Enhanced Intracellular Delivery of a Model Drug Using Microbubbles Produced by a Microfluidic Device

Abstract

Focal drug delivery to a vessel wall facilitated by intravascular ultrasound and microbubbles holds promise as a potential therapy for atherosclerosis. Conventional methods of microbubble administration result in rapid clearance from the blood stream and significant drug loss. To address these limitations, we evaluated whether drug delivery could be achieved with transiently stable microbubbles produced in real-time and in close proximity to the therapeutic site. Rat aortic smooth muscle cells were placed in a flow chamber designed to simulate physiological flow conditions. A flow-focusing microfluidic device (FFMD) produced 8 μm diameter monodisperse microbubbles within the flow chamber, and ultrasound was applied to enhance uptake of a surrogate drug (calcein). Acoustic pressures up to 300 kPa and flow rates up to 18 mL/s were investigated. FFMD generated microbubbles were stabilized with a polyethylene glycol-40 stearate shell and had either a perfluorobutane (PFB) or nitrogen gas core. The gas core composition affected stability, with PFB and nitrogen microbubbles exhibiting half-lives of 40.7 and 18.2 seconds, respectively. Calcein uptake was observed at lower acoustic pressures with nitrogen microbubbles (100 kPa) than with PFB microbubbles (200 kPa) (p < 0.05, n ≥ 3). In addition, delivery was observed at all flow rates, with maximal delivery (> 70% of cells) occurring at a flow rate of 9 mL/s. These results demonstrate the potential of transiently stable microbubbles produced in real-time and in close proximity to the intended therapeutic site for enhancing localized drug delivery.

A bibliometric analysis of micro/nano-bubble related research: current trends, present application, and future prospects

“…Mediated delivery was one kind of assistant measurements for supporting the ultrasound gene or drug transfer process (Koike et al 2005;Wang et al 2008). Intracellular delivery had been extensively applied in short interfering RNA (siRNA) or drug delivery by microbubble-enhanced ultrasound Hynynen 2005a, 2005b;Dixon et al 2013). Nevertheless, the object delivery and delivery pathways are close interaction with each other and aim at eliminating cancer or illness.…”

An IVUS transducer for microbubble therapies

“…This work however cannot determine if sonoporation occurred in these ex vivo arteries because the experiments were conducted at room temperature. However, other research has demonstrated that at comparable pressures and frequencies, sonoporation can be induced in vitro [53]–[55]. Future studies using in vitro and in vivo models may be performed to verify that sonoporation is induced by this system.…”

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

“…11,28,29 The insonation pulse applied to the transducer consisted of a displacement pulse and/or a burst pulse (1 or 2 MPa) based on previously investigated ultrasound conditions. 13,44,47 The displacement pulse was a long (500 cycle), high duty cycle (50%), low peak negative pressure (PNP = 600 kPa) pulse to displace microbubbles from flow to the vessel wall. The burst pulse was a short (50 cycle), low duty cycle (1%), high peak negative pressure (PNP = 1 or 2 MPa) pulse designed to disrupt microbubbles and induce drug release and uptake by cells.…”