Dual Stimuli-Responsive Micelles for Imaging-Guided Mitochondrion-Targeted Photothermal/Photodynamic/Chemo Combination Therapy-Induced Immunogenic Cell Death

Abstract

Yan Liang,1,2 Ping-Yu Wang,1 Ze-Yun Liu,3 Hong-Fang Sun,1 Qin Wang,1 Guang-Bin Sun,1 Xia Zhang,1 You-Jie Li,1 Shu-Yang Xie1,2 1Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, 264003, People’s Republic of China; 2Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, QingDao, ShanDong, 266071, People’s Republic of China; 3School of International Studies, Binzhou Medical University, YanTai, ShanDong, 264003, People’s Republic of ChinaCorrespondence: Shu-Yang Xie; You-Jie Li, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, 264003, People’s Republic of China, Tel/Fax [phone] ; Tel/Fax [phone], Email [email protected]; [email protected]: As the special modality of cell death, immunogenic cell death (ICD) could activate immune response. Phototherapy in combination with chemotherapy (CT) is a particularly efficient tumor ICD inducing method that could overcome the defects of monotherapies.Methods: In this study, new dual stimuli-responsive micelles were designed and prepared for imaging-guided mitochondrion-targeted photothermal/photodynamic/CT combination therapy through inducing ICD. A dual-sensitive methoxy-polyethylene glycol-SS-poly(L-γ-glutamylglutamine)-SS-IR780 (mPEG-SS-PGG-SS-IR780) polymer was synthesized by grafting IR780 with biodegradable di-carboxyl PGG as the backbone, and mPEG-SS-PGG-SS-IR780/paclitaxel micelles (mPEG-SS-PGG-SS-IR780/PTXL MCs) were synthesized by encapsulating PTXL in the hydrophobic core.Results: In-vivo and -vitro results demonstrated that the three-mode combination micelles inhibited tumor growth and enhanced the therapeutic efficacy of immunotherapy. The dual stimuli-responsive mPEG-SS-PGG-SS-IR780/PTXL MCs were able to facilitate tumor cell endocytosis of nanoparticles. They were also capable of promoting micelles disintegration and accelerating PTXL release. The mPEG-SS-PGG-SS-IR780/PTXL MCs induced mitochondrial dysfunction by directly targeting the mitochondria, considering the thermo- and reactive oxygen species (ROS) sensitivity of the mitochondria. Furthermore, the mPEG-SS-PGG-SS-IR780/PTXL MCs could play the diagnostic and therapeutic roles via imaging capabilities.Conclusion: In summary, this study formulated a high-efficiency nanoscale platform with great potential in combined therapy for tumors through ICD.Keywords: immunogenic cell death, photothermal/photodynamic/chemo therapy, dual-stimuli-responsive, poly(amino acid)s micelles, imaging-guided therapy, mitochondria targeting

Keywords

• immunogenic cell death
• photothermal/photodynamic/chemo therapy
• dual-stimuli-responsive
• poly(amino acid)s micelles
• imaging-guided therapy
• mitochondria targeting