title: Ultrasound assisted siRNA delivery using PEG-siPlex loaded microbubbles.
abstract: Short interfering RNA (siRNA) attracts much attention for the treatment of various diseases. However, its delivery, especially via systemic routes, remains a challenge. Indeed, naked siRNAs are rapidly degraded, while complexed siRNAs massively aggregate in the blood or are captured by macrophages. Although this can be circumvented by PEGylation, we found that PEGylation had a strong negative effect on the gene silencing efficiency of siRNA-liposome complexes (siPlexes). Recently, ultrasound combined with microbubbles has been used to deliver naked siRNA but the gene silencing efficiency is rather low and very high amounts of siRNA are required. To overcome the negative effects of PEGylation and to enhance the efficiency of ultrasound assisted siRNA delivery, we coupled PEGylated siPlexes (PEG-siPlexes) to microbubbles. Ultrasound radiation of these microbubbles resulted in massive release of unaltered PEG-siPlexes. Interestingly, PEG-siPlexes loaded on microbubbles were able to enter cells after exposure to ultrasound, in contrast to free PEG-siPlexes, which were not able to enter cells rapidly. Furthermore, these PEG-siPlex loaded microbubbles induced, in the presence of ultrasound, much higher gene silencing than free PEG-siPlexes. Additionally, the PEG-siPlex loaded microbubbles only silenced the expression of genes in the presence of ultrasound, which allows space and time controlled gene silencing.
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium. Roosmarijn.Vandenbroucke@UGent.be
authors.forename: Roosmarijn E
authors.initials: RE
authors.lastname: Vandenbroucke
authors.forename: Ine
authors.initials: I
authors.lastname: Lentacker
authors.forename: Joseph
authors.initials: J
authors.lastname: Demeester
authors.forename: Stefaan C
authors.initials: SC
authors.lastname: De Smedt
authors.forename: Niek N
authors.initials: NN
authors.lastname: Sanders
mesh_terms: D000818:Animals; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000235:genetics; D008081:Liposomes; D008156:Luciferases / Q000235:genetics; D045423:Microbubbles; D018613:Microscopy, Confocal; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014162:Transfection; D014465:Ultrasonics
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D008156:Luciferases