Membrane-permeabilized sonodynamic therapy enhances drug delivery into macrophages

• Published in: PloS one Vol. 14; no. 6; p. e0217511
• Main Authors: Cao, Zhengyu, Zhang, Tianyi, Sun, Xin, Liu, Mingyu, Shen, Zhaoqian, Li, Bicheng, Zhao, Xuezhu, Jin, Hong, Zhang, Zhiguo, Tian, Ye
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10-06-2019; Public Library of Science (PLoS)
• Subjects: Arteriosclerosis; Atherosclerosis; Atherosclerosis - metabolism; Atherosclerotic plaque; Atorvastatin; Atorvastatin - metabolism; Biology and Life Sciences; Biotechnology; Calcium; Calcium (intracellular); Calcium - metabolism; Cardiology; Cell Line; Cell Membrane - metabolism; Cell Membrane Permeability - physiology; Cell membranes; Cell Survival - drug effects; Cell viability; Cholecystokinin; Cholesterol; Cholesterol - metabolism; Confocal microscopy; Deformation; Drug delivery; Drug delivery systems; Drugs; Efflux; Electron microscopy; Enzymes; Fluo-3; Foam Cells; Foams; Gene expression; Humans; Inflammation; Kinases; Laboratories; Lipid Droplets - metabolism; Lipids; Macrophages; Macrophages - metabolism; Medical research; Medicin och hälsovetenskap; Medicine and Health Sciences; Membrane Potential, Mitochondrial - physiology; Microscopy; Nanoparticles; Oxygen; Perforation; Permeability; Plaque, Atherosclerotic - metabolism; Protoporphyrin; Protoporphyrin IX; Protoporphyrins - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research and Analysis Methods; Scanning electron microscopy; Scavenging; Therapy; THP-1 Cells; Transmission electron microscopy; Ultrasonic imaging; Ultrasonic Therapy - methods; Ultrasound; Beijing China; Australia; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0217511

Macrophages play a pivotal role in the formation and development of atherosclerosis as a predominant inflammatory cell type present within atherosclerotic plaque. Promoting anti-atherosclerotic drug delivery into macrophages may provide a therapeutic potential on atherosclerotic plaque. In this study, we investigated whether membrane-permeabilized sonodynamic therapy (MP-SDT) enhances drug delivery into THP-1 macrophages. Images of confocal microscopy confirmed that the optimal plasma distribution of the sonosensitizer protoporphyrin IX (PpIX) was at 1 hour incubation. The non-lethal parameter of MP-SDT was determined by cell viability as measured by a CCK-8 assay. Bright field microscopy demonstrated plasma membrane deformation in response to MP-SDT. Using SYTOX Green, a model drug for cellular uptake, we found that MP-SDT significantly induced membrane permeabilization dependent on ultrasound intensity and exposure time. Using Fluo-3 AM, intracellular calcium elevation during MP-SDT was confirmed as a result of membrane permeabilization. Membrane perforation of MP-SDT-treated cells was observed by scanning electron microscopy and transmission electron microscopy. Moreover, MP-SDT-induced membrane permeabilization and perforation were remarkably prevented by scavenging reactive oxygen species (ROS) during MP-SDT. Furthermore, we assessed the therapeutic effect of MP-SDT in combination with anti-atherosclerotic drug atorvastatin. Our results showed that MP-SDT increased the therapeutic effect of atorvastatin on lipid-laden THP-1-derived foam cells, including decreasing lipid droplets, increasing the cholesterol efflux and the expression of PPARγ and ABCG1. In conclusion, MP-SDT might become a promising approach to facilitating the delivery of anti-atherosclerotic drugs into macrophages via membrane permeabilization.