A polymeric IDO inhibitor based on poly(ethylene glycol)-b-poly(l-tyrosine-co-1-methyl-d-tryptophan) enables facile trident cancer immunotherapy. (30th August 2022)

• Record Type: Journal Article
• Authors: Liu, Yuanyuan; Xie, Jiguo; Zhao, Xiaofei; Zhang, Yueyue; Zhong, Zhiyuan; Deng, Chao
• Is Part Of: Biomaterials science. Volume 10:Number 19(2022)
• Page Start: 5731
• Page End: 5743
• Publication Date: 2022-08-30
• Subjects: Biomedical materials -- Periodicals; 610.28
• DOI: 10.1039/d2bm01181f
• Languages: English
• ISSNs: 2047-4830

Abstract

Abstract : A polymeric IDO inhibitor has been developed for the first time from copolypeptides for facile trident cancer immunotherapy. Abstract : Indoleamine 2, 3-dioxygenase (IDO), with an immunoregulatory effect related to tryptophan metabolism, has emerged as an attractive target for cancer immunotherapy. Here, a polymeric IDO inhibitor based on the poly(ethylene glycol)- b -poly(l -tyrosine- co -1-methyl-d -tryptophan) copolymer (PEG- b -P(Tyr- co -1-MT)) was developed for facile trident cancer immunotherapy. PEG- b -P(Tyr- co -1-MT) could self-assemble into nanoparticles (NPs), which were subject to enzyme degradation and capable of retarding the metabolism of l -tryptophan (TRP) to l -kynurenine (KYN) in B16F10 cancer cells. Notably, cRGD-functionalized NPs showed efficient encapsulation and an enzyme-responsive release of doxorubicin (DOX) and the BET bromodomain inhibitor JQ1. DOX in drug-loaded nanoparticles (cRGD-NPDJ) could activate immunization by inducing the discernible immunogenic cell death (ICD) of cancer cells and promoting the secretion of interferon- γ (IFN- γ ), which besides activating the antitumor cellular immunity often upregulates the expression of PD-L1 and IDO to accelerate tumor progression. The encapsulated JQ1 and polymeric 1-MT in cRGD-NPDJ could reverse the expression by disrupting the binding of BET proteins with chromatin and elevating the TRP/KYN ratio. In B16F10 tumor-bearing C57BL/6 mice, cRGD-NPDJ displayed significantly increased CD8 + T cells, matured dendritic cells (mDCs), and cytokines (IFN-γ, TNF-α), as well as reduced regulatory T cells and downregulated PD-L1 expression at tumor sites, generating immune cascade reactions and a distinct improvement of the tumor microenvironment (TME), leading to significant tumor suppression and survival prolongation. The polymeric IDO inhibitor provides a facile strategy for the co-delivery of chemotherapeutics and inhibitors for efficient and safe combination cancer immunotherapy.