Combined Photosensitive Gene Therapy Effective Against Triple-Negative Breast Cancer in Mice Model

Abstract

Yixue Hu,1 Dongna Wang,2 Tianyu Zhang,2 Meng Lei,3 Yingnan Luo,2 Zhimeng Chen,3 Yuting Li,2 Dandan Duan,2 Liefeng Zhang,1 Yongqiang Zhu1,2 1College of Life Science, Nanjing Normal University, Nanjing, People’s Republic of China; 2School of Food and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, People’s Republic of China; 3College of Science, Nanjing Forestry University, Nanjing, People’s Republic of ChinaCorrespondence: Liefeng Zhang; Yongqiang Zhu, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Qixia District, Nanjing, 210023, People’s Republic of China, Tel/Fax [phone], Email [email protected]; [email protected]: Tumor hypoxia and invasion present significant challenges for the efficacy of photodynamic therapy (PDT) in triple-negative breast cancer (TNBC). This study developed a mitochondrial targeting strategy that combined PDT and gene therapy to promote each other and address the challenges.Methods: The positively charged amphiphilic material triphenylphosphine-tocopherol polyethylene glycol succinate (TPP-TPGS, TPS) and the photosensitizer chloride e6 (Ce6) formed TPS@Ce6 nanoparticles (NPs) by hydrophobic interaction. They electrostatically condensed microRNA-34a (miR-34a) to form stable TPS@Ce6/miRNA NPs.Results: Firstly, Ce6 disrupted the lysosomal membrane, followed by successful delivery of miR-34a by TPS@Ce6/miRNA NPs. Meanwhile, miR-34a reduced ROS depletion and further enhanced the effectiveness of PDT. Consequently, the mutual promotion between PDT and gene therapy led to enhanced anti-tumor effects. Furthermore, the TPS@Ce6/miRNA NPs promoted apoptosis by down-regulating Caspase-3 and inhibited tumor cell migration and invasion by down-regulating N-Cadherin. In addition, in vitro and in vivo experiments demonstrated that the TPS@Ce6/miRNA NPs achieved excellent anti-tumor effects. These findings highlighted the enhanced anticancer effects and reduced migration of tumor cells through the synergistic effects of PDT and gene therapy.Conclusion: Taken together, the targeted co-delivery of Ce6 and miR-34a will facilitate the application of photodynamic and genic nanomedicine in the treatment of aggressive tumors, particularly TNBC. Keywords: photodynamic therapy, gene therapy, hypoxia, invasion, mitochondrial target, triple-negative breast cancer

Keywords

• photodynamic therapy
• gene therapy
• hypoxia
• invasion
• mitochondrial target
• triple-negative breast cancer.