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（CAFs）的纳米药物。这些纳米药物是基于聚合物纳米载体，配备配体和药物，用于重编程或杀死CAFs。在项目的第一部分中，我们制备了基于叠氮端多臂聚乙二醇的平台聚合物用于配体安装，并制备了聚天冬氨酸用于药物偶联。此外，我们还从全抗体中制备了抗fap Fab'作为靶向caf的配体。这些抗体用马来酰亚胺- dbco修饰，通过点击化学偶联到聚合物载体上。此外，我们一直在通过在线会议与塞浦路斯大学的合作者彻底讨论我们的进展。我们已经发送了我们的第一个样品（曲尼司特装载胶束），用于修饰肿瘤的caf和促进乳腺肿瘤的化学免疫治疗。结果表明，负载曲尼司特的胶束，而不是游离曲尼司特，可以抑制CAFs中的TGF-b，从而提高负载阿霉素脂质体（Doxil）和免疫检查点抗体的活性。三种药物联合使用根除了肿瘤。基于这些结果，我们已经向Nature common提交了我们的第一篇论文。，并得到了审稿人的积极评价。我们正在准备修改。此外，我们正在准备一篇关于聚合物合成的论文，以及另一篇关于固体应力和CAFs在人类胰腺肿瘤中的作用的论文，这是一项回顾性研究。后来的出版物将帮助我们决定我们在老鼠身上的策略。

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.