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

开发纳米治疗剂，通过精确靶向癌症相关成纤维细胞来促进免疫治疗

• 批准号: 21KK0197
• 负责人: Cabral Horacio
• 金额: $ 12.15万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
• 财政年份: 2021
• 资助国家: 日本
• 起止时间: 2021-10-07 至 2025-03-31
• 项目状态: 未结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21KK0197/
• 关键词: Nanomedicine; CAFs; Tumor microenvironments; Immunotherapy; Polymeric nanocarriers; Polymeric micelles; Antibody ligands; Tranilast; Fibroblasts

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.

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。这些纳米药物基于聚合物纳米载体，其配备有用于重编程或杀死CAF的配体和药物。在该项目的第一部分中，我们制备了基于叠氮封端的多臂PEG用于配体安装和聚（天冬氨酸）酸用于药物缀合的平台聚合物。此外，我们已经从全抗体制备了抗Fap Fab'，作为靶向CAF的配体。这些抗体用马来酰亚胺-DBCO修饰，用于通过点击化学与聚合物载体缀合。此外，我们一直在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个样品（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-β，导致负载阿霉素的脂质体（Doxil）和免疫检查点抗体的活性提高。这三种药合用根除了肿瘤。基于这些结果，我们已经向Nature Commun提交了我们的第一篇论文，并得到了评论者的积极评价。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和另一份关于固体应力和CAFs在人类胰腺肿瘤中的作用的出版物。后来的出版物将帮助我们决定我们在小鼠中的策略。

项目成果

Mechanically interlocked molecular architectures of valinomycin as cancer targeted prodrugs

• DOI: 10.1002/nano.202100368
• 发表时间: 2022-08-01
• 期刊: NANO SELECT
• 作者: Tachihara，Yoshihiro;Nakagawa，Yasuhiro;Cabral，Horacio
• 通讯作者: Cabral，Horacio