Transferrin receptor-targeted immunostimulant for photodynamic immunotherapy against metastatic tumors through β-catenin/CREB interruption  

作　　者：Mengyi Yan Xiayun Chen Xiaotong Li Qianqian Liu Baixue Yu Yi Cen Wei Zhang Yibin Liu Xinxuan Li Ying Chen Tao Wang Shiying Li 

机构地区：[1]The Fifth Affiliated Hospital,Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacology,the NMPA and State Key Laboratory of Respiratory Disease,the School of Pharmaceutical Sciences,Guangzhou Medical University,Guangzhou 511436,China [2]Department of Anesthesiology,the Second Clinical School of Guangzhou Medical University,Guangzhou 511436,China [3]State Key Laboratory of Respiratory Diseases,Guangdong Key Laboratory of Vascular Diseases,Guangzhou Institute of Respiratory Health,the first Affiliated Hospital,Guangzhou Medical University,Guangzhou 510120,China [4]Department of Pulmonary and Critical Care Medicine,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第9期4118-4133,共16页药学学报（英文版）

基　　金：the financial support of National Key R&D Program of China(No.2021YFD1800600);the National Natural Science Foundation of China(No.32371394);the Guangdong Basic and Applied Basic Research Foundation(No.2021B1515020043,China);the Special Projects in Key Areas of Colleges and Universities in Guangdong Province(No.2022ZDZX2046,China);Open Research Foundation of State Key Laboratory of Respiratory Diseases(No.SKLRD-OP-202204,China).

摘　　要：The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional treatments.In this work,a transferrin receptor(TfR)targeted immunostimulant(PTI)is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting β-catenin signal pathway.To synthesize PTI,the photosensitizer conjugated TfR targeting peptide moiety(Palmitic-K(PpIX)-HAIYPRH)is unitized to encapsulate the transcription interrupter of ICG-001.On the one hand,the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumorassociated antigens.On the other hand,PTI will interrupt the binding between b-catenin andcAMP response element-binding protein(CREB),regulating the gene transcription to downregulate programmed death ligand 1(PD-L1)while upregulating CeC motif chemokine ligand 4(CCL4).Furthermore,the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration,and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung metastasis.This work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.

关 键 词：Transferrin receptor β-Catenin signal pathway Tumor targeting Photodynamic therapy IMMUNOTHERAPY Immunogenic cell death Programmed death ligand 1 C-C motif chemokine ligand 4 

分 类 号：R730.51[医药卫生—肿瘤]