Mitochondria-Targeting Type-I Photodynamic Therapy Based on Phenothiazine for Realizing Enhanced Immunogenic Cancer Cell Death Via Mitochondrial Oxidative Stress

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Date 2025 Jan 13

PMID 39802375

Authors

Zeyu Duan

Lie Li

Qiyu Zhan

Jian Chen

Qiyan Li

Ruiyuan Liu

Yinuo Tu

Affiliations

Soon will be listed here.

Abstract

Purpose: Photo-immunotherapy faces challenges from poor immunogenicity and low response rate due to hypoxic microenvironment. This study presents Rh-PTZ, a small organic molecule with a D-π-A structure, that simultaneously amplifies mitochondria-targeted type-I PDT-dependent immune stimulation for the treatment of hypoxic cancer.

Methods: The hydrophobic Rh-PTZ was encapsulated into F127 to prepare Rh-PTZ nanoparticles (Rh-PTZ NPs). The type-I ROS generation ability, mitochondrial targeting capacity, and ICD triggering effect mediated by Rh-PTZ NPs under LED light irradiation were investigated. Based on a 4T1 subcutaneous tumor model, the in vivo biological safety assessment, in vivo NIR fluorescent imaging, and the efficacy of PDT were assessed.

Results: Rh-PTZ could efficiently accumulate in the mitochondrial site and induce O and •OH burst in situ under LED light irradiation, thereby causing severe mitochondrial dysfunction. Rh-PTZ can amplify mitochondrial stress-caused immunogenic cell death (ICD) to stimulate the immune response, promote the maturation of sufficient dendritic cells (DCs), enhance the infiltration of immune cells, and alleviate the tumor immunosuppressive microenvironment.

Conclusion: The mitochondria-targeting type-I PDT holds promise to enhance photo-immunotherapy for hypoxia tumor treatment and overcoming the limitations of traditional immunotherapy.

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