A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma.

IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Ting Zou, Yun Huang, Zongtao Zhou, Shuangyan He, Jia Liu, Yalan Chen, Hongdu Liu, Zhonghui Luo, Miaoxin Liu, Hua Wei, CuiYun Yu
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Abstract

Clinical treatment of hepatocellular carcinoma (HCC) with 5-fluorouracil (5-FU), the primary anticancer agent, remains unsatisfactory due to the glutathione (GSH)-associated drug resistance and immunosuppressive microenvironment of HCC. To develop a facile yet robust strategy to overcome 5-FU resistance for enhanced immunotherapy treatment of HCC via all dimensional GSH exhaustion, we report in this study construction of a minimalist prodrug consisting of 5-FU linked to an indoleamine-(2,3)-dioxygenase (IDO) inhibitor (IND) via a disulfide bridge, FU-SS-IND that can further self-assemble into stabilized nanoparticles, FU-SS-IND NPs. Specifically, besides the disulfide linker-induced GSH exhaustion, IND inhibits GSH biosynthesis and enhances the effector function of T cells for turning a "cold" tumor to a "hot" one, which synergistically achieving a tumor inhibition rate (TIR) of 92.5% in a 5-FU resistant mice model. Most importantly, FU-SS-IND NPs could upregulate programmed death ligand 1 (PD-L1) expression on the surface of tumor cells, which enables facile combination with immune checkpoint blockade (ICB) for a ultimate prolonged survival lifetime of 5-FU-resistant tumors-bearing mice. Overall, the minimalist bioreducible nano-prodrug developed herein demonstrates great translatable potential for efficiently reversing drug resistance and enhancing immunotherapy of HCC.

一种极简多功能纳米前药,用于逆转耐药,并与PD-L1单抗结合,用于增强肝细胞癌的免疫治疗。
由于谷胱甘肽(GSH)相关的耐药和肝细胞癌的免疫抑制微环境,以5-氟尿嘧啶(5-FU)作为主要抗癌药物治疗肝细胞癌的临床效果仍不理想。为了开发一种简单而强大的策略来克服5-FU耐药性,通过全尺寸GSH耗尽来增强肝癌的免疫治疗,我们在本研究中报道了一种极简前药的构建,该前药由5-FU通过二硫桥连接到吲哚胺-(2,3)-双加氧酶(IDO)抑制剂(IND), FU-SS-IND可以进一步自组装成稳定的纳米颗粒FU-SS-IND NPs。具体而言,除了二硫连接体诱导的GSH耗竭外,IND还抑制GSH的生物合成,增强T细胞将“冷”肿瘤转化为“热”肿瘤的效应功能,在5-FU耐药小鼠模型中协同实现92.5%的肿瘤抑制率(TIR)。最重要的是,FU-SS-IND NPs可以上调肿瘤细胞表面的程序性死亡配体1 (PD-L1)的表达,从而使其易于与免疫检查点阻断(ICB)结合,从而最终延长5- fu耐药荷瘤小鼠的生存期。总之,本文开发的极简生物可降解纳米前药在有效逆转肝癌耐药和增强肝癌免疫治疗方面显示出巨大的可翻译潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Nanobiotechnology
Journal of Nanobiotechnology BIOTECHNOLOGY & APPLIED MICROBIOLOGY-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
13.90
自引率
4.90%
发文量
493
审稿时长
16 weeks
期刊介绍: Journal of Nanobiotechnology is an open access peer-reviewed journal communicating scientific and technological advances in the fields of medicine and biology, with an emphasis in their interface with nanoscale sciences. The journal provides biomedical scientists and the international biotechnology business community with the latest developments in the growing field of Nanobiotechnology.
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麦克林
Potassium hydroxide (KOH)
麦克林
Di-tert-butyl dicarbonate ((BOC)2O)
麦克林
4-dimethylaminopyridine (DMAP)
麦克林
Bromoacetic acid
麦克林
Dicyclohexylcarbodiimide (DCC)
麦克林
Trifluoroacetic acid (TFA)
麦克林
5-FU
麦克林
Potassium hydroxide (KOH)
麦克林
Di-tert-butyl dicarbonate ((BOC)2O)
麦克林
4-dimethylaminopyridine (DMAP)
麦克林
Bromoacetic acid
麦克林
Dicyclohexylcarbodiimide (DCC)
麦克林
Trifluoroacetic acid (TFA)
麦克林
5-FU
麦克林
Potassium hydroxide (KOH)
麦克林
Di-tert-butyl dicarbonate ((BOC)2O)
麦克林
4-dimethylaminopyridine (DMAP)
麦克林
Bromoacetic acid
麦克林
Dicyclohexylcarbodiimide (DCC)
麦克林
Trifluoroacetic acid (TFA)
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5-FU
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Potassium hydroxide (KOH)
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Di-tert-butyl dicarbonate ((BOC)2O)
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4-dimethylaminopyridine (DMAP)
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Bromoacetic acid
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Dicyclohexylcarbodiimide (DCC)
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Trifluoroacetic acid (TFA)
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5-FU
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GSH (Reduced)
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Sodium bicarbonate (NaHCO3)
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GSH (Reduced)
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Sodium bicarbonate (NaHCO3)
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GSH (Reduced)
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