The Destruction Of Laser-Induced Phase-Transition Nanoparticles Triggered By Low-Intensity Ultrasound: An Innovative Modality To Enhance The Immunological Treatment Of Ovarian Cancer Cells

Abstract

Wan Xie,1,2 Shenyin Zhu,3 Biyong Yang,4 Chunyan Chen,1 Shuning Chen,1 Yujiao Liu,1 Xuyuan Nie,5 Lan Hao,2 Zhigang Wang,2 Jiangchuan Sun,1 Shufang Chang1 1Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of China; 2Institute of Ultrasound Imaging, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China; 4Chongqing Institute for Food and Drug Control, Chongqing 401121, People’s Republic of China; 5School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, People’s Republic of ChinaCorrespondence: Shufang Chang; Jiangchuan SunDepartment of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjian Road, Yuzhong District, Chongqing 400010, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]; [email protected]: Photodynamic therapy (PDT), sonodynamic therapy (SDT), and oxaliplatin (OXP) can induce immunogenic cell death (ICD) following damage-associated molecular patterns (DAMPs) exposure or release and can be united via the use of nanoplatforms to deliver drugs that can impart anti-tumor effects. The aim of this study was to develop phase-transition nanoparticles (OI_NPs) loaded with perfluoropentane (PFP), indocyanine green (ICG), and oxaliplatin (OXP), to augment anti-tumor efficacy and the immunological effects of chemotherapy, photodynamic therapy and sonodynamic therapy (PSDT).Methods: OI_NPs were fabricated by a double emulsion method and a range of physicochemical and dual-modal imaging features were characterized. Confocal microscopy and flow cytometry were used to determine the cellular uptake of OI_NPs by ID8 cells. The viability and apoptotic rate of ID8 cells were investigated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry. Flow cytometry, Western blotting, and luminometric assays were then used to investigate the exposure or release of crucial DAMPs such as calreticulin (CRT), high mobility group box 1 (HMGB1), and adenosine-5ʹ-triphosphate (ATP). Tumor rechallenge experiments were then used to investigate whether treated ID8 cells underwent ICD. Finally, cytotoxic T lymphocyte (CTL) activity was determined by a lactate dehydrogenase (LDH) assay.Results: Spherical OI_NPs were able to carry OXP, ICG and PFP and were successfully internalized by ID8 cells. The application of OI_NPs significantly enhanced the phase shift ability of PFP and the optical characteristics of ICG, thus leading to a significant improvement in photoacoustic and ultrasonic imaging. When combined with near-infrared light and ultrasound, the application of OI_NPs led to improved anti-tumor effects on cancer cells, and significantly enhanced the expression of DAMPs, thus generating a long-term anti-tumor effect.Conclusion: The application of OI_NPs, loaded with appropriate cargo, may represent a novel strategy with which to increase anti-tumor effects, enhance immunological potency, and improve dual-mode imaging.Keywords: ovarian cancer, multifunctional nanoparticles, photo-sonodynamic therapy, immunogenic cell death, reactive oxygen species

Keywords

• ovarian cancer
• multifunctional nanoparticles
• photo-sonodynamic therapy
• immunogenic cell death
• reactive oxygen species