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.
Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China.
Adv Mater. 2024 Jan;36(2):e2307263. doi: 10.1002/adma.202307263. Epub 2023 Nov 23.
Unsatisfied 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.
化疗药物在肿瘤部位的蓄积不理想和复杂的免疫抑制微环境降低了免疫反应率和治疗效果。用靶向配体对这些药物进行表面修饰可以促进它们的细胞内化，但修饰后的药物可能会受到意想不到的免疫识别和清除。本文报道了一种苯硼酸（PBA）基团屏蔽的树枝状纳米药物，它将免疫原性细胞死亡（ICD）诱导剂（表柔比星，Epi）和吲哚胺 2,3-双加氧酶 1（IDO1）抑制剂（NLG919）整合在一起，用于肿瘤化疗免疫治疗。这种负载 NLG919 的 Epi 缀合的聚乙二醇化树枝状聚合物通过硼酸酯键桥接（NLG919@Epi-DBP），在循环过程中保持稳定的纳米结构。在中等酸性条件下，PBA 基团暴露在肿瘤细胞膜上的唾液酸残基上，以增强 NLG919@Epi-DBP 的内化和穿透。在 pH 5.0 时，NLG919@Epi-DBP 迅速解体，释放出所包含的 Epi 和 NLG919。Epi 引发肿瘤细胞强烈的 ICD，引发强烈的免疫反应。此外，抑制 IDO1 活性可下调 L-色氨酸向犬尿氨酸的代谢，从而减少免疫抑制细胞的募集和肿瘤免疫微环境的调节。总的来说，这种有前景的策略被证明可以引发强烈的免疫反应，并重塑免疫抑制微环境，从而增强化疗免疫治疗效果。
