Enhanced delivery and effectiveness of antisense oligonucleotides when bound to intravenous perfluorocarbon-filled microbubbles: Effect of ultrasound and therapeutic implications

Thomas Porter, Shouping Li, Karen Kilzer, John Desjardins, Patrick Iversen

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

In addition to ultrasound contrast, perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles (MB) are capable of binding agents which modulate gene expression like antisense oligonucleotides (AON). Targeted AON delivery could selectively inhibit gene expression (exp). Since diagnostic ultrasound (DUS) is capable of destroying PESDA microbubbles, we tested the effect of DUS on the amount of vascular deposition of both a 15-mer, 20-mer, and 24-mer AON bound to intravenously injected PESDA in 14 dogs. The right carotid artery underwent external ultrasound with a 2.0 MHZ diagnostic ultrasound probe, while the left carotid was not insonified. Secondly, we tested the ability of AON bound to PESDA to modulate gene expression in the liver of adult male rats by testing the changes in efficacy, potency, and specificity of AON which inhibit cytochrome P450 3A2 (CYP3A2) expression. These AON were given intravenously in equal doses to adult male rats bound and unbound to PESDA without DUS. Vascular uptake of 15-mer, 20-mer, and 24-mer AON in dogs were all significantly higher in both the insonified right and uninsonified left carotid artery when given intravenously bound to PESDA, while no or only trace uptake of the same dose of these AON were observed when given unbound to PESDA. There was a trend toward higher deposition of AON in the inconified right carotid artery when bound to PESDA. In rats, it took 4mg/kg of AON to inhibit CYP3A2 expression when administered unbound to PESDA, while a dose of only 0.06 mg/kg of the same AON produced equivalent inhibition when given bound to PESDA microbubbles. This neatly 10-fold increase in antisense inhibition of CYP3A2 expression was also seen with other forms of antisense oligonucleotides given bound to PESOA, and was specific for inhibition of CYP3A2 expression. These studies demonstrate that PESDA microbubbles in the absence of ultrasound can significantly improve the biologic effectiveness of targeted gene therapy.

Original languageEnglish (US)
Pages (from-to)413
Number of pages1
JournalJournal of the American Society of Echocardiography
Volume10
Issue number4
StatePublished - 1997

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Enhanced delivery and effectiveness of antisense oligonucleotides when bound to intravenous perfluorocarbon-filled microbubbles: Effect of ultrasound and therapeutic implications'. Together they form a unique fingerprint.

  • Cite this