Reducing Neointima Formation in a Swine Model with IVUS and Sirolimus Microbubbles

Abstract

Potent therapeutic compounds with dose dependent side effects require more efficient and selective drug delivery to reduce systemic drug doses. Here, we demonstrate a new platform that combines intravascular ultrasound (IVUS) and drug-loaded microbubbles to enhance and localize drug delivery, while enabling versatility of drug type and dosing. Localization and degree of delivery with IVUS and microbubbles was assessed using fluorophore-loaded microbubbles and different IVUS parameters in ex vivo swine arteries. Using a swine model of neointimal hyperplasia, reduction of neointima formation following balloon injury was evaluated when using the combination of IVUS and sirolimus-loaded microbubbles. IVUS and microbubble enhanced fluorophore delivery was greatest when applying low amplitude pulses in the ex vivo model. In the in vivo model, neointima formation was reduced by 50% after treatment with IVUS and the sirolimus-loaded microbubbles. This reduction was achieved with a sirolimus whole blood concentration comparable to a commercial drug-eluting stent (0.999 ng/mL). We anticipate this therapy will find clinical use localizing drug delivery for numerous other diseases in addition to serving as an adjunct to stents in treating atherosclerosis.

Rapamycin: A Bacteria-Derived Immunosuppressant That Has Anti-atherosclerotic Effects and Its Clinical Application

“…Novel methods for achieving safer and more effective administration of RAPA than by systemic administration are being explored. Various types of delivery systems have been developed to reduce systemic side effects in AS, including a liposomal delivery system, a nanoparticle system, and drug-loaded microbubbles (Kilroy et al, 2015; Miao et al, 2015; Dou et al, 2016). (1) RAPA-containing liposomes have been prepared in vitro through an ethanol injection method.…”

Microbubble-mediated intravascular ultrasound imaging and drug delivery

“…Arteries treated with both rapamycin-loaded MBs and 5.1-MHz IVUS exhibited a 50% decrease in neointimal formation when compared with arteries treated with rapamycinloaded MBs alone (Fig. 5) [116]. IVUS-mediated gene and drug delivery, as demonstrated in these studies, has potential application for the management and study of coronary atherosclerosis and may permit real-time, image-guided delivery of both drug and gene therapeutic agents.…”

“…The combination of IVUS catheters and MB contrast agents has only been reported in a handful of clinical trials [82], [86], [88] and animal studies [87], [93], [109], [116], [120], [122]. However, new applications enabled by novel IVUS transducer designs [87], [90], [95], [98]- [100] and versatile MB formulations [122]- [124] have been demonstrated in both in vitro and in vivo animal models, and some of these applications or their derivatives may eventually impact patient care.…”

“…When combined with MBs, this therapeutic-IVUS catheter enhanced delivery of a model drug to smooth muscle cells while resulting in minimal cell death in vitro. In a second study with a similar catheter, in vivo delivery of the anti-proliferative drug rapamycin using MBs and IVUS was investigated [116]. Balloon angioplasty was performed on the left anterior descending, the right coronary, and the left circumflex arteries in a swine model.…”

Efficacy of Sonothrombolysis Using Microbubbles Produced by a Catheter-Based Microfluidic Device in a Rat Model of Ischemic Stroke

“…Thus, it was important to evaluate the feasibility of miniaturizing the FFMD to human-compatible dimensions. The catheter-based design is also intended for integration onto a catheter that emits therapeutic levels of ultrasound energy via either a forward-looking 44 or radially-emitting ultrasound transducer 45 and contains on-chip sensors for real-time monitoring and control of microbubble production rate and diameter. 46 The present study focused on ischemic stroke, but a multi-function sonothrombolysis catheter could find application in stroke, deep vein thrombosis, myocardial infarction, and other thrombosis-related conditions including those pertaining to the microvasculature.…”