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Journal of Nanobiotechnology

Journal of Nanobiotechnology

IF: 10.6
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A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma

Published:3 December 2024 DOI: 10.1186/s12951-024-03027-w PMID: 39627819
Ting Zou,?Yun Huang,?Zongtao Zhou,?Shuangyan He,?Jia Liu,?Yalan Chen,?Hongdu Liu,?Zhonghui Luo,?Miaoxin Liu,?Hua Wei,?CuiYun Yu

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.

Substances (10)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Dichloromethane 75-09-2 CH2Cl2 1396 suppliers $10.00-$27982.90
4-Dimethylaminopyridine 1122-58-3 C7H10N2 1362 suppliers $6.00-$7880.00
Tetrahydrofuran 109-99-9 C4H8O 1176 suppliers $9.00-$28146.80
5-Fluorouracil 51-21-8 C4H3FN2O2 1096 suppliers $5.00-$3543.55
Methanol 67-56-1 CH4O 913 suppliers $9.00-$19915.10
Ethyl acetate 141-78-6 C4H8O2 692 suppliers $22.03-$23615.90
Thiazolyl Blue 298-93-1 C18H16N5S.Br 611 suppliers $7.00-$5262.50
Bromoacetic acid 79-08-3 C2H3BrO2 374 suppliers $9.00-$2076.80
FETUIN 9014-81-7 NULL 92 suppliers $37.07-$4810.00
MTT 2348-71-2 C18H16BrN5S 49 suppliers Inquiry

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