克服三阴性乳腺癌耐药的共输送载药系统的筛选及基于PDX模型的治疗价值研究

Triple negative breast cancer (TNBC) is one of the highly invasive malignancies among woman. However, no standard therapies have been documented to be effective and approved for this aggressive subtype of breast cancer. This is presumably attributable to the rapid occurrence of drug resistance after initial responsiveness to chemotherapeutic drugs such as paclitaxel and docetaxel. Cabazitaxel (CTX), a newly developed semi-synthetic taxane, is of particular interest to treat breast cancers due to its potential to circumvent the obstacles of drug resistance induced by taxanes. However, repeated dosing of CTX still confers TNBC with the resistance to this drug. Therefore, effective therapeutic strategies against TNBC are urgently desirable. In this project, we thus attempt to develop novel drug co-delivery systems wherein anticancer agent CTX and bioactive compound candidates are simultaneously included. To achieve this goal, we first will conduct a high-throughput screening procedure to screen a library containing nearly 2,600 bioactive compounds. This procedure will allow us to identify several drug candidates that are able to overcome the drug resistance induced by CTX. Next, we will elaborate synergistic combination of two distinct mode-of-action drugs, and the mechanisms underlying the synergistic cytotoxicity from cell-based assays. Finally, we will validate whether drug combinations that are delivered in single nanocarriers are able to overcome drug resistance in several TNBC parent-derived xenograft mouse models. These studies will provide preliminary experimental data and possible applications for the combination of CTX and other drugs and will be a breakthrough for anti-TNBC therapies.

三阴性乳腺癌（TNBC）对化学药物治疗不敏感，临床预后差，尚无有效的药物能够抑制或者根除TNBC的复发与进展。卡巴他赛（CTX）是新一代紫杉烷类药物，能有效克服紫杉醇及多西紫杉醇引起的耐药。本项目拟构建CTX与逆转CTX耐药的活性分子联用的的纳米药物体系并阐述其逆转TNBC耐药性及在TNBC病人组织来源的移植瘤模型(PDX)中的应用价值。首先，拟对生物活性药物文库进行高通量筛选并获得若干可以克服TNBC对CTX的耐药的候选化合物，同时构建CTX和活性分子的共载纳米药物体系。其次，运用细胞及分子生物学等技术手段，阐述纳米药物在药物联用上的分子机制及克服耐药效果。进一步地，我们将研究这些共载纳米药物在TNBC患者来源的PDX模型中的抗癌效果。本项目针对“TNBC的精准靶向治疗”关键科学问题，为临床的转化提供初步的实验数据与应用基础，有望为三阴性乳腺癌的治疗实现理论及技术上的突破。

三阴性乳腺癌缺乏有效的治疗靶点，临床上预后较差。卡巴他赛是新一代紫杉烷类药物，能有效克服紫杉醇和多西紫杉醇引起的多药耐药，在三阴性乳腺癌中显示出较好的抗肿瘤活性。在本项目中，我们构建新型药物制剂并联合多种药物精准靶向癌变病灶，探索提高临床药物疗效的递送方案，具有较好的临床研究意义和科学价值。.1）探索抗癌药物的“分子编辑”技术，构建基于小分子前药策略的新型药物制剂：针对卡巴他赛体内毒副作用大的临床现状，利用多种长链不饱和脂肪酸合成化合物文库，获得高效安全，可快速药物激活的体内递送新方案（Cancer Res. 2017；Mol. Cancer Ther., 2020；Nano Today, 2021；J. Controlled Release, 2020）。此外，我们发现多不饱和脂肪酸化也适用于免疫抑制剂的纳米自组装，可用于器官移植术后的抗排异治疗；这些研究为免疫抑制剂的局部递送和抗排异新药的研发提供了新思路（J. Controlled Release, 2020；Am. J. Transplantation, 2021）。.2）聚合物衍生药物技术用于精准调控药物的药代动力学、药效及副作用：选用不同分子量的寡/聚乳酸或寡/聚己内酯共价衍生生物活性分子，制备的前药易与两亲性共聚物组装成长循环纳米制剂，拓宽了药物的临床应用前景（Adv. Funct. Mater., 2018；Biomaterials, 2021；Theranostics, 2021；Theranostics, 2018；ACS Appl. Mater. Interfaces, 2020）。.3）利用分子间的非共价相互作用构建高载药量的超分子药物递送系统：利用药物的两亲性及疏水性的分子特征，构建具有自组装能力的新型药物制剂并可用于注射给药，在提高载药量和生物利用度的同时，一定程度上减轻了药物的体内毒副作用（Nanoscale Horizons, 2021；J. Controlled Release, 2020；Acta Biomaterialia, 2020；Theranostics, 2021）。.在本项目的资助下，项目负责人以通讯作者（含共同通讯）累计发表学术论文42篇，篇均影响因子9.58，其中影响因子10以上论文15篇。以第一发明人获得国家发明专利授权11项。