In situ activation of STING pathway with polymeric SN38 for cancer chemoimmunotherapy

Jiayu Zhao; Sheng Ma; Yudi Xu; Xinghui Si; Haochen Yao; Zichao Huang; Yu Zhang; Haiyang Yu; Zhaohui Tang; Wantong Song; Xuesi Chen

doi:10.1016/j.biomaterials.2020.120542

In situ activation of STING pathway with polymeric SN38 for cancer chemoimmunotherapy

Biomaterials. 2021 Jan:268:120542. doi: 10.1016/j.biomaterials.2020.120542. Epub 2020 Nov 21.

Authors

Jiayu Zhao¹, Sheng Ma¹, Yudi Xu², Xinghui Si¹, Haochen Yao³, Zichao Huang¹, Yu Zhang⁴, Haiyang Yu⁴, Zhaohui Tang⁵, Wantong Song⁶, Xuesi Chen⁷

Affiliations

¹ Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; University of Science and Technology of China, Hefei, 230026, China.
² Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; University of Chinese Academy of Sciences, Beijing, 100039, China.
³ Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medical Science, Jilin University, Changchun, 130012, China.
⁴ Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, China.
⁵ Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; University of Science and Technology of China, Hefei, 230026, China; Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, China. Electronic address: ztang@ciac.ac.cn.
⁶ Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, China. Electronic address: wtsong@ciac.ac.cn.
⁷ Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; University of Science and Technology of China, Hefei, 230026, China; Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, China.

PMID: 33249316
DOI: 10.1016/j.biomaterials.2020.120542

Abstract

STING (stimulator of interferon genes) signaling pathway has attracted considerable attention in cancer immunotherapy due to its capacity to boost vigorous antitumor immunity. However, the shortage of effective STING agonists limits the promotion of STING pathway in cancer treatment. Herein, we present an approach for in situ activation of STING pathway with nanoparticles delivered DNA-targeting chemo agents, based on the understanding that cytosol DNA is a pre-requisite for STING pathway activation. Through in vitro screening among several DNA-targeting chemo agents, we identified 7-ethyl-10-hydroxycamptothecin (SN38) as the most potent drug for stimulating interferon (IFN)-β secretion and proved that this process is mediated by the passage of DNA-containing exosomes from treated tumor cells to bone marrow-derived dendritic cells (BMDCs) and subsequent activation of the STING pathway. Furthermore, we designed a polymeric-SN38 conjugate that could self-assemble into nanoparticles (SN38-NPs) for in vivo application. The SN38-NPs formulation reduced toxicity of free SN38, effectively stimulated the activation of STING pathway in E0771 tumors, and resulted in a tumor suppression rate (TSR%) of 82.6%. Our results revealed a new mechanism of SN38 in cancer treatment and should inspire using more DNA-targeting agents, especially in nanoformulation, for activating STING pathway and cancer chemoimmunotherapy.

Keywords: Chemoimmunotherapy; DNA-Targeting agents; Exosome; SN38; STING pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents*
Humans
Immunotherapy
Irinotecan
Neoplasms* / drug therapy
Polymers

Substances

Antineoplastic Agents
Polymers
Irinotecan