Targeting of Magnetic Nanoparticle-coated Microbubbles to the Vascular Wall Empowers Site-specific Lentiviral Gene Delivery in vivo

Abstract

In the field of vascular gene therapy, targeting systems are promising advancements to improve site-specificity of gene delivery. Here, we studied whether incorporation of magnetic nanoparticles (MNP) with different magnetic properties into ultrasound sensitive microbubbles may represent an efficient way to enable gene targeting in the vascular system after systemic application. Thus, we associated novel silicon oxide-coated magnetic nanoparticle containing microbubbles (SO-Mag MMB) with lentiviral particles carrying therapeutic genes and determined their physico-chemical as well as biological properties compared to MMB coated with polyethylenimine-coated magnetic nanoparticles (PEI-Mag MMB). While there were no differences between both MMB types concerning size and lentivirus binding, SO-Mag MMB exhibited superior characteristics regarding magnetic moment, magnetizability as well as transduction efficiency under static and flow conditions in vitro. Focal disruption of lentiviral SO-Mag MMB by ultrasound within isolated vessels exposed to an external magnetic field decisively improved localized VEGF expression in aortic endothelium ex vivo and enhanced the angiogenic response. Using the same system in vivo, we achieved a highly effective, site-specific lentiviral transgene expression in microvessels of the mouse dorsal skin after arterial injection. Thus, we established a novel lentiviral MMB technique, which has great potential towards site-directed vascular gene therapy.

Polymer‐coated viral vectors: hybrid nanosystems for gene therapy

“…Ex vivo treatment with Lenti‐SO‐Mag MMB showed a higher angiogenic effect and also elevated expression of vascular endothelial growth factor in aortic endothelium. The MNP‐coated lentiviral showed site‐specific tropism and enhanced transduction in vivo …”

Nanoparticles for Detection and Treatment of Peripheral Arterial Disease

“…Microbubbles have been used as imaging agents via ultrasound (US) imaging; however, one of their limitations includes off‐targeting and retention. Recently, magnetic microbubbles containing silicon oxide‐coated MNPs (SO‐Mag) have been used for the delivery of VEGF into mice via US‐induced VEGF release, and these microbubbles resulted in increased angiogenesis by 72 h under flow when compared to the control microbubbles delivering GFP (60 vs 30 sprouts and 400 µm 2 vs 150 µm 2 vascularized area). Also, 8 d post treatment, ultrasound and magnetic imaging showed strong and local bioluminescence signals from mice treated with SO‐MNPs microbubbles when compared to that of controls (GFP microbubbles without magnetic field or ultrasound exposure).…”

Comparing Strategies for Magnetic Functionalization of Microbubbles

“…Whereas polymer MBs provide good physical stability, cross-linked polymers are more resistant to compression and expansion, thus producing less echogenic MBs . Most commercial contrast agents use phospholipids and lipid-mix systems, which offer excellent echogenicity, biocompatibility, and circulatory stability. , The spontaneous self-assembly of lipids into monolayers at interfaces, with hydrophobic tails facing the gas phase, facilitates MB formation and manufacturing and promotes physical stability. , Previous studies on magnetic lipid-coated MBs have incorporated hydrophobic IONPs on the internal surface of the shell enabling the targeted delivery of genes or thrombolytic drugs, − have embedded different types of IONPs within the MB coating, enabling magnetic targeting of nucleic acids − and antirestenotic drugs, or have attached hydrophilic IONPs to the surface of MBs through biotin–avidin , or protamine–heparin interactions. MBs coated with ionic surfactants and charged IONPs have also been reported, − but the toxicity concerns related to these systems limit their clinical feasibility.…”