Hollow copper sulfide nanoparticles carrying ISRIB for the sensitized photothermal therapy of breast cancer and brain metastases through inhibiting stress granule formation and reprogramming tumor-associated macrophages

Fan Tong; Haili Hu; Yanyan Xu; Yang Zhou; Rou Xie; Ting Lei; Yufan Du; Wenqin Yang; Siqin He; Yuan Huang; Tao Gong; Huile Gao

doi:10.1016/j.apsb.2022.11.003

Hollow copper sulfide nanoparticles carrying ISRIB for the sensitized photothermal therapy of breast cancer and brain metastases through inhibiting stress granule formation and reprogramming tumor-associated macrophages

Acta Pharm Sin B. 2023 Aug;13(8):3471-3488. doi: 10.1016/j.apsb.2022.11.003. Epub 2022 Nov 5.

Authors

Fan Tong¹, Haili Hu¹, Yanyan Xu¹, Yang Zhou¹, Rou Xie¹, Ting Lei¹, Yufan Du¹, Wenqin Yang¹, Siqin He¹, Yuan Huang¹, Tao Gong¹, Huile Gao¹

Affiliation

¹ Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

Abstract

As known, the benefits of photothermal therapy (PTT) are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins (HSPs). Then HSPs further trigger the formation of stress granules (SGs) that regulate protein expression and cell viability under various stress conditions. Inhibition of SG formation can sensitize tumor cells to PTT. Herein, we developed PEGylated pH (low) insertion peptide (PEG-pHLIP)-modified hollow copper sulfide nanoparticles (HCuS NPs) encapsulating the SG inhibitor ISRIB, with the phase-change material lauric acid (LA) as a gate-keeper, to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system (IL@H-PP). The nanomedicine could specifically target slightly acidic tumor sites. Upon irradiation, IL@H-PP realized PTT, and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT, thereby increasing the antitumor effect and inducing potent immunogenic cell death (ICD). Moreover, IL@H-PP could promote the production of reactive oxygen species (ROS) by tumor-associated macrophages (TAMs), repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment. In vitro/vivo results revealed the potential of PTT combined with SG inhibitors, which provides a new paradigm for antitumor and anti-metastases.

Keywords: Anti-metastases; Hollow copper sulfide nanoparticles; Immunotherapy; Photothermal responsiveness; SG inhibition; Sensitized PTT; TAMs repolarization; pH-driven targeting.