Abstract
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.
Highlights
Atherosclerosis is a major contributor to the global burden of cardiovascular events, such as myocardial infarction and stroke [1]
Sonodynamic therapy and drug delivery the optimal distribution of protoporphyrin IX (PpIX) on cell membrane, we used membrane probe PKH67 to study the co-localization of PpIX and plasma membrane for different PpIX incubation times
Our results showed that the atorvastatin + membrane-permeabilized sonodynamic therapy (MP-Sonodynamic therapy (SDT)) group had a significant increase in the expressions of peroxisome proliferator-activated receptor γ (PPARγ) and ATP binding cassette subfamily G member 1 (ABCG1) compared with those treated with atorvastatin alone (Fig 7C and 7D)
Summary
Atherosclerosis is a major contributor to the global burden of cardiovascular events, such as myocardial infarction and stroke [1]. Enhancement of anti-atherosclerotic drug delivery into intraplaque macrophages will greatly promote therapeutic efficiency [4]. Increasing membrane permeability induces the passive diffusion of drugs into the cells, representing a promising strategy to facilitate drug delivery into target cells [5]. Ultrasound in combination with microbubbles (USMB) increases cellular permeability in which ultrasound activates microbubbles to oscillate nearby cells and creates sonoporation [7]. These methods have been applied in anti-cancer chemotherapy [8, 9]. Cell targeting of these techniques is limited, so that they may not be very effective for delivering drug into intraplaque macrophages. The technique that increases membrane permeability of intraplaque macrophages has not been reported and is highly desirable
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
