Shen Fengyun, Feng Liangzhu, Zhu Yujie, Tao Danlei, Xu Jun, Peng Rui, Liu Zhuang
Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Institute of Functional Nano and Soft Materials (FUNSOM), Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu, 215123, China.
Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Institute of Functional Nano and Soft Materials (FUNSOM), Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu, 215123, China.
Biomaterials. 2020 Oct;255:120190. doi: 10.1016/j.biomaterials.2020.120190. Epub 2020 Jun 12.
High expression of indoleamine 2,3-dioxygenase 1 (IDO1) is a major cause of tumor induced immunosuppression, and appears to be associated with poor prognosis in human colorectal cancer and some others. In this study, we construct a bifunctional liposome by self-assembly of oxaliplatin-prodrug (Oxa(IV)) conjugated phospholipid and alkylated NLG919 (aNLG), an IDO1 inhibitor, together with other commercial lipids. The obtained aNLG/Oxa(IV)-Lip can not only release cytotoxic oxaliplatin inside the reductive cytosol to trigger immunogenic cell death (ICD) of cancer cells, but also efficiently retard the degradation of tryptophan to immunosuppressive kynurenine via the NLG919 mediated inhibition of IDO1. Moreover, in vivo pharmacokinetic studies indicate that such aNLG/Oxa(IV)-Lip has a long blood circulation time, thereby enables highly-efficient passive tumor homing. Upon tumor accumulation, such aNLG/Oxa(IV)-Lip presents superior synergistic antitumor efficacies to both subcutaneous and orthotopic CT26 tumors, ascribing to significantly primed anti-tumor immunity of enhanced intratumoral infiltration of CD8 T cells, scretion of cytotoxic cytokines and downregulation of immunosuppressive regulatory T cells. This work highlights that such bifunctional aNLG/Oxa(IV)-Lip is a potent candidate for future clinical translation owing to its excellent biocompatibility and high therapeutic efficacy.
吲哚胺2,3-双加氧酶1（IDO1）的高表达是肿瘤诱导免疫抑制的主要原因，并且似乎与人类结直肠癌和其他一些癌症的不良预后相关。在本研究中，我们通过将奥沙利铂前药（Oxa(IV)）共轭磷脂与IDO1抑制剂烷基化NLG919（aNLG）以及其他商业脂质自组装，构建了一种双功能脂质体。所获得的aNLG/Oxa(IV)-Lip不仅可以在还原性胞质溶胶中释放细胞毒性奥沙利铂，触发癌细胞的免疫原性细胞死亡（ICD），还可以通过NLG919介导的IDO1抑制作用有效延缓色氨酸向免疫抑制性犬尿氨酸的降解。此外，体内药代动力学研究表明，这种aNLG/Oxa(IV)-Lip具有较长的血液循环时间，从而能够实现高效的被动肿瘤归巢。在肿瘤蓄积后，这种aNLG/Oxa(IV)-Lip对皮下和原位CT26肿瘤均呈现出优异的协同抗肿瘤疗效，这归因于肿瘤内CD8 T细胞浸润增强、细胞毒性细胞因子分泌以及免疫抑制性调节性T细胞下调所显著引发的抗肿瘤免疫。这项工作突出表明，由于其优异的生物相容性和高治疗效果，这种双功能aNLG/Oxa(IV)-Lip是未来临床转化的有力候选者。
