多模式智能诊断及明胶酶刺激响应的纳米抗癌药物载体的研制

Nanomedicine is one of the most important technologies in the 21st century. It is promising to be a novel platform for disease diagnosis and therapy. In this project, we plan to fabricate a complex assembly consisting of hollow and mesoporous Fe3O4@mSiO2 (MCM-41) nanocapsule and gelatin-coated NaGdF4:Yb3+/Tm3+ nanocrystallines by a facile pathway. Among them, Fe3O4 and NaGdF4:Yb3+/Tm3+ play the roles of negative (T2) and positive (T1) contrast agent for magnetic resonance imaging (MRI), respectively. Simultaneously NaGdF4:Yb3+/Tm3+ is considered as an effective NIR-to-NIR probe for upconversion fluorescence imaging. The novel multi-mode medical imaging technology is significant for the early and accurate diagnosis of cancer. In addition, gelatin can be degraded by the gelatinase (MMP-2/MMP-9) which is over-expressed in the tumor tissues, and trigger the drug release from the nanocarriers. Because gelatinase is an important diagnosis index for cancer evaluation, the stimuli-responsive property to gelatinase of the multi-mode imaging agent is expected to be a smart diagnosis platform for cancer and provide the intelligent analysis capabilities.

纳米医学是21世纪医学技术的重要方向之一，有希望为疾病的诊断和治疗提供新颖的综合性平台。本项目拟通过一系列简单可行的手段制备具有中空和介孔结构的Fe3O4@mSiO2（MCM-41）纳米胶囊与明胶包覆的NaGdF4:Yb3+/Tm3+纳米晶的组装体。其中Fe3O4为T2负向磁共振（MRI）造影剂，NaGdF4:Yb3+/Tm3+为T1正向MRI造影剂同时具有上转换荧光性质，多模式医学造影功能对于癌症的早期和精确诊断具有重要的意义。另外，载体能够对肿瘤组织中高表达的明胶酶（MMP-2/MMP-9）做出响应并引发药物释放。同时，由于明胶酶是癌症诊断等重要指标，T1和T2复合造影剂的组装/解体行为有希望为癌症诊断提供智能分析功能和更加丰富的信息。

本项目中，我们围绕项目背景制备了多种模式的具有诊断功能及酶刺激响应的纳米抗癌药物载体，为癌症的治疗提供潜在的智能的多功能药物平台。取得的主要成果如下：（1）我们发现明胶作为一种新颖的生物相容性好的高分子可以包裹疏水的纳米粒子，使其分散于水中，由于明胶具有丰富的羧基/胺基/羟基，为纳米粒子的进一步表面功能化提供了活性基团，因此明胶为纳米粒子的生物应用提供了多种多样的可能性。另外明胶可以被胰酶降解，促进药物的释放。因此，我们制备了明胶包裹的Fe3O4纳米粒并共价键偶联铂前药，对酶刺激响应释放药物及MRI进行了研究。（2）以中空FeOOH为模板包覆SiO2后还原，制备中空的Fe3O4@SiO2棒状纳米胶囊，并在表面沉积NaYF4:Yb,Er上转换发光材料，制备了多模式成像的纳米药物载体。（3）利用明胶包裹上转换发光纳米粒子，并利用羧基和抗癌药物DOX通过腙键偶联，获得了pH 响应释放的DOX前药，同时获得了上转换发光及核磁共振生物成像多功能的药物负载平台。