國家衛生研究院 NHRI:Item 3990099045/14318
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    题名: Rejuvenating hepatic tumor microenvironment immunity with a phosphatidylserine-targeting small molecule drug conjugate
    作者: Huang, KH;Liu, YT;Pan, PY;Lo, CF;Liu, KL;Yeh, TK;Huang, LR;Tsou, LK
    贡献者: Institute of Biotechnology and Pharmaceutical Research;Institute of Molecular and Genomic Medicine
    摘要: We report the design, synthesis and evaluation of a class of phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates and show that conjugate 16b elicits immune cell infiltration and remodels the “cold” hepatic tumor microenvironment to the inflamed “hot” tumor. Structure-property relationship study via linker modifications and subsequent pharmacokinetics profiling were carried out to improve the solubility and stability of the conjugates in vivo. In a spontaneous hepatocellular carcinoma mouse model, we showed that conjugate 16b exhibited better antitumor efficacy than sorafenib. In particular, significant increase of CD8+ T cell infiltration and granzyme B level was observed, providing insights in sensitizing tumors from intrinsic immune suppressive microenvironment. Evaluation of tumor inflammation-related mRNA expression profile revealed that conjugate 16b, through inductions of key gene expressions including STAT1, CXCL9, CCL5, and PD-L1, rejuvenated tumor microenvironment with enhancement in T cell-, macrophage-, NK cell-, chemokines and cytokines’- functions. Our study establishes that an apoptosis-targeting theranostic enables enrichment of multifaceted immune cells into the tumor mass, which provides potential therapeutic strategies in the combination with immune checkpoint blockade treatment.
    日期: 2022-07
    關聯: Biomedicine and Pharmacotherapy. 2022 Jul;151:Article number 113084.
    Link to: http://dx.doi.org/10.1016/j.biopha.2022.113084
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0753-3322&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000806751700005
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85129960694
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