转铁蛋白受体单克隆抗体修饰的靶向载药纳米粒抗淋巴瘤效应的研究

More attention has been focused on the targeting therapy on cancer in resent years. Transferrin receptor (TfR) was found to be highly expressed on the surface of lymphoma cell in many studies.Polymer nanocarrier linked with transferrin receptor monoclonal antibody (TfR mAb) with more drug entrapping rate will show better targeting ablitily and be more safety, which can also help drugs cross the blood-brain barrier into central nervous system (CNS).Our initial studies have prepared PLGA-PLL-PEG copolymer modified with transferrin (Tf), act as DNR and Tet carrier, which had better targeting effect on killing leukemia in vitro and in vivo.In this study we intend to optimize the synthesis of PEG-PLL-PLGA，coloaded with MTX and Rituximab，then conjugate TfR mAb to the surface of PEG-PLL-PLGA to construct a drug delivery system with active targeting ability to tumor cells. Different detection technology will be used for the quality control. The targeting antitumor ability against central nervous system lymphoma (CNSL) will be observed. Biocompatibility, pharmacokinetic and side effects will also be studied at the same time. TfR mAb-PEG-PLL-PLGA will be an effective approach to the clinic targeted therapy of CNSL.

淋巴瘤细胞膜表面转铁蛋白受体（TfR）高表达，偶联TfR配体——转铁蛋白受体单克隆抗体（TfR mAb）的靶向纳米粒作为抗肿瘤药物的给药载体，具有更好的靶向性、包载率及安全性，并可提高运送药物进入血脑屏障的能力。我们前期已成功构建转铁蛋白（Tf）修饰的PLGA-PLL-PEG多聚物纳米载体，并同时包载了亲水性及疏水性药物，体内外模型中均显示了良好的靶向抗肿瘤效应。本项目拟构建新型TfR mAb修饰的同时包裹化疗药MTX和抗CD20单抗的载药纳米粒，探索临床治疗淋巴瘤尤其是颅内淋巴瘤的新策略:1.优化TfR mAb与MTX、抗CD20单抗的装载条件，拟开发出一种新型安全高效的靶向纳米药物，评估其安全性、稳定性和生物相容性；2.观察其对B细胞淋巴瘤细胞的杀伤效应及摄取分布；3.应用颅内及多部位荷瘤动物模型，进行疗效、安全性及体内分布的研究，探讨其在体内靶向抗肿瘤效应的机制，为临床应用提供依据。

纳米颗粒可以同时将两种抗癌药物运送至癌细胞并增加其药物浓度，从而达到靶向抗癌的效果。本研究中我们制备了一种有效的药物装载纳米颗粒，首先合成利妥昔单抗/甲氨蝶呤-聚乙二醇-聚赖氨酸-聚乳酸羟基乙酸多聚物（Rituximab/MTX-PEG-PLL-PLGA），并交联转铁蛋白单克隆抗体（TfR mAb）。与传统单药联合相比，载药纳米粒可以精确有效的将利妥昔单抗和甲氨蝶呤运送至SU-DHL-4细胞株并增加其凋亡。载有多种功能药物的纳米颗粒显示出持久的稳定性和精确的靶向特性，增强了B淋巴细胞的抗癌效率。.经筛选后2套数据集纳入我们的研究：GSE32918和GSE57611。使用Limma鉴定了与R-CHOP治疗相关的差异表达基因（DEGs）。结合GSE32918中的预后信息，使用单变量Cox回归分析选择与预后显著相关的DEGs，并构建风险预测模型。基于此模型，将GSE32918分为高风险组和低风险组。从这116个与预后相关的基因中，在初发弥漫大B细胞淋巴瘤（DLBCL）和R‑CHOP治疗后样本之间共鉴定出801个DEGs。使用风险预测模型，选择了12个基因的最佳组合，并建立了样本风险评分预测模型且进行了验证。以期为DLBCL的临床治疗方案选择与预后判断提供指导。