Affiliation:
1. Department of Radiology Huaxi MR Research Center (HMRRC) Metabolomics and Proteomics Technology Platform Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 China
2. Functional and Molecular Imaging Key Laboratory of Sichuan Province and Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 China
3. Department of Radiology West China Xiamen Hospital of Sichuan University Xiamen 361021 China
Abstract
AbstractUnsatisfied tumor accumulation of chemotherapeutic drugs and a complicated immunosuppressive microenvironment diminish the immune response rate and the therapeutic effect. Surface modification of these drugs with target ligands can promote their cellular internalization, but the modified drugs may be subjected to unexpected immune recognition and clearance. Herein, a phenylboronic acid (PBA) group‐shieldable dendritic nanomedicine that integrates an immunogenic cell death (ICD)‐inducing agent (epirubicin, Epi) and an indoleamine 2,3‐dioxgenase 1 (IDO1) inhibitor (NLG919) is reported for tumor chemo‐immunotherapy. This NLG919‐loaded Epi‐conjugated PEGylated dendrimers bridged with boronate bonds (NLG919@Epi‐DBP) maintains a stable nanostructure during circulation. Under a moderate acidic condition, the PBA group exposes to the sialic acid residue on the tumor cell membrane to enhance the internalization and penetration of NLG919@Epi‐DBP. At pH 5.0, NLG919@Epi‐DBP rapidly disassembles to release the incorporated Epi and NLG919. Epi triggers robust ICD of tumor cells that evokes strong immune response. In addition, inhibition of the IDO1 activity downregulates the metabolism of L‐tryptophan to kynurenine, leading to a reduction in the recruitment of immunosuppressive cells and modulation of the tumor immune microenvironment. Collectively, this promising strategy has been demonstrated to evoke robust immune response as well as remodel the immunosuppressive microenvironment for an enhanced chemo‐immunotherapeutic effect.
Funder
National Natural Science Foundation of China
National Key Research and Development Program of China
West China Hospital, Sichuan University
China Postdoctoral Science Foundation
Subject
Mechanical Engineering,Mechanics of Materials,General Materials Science