Upconversion nanoparticle-mediated photodynamic therapy induces THP-1 macrophage apoptosis via ROS bursts and activation of the mitochondrial caspase pathway

Abstract

Xing Zhu,1,* Hao Wang,2,* Longbin Zheng,1 Zhaoyu Zhong,1 Xuesong Li,1 Jing Zhao,3 Jiayuan Kou,1 Yueqing Jiang,1 Xiufeng Zheng,1 Zhongni Liu,1 Hongxia Li,1 Wenwu Cao,4,5 Ye Tian,1,6 You Wang,2 Liming Yang1 1Department of Pathophysiology, Harbin Medical University, Harbin, People’s Republic of China; 2Materials Physics and Chemistry Department, Harbin Institute of Technology, Harbin, People’s Republic of China; 3Blood Transfusion Department, Jining No 1 People’s Hospital, Jining, People’s Republic of China; 4Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, People’s Republic of China; 5Materials Research Institute, The Pennsylvania State University, University Park, PA, USA; 6Division of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin, People’s Republic of China *These authors contributed equally to this work Abstract: Atherosclerosis (AS) is the most vital cardiovascular disease, which poses a great threat to human health. Macrophages play an important role in the progression of AS. Photodynamic therapy (PDT) has emerged as a useful therapeutic modality not only in the treatment of cancer but also in the treatment of AS. The purpose of this study was to determine the molecular mechanisms underlying the activity of PDT, using mesoporous-silica-coated upconversion fluorescent nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) in the induction of apoptosis in THP-1 macrophages. Here, we investigated the ability of UCNPs-Ce6-mediated PDT to induce THP-1 macrophage apoptosis by facilitating the induction of reactive oxygen species (ROS) and regulation of mitochondrial permeability transition pore (MPTP) to depolarize mitochondrial membrane potential (MMP). Both Bax translocation and the release of cytochrome C were examined using immunofluorescence and Western blotting. Our results indicated that the levels of ROS were significantly increased in the PDT group, resulting in both MPTP opening and MMP depolarization, which led to apoptosis. In addition, immunofluorescence and Western blotting revealed that PDT induced both Bax translocation and the release of cytochrome C, as well as upregulation of cleaved caspase-9, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase. Therefore, we demonstrated that UCNPs-Ce6-mediated PDT induces apoptosis in THP-1 macrophages via ROS bursts. The proapoptotic factor Bax subsequently translocates from the cytosol to the mitochondria, resulting in the MPTP opening and cytochrome C release. This study demonstrated the great potential of UCNPs-Ce6-mediated PDT in the treatment of AS. Keywords: atherosclerosis, photodynamic therapy, fluorescent nanoparticles, reactive oxygen species, apoptosis, macrophages