构建优化胰腺癌mFOLFIRINOX方案的仿生靶向给药系统及可视化定量评价体系

mFOLFIRINOX multi-drug combination scheme enables patients to achieve a longer survival period and is expected to become the standard adjuvant therapy for pancreatic cancer. However, this regimen has poor selectivity, wide distribution in vivo, no specificity and severe toxic and side effects, which greatly limits its clinical promotion. Therefore, how to ensure the standardized application of this protocol while significantly reducing the toxic and side effects of multi-drug combination has become one of the bottleneck problems to be solved in the adjuvant treatment of pancreatic cancer at present. In this study, pancreatic cancer cell membrane fragments were used as homologous chemotactic elements to synthesize the "shell" coating (PCs-C) of bionic targeted drug carrier, covering the PLA-TPGS polymerization. The drug and optical/magnetic particle ICG&Fe3O4 core were used as the "treatment/tracer core". Firstly, the homotactic chemotaxis of the bionic "shell" was used to improve the intradermal enrichment and prolong the circulation time. Secondly, PLA-TPGS/m@ICG&Fe3O4 kernel-mediated drug entry was performed. Thus, "homologous trend" and "regional targeting" can be superimposed to deliver drugs. The critical cellular molecular events of PCs-C/PLA-TPGS/m were visualized by multi-modal molecular imaging and evaluation of the efficacy of the system with the IC50 quantitative comparison.

mFOLFIRINOX多药联合方案使患者获得更长生存期，有望成为胰腺癌辅助治疗标准方案。然而，该方案给药方式选择性差，体内分布广泛、无特异性且毒副反应严重，极大地限制其临床推广。故此，如何在确保该方案标准化应用的同时显著降低多药联合的毒副作用已成为目前胰腺癌辅助治疗亟待解决的瓶颈问题之一。本课题以胰腺癌细胞膜片段作为同源趋化元件合成仿生靶向药物载体“外壳”涂层（PCs-C），覆盖PLA-TPGS聚合该方案药物与光学/磁性粒子ICG&Fe3O4核心作为“治疗/示踪内核”。首先，利用仿生 “外壳”的同源趋化作用提高药物瘤内富集能力和延长循环时间；其次，以PLA-TPGS/m@ICG&Fe3O4内核介导药物入胞。从而，实现“同源趋向”与“区域靶向”的叠加药物递送。以多模态分子显像将PCs-C/PLA-TPGS/m给药体系治疗胰腺癌的关键性细胞分子事件可视化并以IC50定量比较评价该体系疗效。

mFOLFIRINOX多药联合方案使患者获得更长生存期，有望成为胰腺癌辅助治疗标准方案。然而，该方案给药方式选择性差，体内分布广泛、无特异性且毒副反应严重，极大地限制其临床推广。故此，如何在确保该方案标准化应用的同时显著降低多药联合的毒副作用已成为目前胰腺癌辅助治疗亟待解决的瓶颈问题之一。本课题以胰腺癌细胞膜片段作为同源趋化元件合成仿生靶向药物载体“外壳”涂层（PCs-C），覆盖PLGA聚合该方案药物与光学/磁性粒子的PLGA/m@ICG&Fe3O4核心作为“治疗/示踪内核”。首先，利用仿生“外壳”的同源趋化作用提高药物瘤内富集能力和延长循环时间；其次，以PLGA聚合的治疗/示踪内核介导药物入胞。从而，实现“同源趋向”与“区域靶向”的叠加药物递送。并且，以光学/磁性粒子的多模态分子显像能力，将优化给药体系PCs-C/PLGA/m治疗胰腺癌过程中的生物分布、药物代谢及关键细胞分子事件可视化。