Lipid-Iron Nanoparticle with a Cell Stress Release Mechanism Combined with a Local Alternating Magnetic Field Enables Site-Activated Drug Release

Abstract

Most available cancer chemotherapies are based on systemically administered small organic molecules, and only a tiny fraction of the drug reaches the disease site. The approach causes significant side effects and limits the outcome of the therapy. Targeted drug delivery provides an alternative to improve the situation. However, due to the poor release characteristics of the delivery systems, limitations remain. This report presents a new approach to address the challenges using two fundamentally different mechanisms to trigger the release from the liposomal carrier. We use an endogenous disease marker, an enzyme, combined with an externally applied magnetic field, to open the delivery system at the correct time only in the disease site. This site-activated release system is a novel two-switch nanomachine that can be regulated by a cell stress-induced enzyme at the cellular level and be remotely controlled using an applied magnetic field. We tested the concept using sphingomyelin-containing liposomes encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin. We engineered the liposomes by adding paramagnetic beads to act as a receiver of outside magnetic energy. The developed multifunctional liposomes were characterized in vitro in leakage studies and cell internalization studies. The release system was further studied in vivo in imaging and therapy trials using a squamous cell carcinoma tumor in the mouse as a disease model. In vitro studies showed an increased release of loaded material when stress-related enzyme and magnetic field was applied to the carrier liposomes. The theranostic liposomes were found in tumors, and the improved therapeutic effect was shown in the survival studies.

Bioactive Lipids and Their Derivatives in Biomedical Applications

“…The members of the acid sphingomyelinase family of sphingomyelinases are activated by oxidative stress or ionizing radiation ( Paris et al ., 2001 ) and function to convert sphingomyelins to ceramide ( Ogretmen, 2017 ). Iron nanoparticle-containing sphingomyelin lipid nanoparticles have been developed for site-specific drug release ( Medina et al ., 2020 ). In this study, the lipid nanoparticles were composed of DSPC, DOTAP, cholesterol, and sphingomyelin.…”

“…The particles were designed to be broken down by acid sphingomyelinase-secretory cells, such as those represented by the cisplatin-exposed SCC-9 cell line ( Lacour et al ., 2004 ), and could be remotely localized to the tumor site by altering magnetic field (AMF), due to the presence of iron nanoparticles in the lipid layer. In the orthotropic SCC-9 tumor bearing mouse model, lipid-iron nanoparticles were specifically delivered to tumor tissue, where they released indocyanine green and cisplatin for diagnostic and therapeutic purposes, respectively ( Medina et al ., 2020 ).…”

Imaging Inflammation – From Whole Body Imaging to Cellular Resolution

“…Fluorescence imaging requires always contrast agents, whereas inflammation imaging with PAI can be used to quantify the increased tissue oxygenation ( 136 ), vascularization ( 137 ), or fibrosis ( 138 ) typical for inflammation. Besides, non-targeted contrast agents like ICG, IRDye, or melanin, or targeted contrast agents like liposomes ( 139 ), microbubbles ( 137 ), or gold nanoparticles ( 140 , 141 ) may enhance or specify the photoacoustic signal. Nanoparticle imaging has been shown to offer promising results in immune cell and disease imaging studies ( 139 , 142 , 143 ).…”

“…Besides, non-targeted contrast agents like ICG, IRDye, or melanin, or targeted contrast agents like liposomes ( 139 ), microbubbles ( 137 ), or gold nanoparticles ( 140 , 141 ) may enhance or specify the photoacoustic signal. Nanoparticle imaging has been shown to offer promising results in immune cell and disease imaging studies ( 139 , 142 , 143 ). The excellent and encouraging results from small animal imaging should be converted to clinical applications in the future.…”

Exploring the Usability of α-MSH-SM-Liposome as an Imaging Agent to Study Biodegradable Bone Implants In Vivo

“…Our group has developed a liposomal imaging system that consists of sphingomyelin (SM)-liposomes ( Figure 1 ). The SM-liposomes are loaded with indocyanine green (ICG), which is a fluorescent marker used in clinical setups and in optical and photoacoustic imaging [ 26 , 43 , 44 ]. The SM-liposomes have been shown to target early implant inflammation after surgery, such as the Mg-10Gd implants in mice [ 45 ].…”