Abstract
Simple SummaryA novel active release system magnetic sphingomyelin-containing liposome encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin was evaluated. The liposomal sphingomyelin is a target for the sphingomyelinase enzyme, which is released by stressed cells. Thus, sphingomyelin containing liposomes behave as a sensitizer for biological stress situations. In addition, the liposomes were engineered by adding paramagnetic beads to act as a receiver of outside given magnetic energy. The enzymatic activity towards liposomes and destruction caused by the applied magnetic field caused the release of the content from the liposomes. By using these novel liposomes, we could improve the drug release feature of liposomes. The improved targeting and drug-release were shown in vitro and the orthotopic tongue cancer model in mice optical imaging. The increased delivery of cisplatin prolonged the survival of the targeted delivery group versus free cisplatin.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.
Highlights
Drug delivery allows a higher local concentration of the drug at the disease site while the side effects are reduced
Small 5 nm core-shell iron nanoparticles were used; previous studies indicate that particles of this size can be incorporated into the lipid membrane [24], which was demonstrated in our liposomes by transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) analysis (Figure 1b,c)
When our liposomes were analyzed with TEM, in addition to the clear association of the 5 nm iron nanoparticles on the membrane, a formation of large agglomerates in the liposomal membrane could be observed after sphingomyelinase treatment (Figure 1b, panel III)
Summary
Drug delivery allows a higher local concentration of the drug at the disease site while the side effects are reduced. By preferentially enhancing the localization of pharmaceutical activity in the organ or tissue of interest, their use can reduce the required systemic doses. Targeted delivery enables new drugs with nonsuitable pharmacokinetics as a conventional therapy to be implemented for clinical use. A substantial step forward would be a targeted and controlled release system that could increase biologically active molecules at the disease site. Nanoparticle- and nanostructure-based delivery systems are widely developed and used to promote the efficacy of drug therapies. Most nanoparticle delivery systems accumulate close to tumors because of the enhanced permeation and retention (EPR) effect [1]. A delivery system that could reliably open on the target site to elevate the biologically available drug would solve this problem
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