Rejuvenating hepatic tumor microenvironment immunity with a phosphatidylserine-targeting small molecule drug conjugate - 03/06/22
Abstract |
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.
El texto completo de este artículo está disponible en PDF.Graphical Abstract |
Highlights |
• | Designing phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates. |
• | Reducing hepatic tumor burden and increasing immune cells infiltration. |
• | Remodeling of hepatic tumor microenvironment to inflamed “hot” tumor. |
Keywords : Zinc dipicolylamine, Small molecule drug conjugates, Phosphatidylserine, Inflammed tumor microenvironment
Esquema
Vol 151
Artículo 113084- juillet 2022 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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