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

Abstract

Introduction

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.

Graphical Abstract

Keywords:

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

Abbreviations

AST, aspartate aminotransferase; BUN, blood urea nitrogen; ALT, alanine aminotransferase; UA, uric acid; H&E, Hematoxylin-eosin; NIRF, near-infrared fluorescence; ROS, reactive oxygen species; DCFH-DA, 2’,7’-dichlorofluorescin diacetate; PCI, photochemical internalization effect; CLSM, confocal laser scanning microscopy; + L, with NIR irradiation; NIR, near-infrared irradiation; TEM, transmission electronic microscopy; RNase, ribonuclease; PDI, polydispersity index; N/P, nitrogen/phosphate ratios; O/W, oil-in-water; TPGS, tocopheryl polyethylene glycol succinate; TPP, triphenylphosphine; SD, standard deviation; RT-qPCR, reverse transcription qPCR; HRP, horseradish peroxidase; TBST, Tris-buffered saline Tween 20; BCA, bicinchoninic acid; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; PVDFM, polyvinylidene difluoride membrane; DCFH, 2’,7’-dichlorodihydrofluorescein; DCF, 2’,7’-dichlorofluorescein; PBS, phosphate-buffered saline. FBS, fetal bovine serum; SDS,2% sodium dodecyl sulfate; EE, encapsulation efficiency; DL, drug loading; miR-34a, MicroRNA-34a; RNAi, RNA interference; Ce6, chloride e6; NPs, nanoparticles; TPP-COOH, 5-carboxymethyl triphenylphosphine; TPGS, Tocopheryl polyethylene glycol succinate; MCF-10A, Michigan Cancer Foundation-10A.

Acknowledgments

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure

The authors report no conflicts of interest in this work.