PVA修饰的超小型磁性氧化铁，并进行了体外表征。结果显示，两种载体均具有易于修饰、能够高效负载和递送化疗药物的功能，并且具有响应肠道pH环境的特点，从而增强药物在胃酸环境中的稳定性及在结肠部位释放治疗药物。体内外研究表明，该纳米载体在体内外均具有较好的T1/T2加权成像效果。研究显示，所构建的掺入钆离子的介孔羟基磷灰石纳米棒以及PVA修饰的超小型磁性氧化铁两种载体负载化疗药物的能力都较强，两者分别用肠道pH响应的材料修饰后，均成功实现了肿瘤的靶向诊断功能。此外，鉴于基于肠道微环境变化构建口服纳米药物递送系统展现出的巨大潜力，我们创新性地构建了一种口服自主纳米“生成器”，也能克服药物递送中的多重生物屏障，实现肿瘤靶向治疗的功能。与此同时，我们还探索了其他肿瘤联合治疗策略的研究。通过本项目的实施，到目前为止已有5篇SCI论文发表，授权发明专利1项。通过本项目的实施，培养了6名硕士研究生和2名博士研究生。

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