Initiating and imaging cavitation from infused echo contrast agents through the EkoSonic catheter

Abstract

Ultrasound-enhanced delivery of therapeutic-loaded echogenic liposomes is under development for vascular applications using the EkoSonic Endovascular System. In this study, fibrin-targeted echogenic liposomes loaded with an anti-inflammatory agent were characterized before and after infusion through an EkoSonic catheter. Cavitation activity was nucleated by Definity or fibrin-targeted, drug-loaded echogenic liposomes infused and insonified with EkoSonic catheters. Passive cavitation imaging was used to quantify and map bubble activity in a flow phantom mimicking porcine arterial flow. Cavitation was sustained during 3-min infusions of Definity or echogenic liposomes along the distal 6 cm treatment zone of the catheter. Though the EkoSonic catheter was not designed specifically for cavitation nucleation, infusion of drug-loaded echogenic liposomes can be employed to trigger and sustain bubble activity for enhanced intravascular drug delivery.

Figure 1

Concept for ultrasound-medicated delivery of pioglitazone-loaded echogenic liposomes infused through an EkoSonic catheter into the porcine iliofemoral arterial vasculature.

Figure 2

(a) Size distribution and (b) attenuation spectroscopy measurements of OFP-PAFb-PGN-ELIP from the vial and after infusion through EkoSonic catheters. The mean number-weighted (solid lines) and volume-weighted (dot-dot-dash lines) size distributions are plotted against the particle diameter. The mean attenuation values are plotted as a function of frequency. Error bars represent ± 1 standard deviation (s.d.), n = 3 vials each.

Figure 3

Mean PGN dose of one vial of reconstituted OFP-PAFb-PGN-ELIP measured directly from the vial and after infusion through EkoSonic catheters. Each vial contains 0.5 mL reconstituted solution and 10 mg lipid/ mL solution. Error bars represent ± s.d., n = 3 vials each.

Figure 4

Spatial light interference microscopy (SLIM) images of (a, b) Definity and (c, d) OFP-PAFb-PGN-ELIP using a 10 × objective. Images were taken of microbubbles withdrawn directly from vials (no infusion). The black arrows indicate lipid shells, and the red arrows indicate diffraction artifacts which appear as white rings.

Figure 5

Cavitation energy along the active distal six transducer pairs of the EkoSonic catheter as OFP-PAFb-PGN-ELIP or Definity was infused. The mean ultraharmonic (green) and inharmonic (red) cavitation with electrical drive powers of (a) 4, (b) 9, (c) 18, and (d) 47 W. Note that the PCI post-processing protocol plots the ultraharmonic energy in excess of the inharmonic energy. Error bars represent ± 1 standard deviation, n = 3 each.

Figure 6

Composite PCI and B-Mode images of ultraharmonic (green) and inharmonic (red) emissions from cavitation nucleated by infused Definity or OFP-PAFb-PGN-ELIP insonified by one pair of EkoSonic transducers driven with 4, 9, 18, or 47 W electrical power. The B-mode images (visualizing echogenicity alone) are shown in rows 1 and 3, and the corresponding composite images are shown in rows 2 and 4.

Figure 7

Hydrodynamic pressure within the EkoSonic catheter drug delivery lumen as (a) Definity microspheres or saline was infused at 2.0 mL/min or (b) OFP-PAFb-PGN-ELIP or saline was infused 0.6 mL/min, respectively. Error bars represent ± standard deviation, n = 12 each.

Figure 8

Schematic of EkoSonic catheter drug delivery hole and transducer layout. Along the 12 cm treatment zone of the catheter, the first six ultrasound transducer pairs were quiescent while the distal six transducer pairs were active and insonified the echogenic liposomes. The first drug delivery hole was located 0.5 cm after the first of six quiescent transducer pairs (modified from Lafond et al.).

Figure 9

Schematic of flow phantom setup for passive cavitation imaging. Saline at 37 °C was pumped from the reservoir, over the catheter, to the afterload, and to the waste reservoir. During each experimental run, the catheter was pulled back within the tubing so that the L11-5v array scanned across the active transducer pairs (modified from Lafond et al.).