基于超支化聚乙烯亚胺的多功能纳米平台的构建及其肿瘤诊断与治疗应用

Development of multifunctional molecular imaging contrast agents and drug delivery systems for early-stage targeted cancer diagnosis and cancer therapy is one of the major topics in current nanomedicine and imaging diagnosis science. In this study, we aim to employ branched polyethyleneimine (PEI) partially modified with polyethylene glycol (PEG) as a basic platform to entrap gold nanoparticles (AuNPs) within the interior of the core-shell PEI/PEG polymers and modify Gd chelating agent with PEI surface primary amines for Gd(III) ion complexation. The final PEGylated PEI integrated with both AuNPs and Gd(III) will be used as a dual mode CT/MRI contrast agent. Furthermore, modification of the PEI primary amines with PEGylated folic acid is expected to be able to render the particles with ability to specifically target cancer cells overexpressing folic acid receptors. Meanwhile, the same targeting ligand-modified core-shell PEI/PEG polymers that do not contain AuNPs and Gd(III) ions will be used as a platform for encapsulation and release of a model anticancer drug doxorubicin for targeted therapy of the related tumor models. The use of cost-effective branched PEI as the basic platform and the functional PEGylation modification of PEI periphery are expected to be able to significantly improve the biocompatibility of the multifunctional nanoparticulate systems, realize the integration of the dual mode imaging elements in one nanaoparticle system, and render the particles with targeting specificity. This study will open new directions for the exploration of novel multifunctional nanoprobes and nanoparticulate drug delivery systems for accurate dual mode diagnosis and targeted therapy of cancer.

发展多功能分子影像学造影剂和药物缓释体系应用于癌症早期靶向诊断和治疗是当前纳米医学和影像诊断学发展的趋势。项目拟采用聚乙二醇（PEG）部分修饰的超支化聚乙烯亚胺（PEI）高分子为基础平台，通过在其内部包裹合成纳米金颗粒和在其表面部分伯氨基上修饰钆离子螯合剂进而螯合钆离子，获得双模态CT/MRI造影剂；通过对其表面修饰连接了靶向试剂叶酸的PEG链段，赋予纳米颗粒对表面表达叶酸受体的癌细胞的精确靶向。同时，项目利用相同的靶向试剂修饰的未整合造影元素的纳米平台，实现对模型抗癌药物阿霉素的包裹和释放，完成对相关癌细胞的靶向治疗。本研究采用价廉易得的超支化PEI作为基础平台，通过功能化PEG修饰，预期可以大大提高纳米颗粒的生物相容性、实现双重造影元素的整合和纳米颗粒的靶向功能，为探索新型的、多功能纳米造影剂和纳米载药体系应用于癌症的双模态精确诊断和靶向治疗开辟新的思路。

发展多功能分子影像学造影剂和药物缓释体系应用于癌症早期靶向诊断和治疗是当前纳米医学和影像诊断学发展的趋势。项目采用了聚乙二醇（PEG）部分修饰的超支化聚乙烯亚胺（PEI）高分子为基础平台，通过在其内部包裹合成纳米金颗粒得到了可用于血池CT造影和肿瘤造影的CT造影剂；进而在包裹纳米金颗粒的PEI外围修饰PEG化的叶酸，得到可用于高叶酸受体表达的肿瘤的特异性靶向CT探针，用于肿瘤的靶向CT诊断；在包裹纳米金颗粒的PEI外围修饰钆离子螯合剂进而螯合钆离子，获得双模态CT/MRI造影剂；通过对其表面修饰连接了靶向试剂叶酸或半乳糖酸的PEG链段，赋予纳米颗粒对表面表达叶酸受体或去唾液酸糖蛋白受体表达的癌细胞的精确靶向CT/MR诊断。同时，项目利用相同的靶向试剂修饰的未整合造影元素的纳米平台，实现对模型抗癌药物阿霉素的包裹和释放，完成对相关癌细胞的靶向治疗。本研究采用价廉易得的超支化PEI作为基础平台，通过功能化PEG修饰，大大提高纳米颗粒的生物相容性、实现双重造影元素的整合和纳米颗粒的靶向功能，为探索新型的、多功能纳米造影剂和纳米载药体系应用于癌症的双模态精确诊断和靶向治疗提供了重要借鉴，具有重要的理论和现实意义。