Development of nanotherapeutic agents that boost immunotherapy by precision targeting of cancer-related fibroblasts

在这个项目中，我们的目标是开发针对癌症相关成纤维细胞(CAF)的纳米药物。这些纳米药物是基于配备了配体和药物的聚合物纳米载体，用于重新编程或杀死CAF。在本项目的第一部分中，我们制备了用于配体安装的叠氮端多臂聚乙二醇基平台聚合物和用于药物偶联的聚天冬氨酸。此外，我们还从完整的抗体中制备了抗Fap Fab‘作为靶向CAF的配体。这些抗体用马来酰亚胺-DBCO修饰，通过点击化学与聚合物载体偶联。此外，我们一直通过在线会议与塞浦路斯大学的合作者深入讨论我们的进展。我们已经发送了我们的第一批样品(曲尼司特负载胶束)，用于修饰肿瘤CAF和促进乳腺肿瘤的化疗免疫治疗。结果表明，曲尼司特胶束能抑制CAF中的转化生长因子-β，但不能抑制游离曲尼司特，从而提高阿霉素脂质体和免疫检查点抗体的活性。这三种药物的组合根除了肿瘤。基于这些结果，我们已经向《自然》杂志提交了我们的第一份出版物，并得到了评审者的积极评价。我们现在正在准备修订。此外，我们正在准备一份关于聚合物合成的出版物，以及另一份关于固体压力和CAF在人类胰腺肿瘤中的作用的出版物，进行一项回顾性研究。后来的出版物将帮助我们决定我们在MICE上的策略。

In this project, we aim to develop nanomedicines for targeting cancer associated fibroblasts (CAFs). These nanomedicines are based on polymeric nanocarriers equipped with ligands and drugs for reprogramming or killing CAFs. In this first part of the project, we have prepared the platform polymer based on azide-terminated multi-arm PEG for ligand installation and a poly(aspartic) acid for drug conjugation. Moreover, we have prepared anti-Fap Fab' from whole antibodies as a ligand for targeting CAFs. These antibodies where modified with maleimide-DBCO for conjugation to the polymeric carriers via click chemistry. In addition, we have been discussing our progress thoroughly with our collaborators in Cyprus University via online meetings. We have sent our first samples (tranilast-loaded micelles) for modifying the tumor CAFs and promoting chemoimmmunotherapy in breast tumors. The results showed that the tranilast-loaded micelles, but not free tranilast, can inhibit TGF-b in CAFs, leading to the improved activity of doxorubicin-loaded liposomes (Doxil) and immune checkpoint antibodies. The combination of the three drugs eradicated the tumors. Based on these results, we have submitted our first publication to Nature Commun., and received positive commments from the reviewers. We are now preparing the revision. Also, we are preparing a publication on the polymer synthesis and another publication on the role of solid stress and CAFs in human pancreatic tumors by doing a retrospective study. The later publication will help us decide our strategies in mice.