Microvessels-on-a-Chip to Assess Targeted Ultrasound-Assisted Drug Delivery

Abstract

Microbubbles have been used in ultrasound-assisted drug delivery to help target solid tumors via blood vessels in vivo; however, studies to understand the phenomena at the cellular level and to optimize parameters for ultrasound or microbubbles in vivo are challenging and expensive to perform. Here, we utilize microfluidic microvessels-on-a-chip that enable visualization of microbubble/ultrasound-dependent drug delivery to microvasculature. When exposed to pulsed ultrasound, microbubbles perfused through microvessels-on-a-chip were observed to stably oscillate. Minimal cellular damage was observed for both microbubbles and untargeted doxorubicin-encapsulating liposomes (DOX-liposomes) perfused through chip microvessels. In contrast, passive and ultrasound-assisted perfusion of integrin-targeted DOX-liposomes induced cytotoxicity, which was only significantly enhanced for ultrasound-assisted perfusion when microbubbles were coperfused. These results suggest that stably oscillating microbubbles enhance targeted DOX-liposome internalization/cytotoxicity largely by stimulating integrin receptor endocytosis. Furthermore, our study demonstrates the utility of our microvessels-on-a-chip as a screening platform for optimizing drug dosage, targeting ligands and drugs.

Sonoprinting liposomes on tumor spheroids by microbubbles and ultrasound

“…Targeting can be achieved through the incorporation of tumor vasculature-specific ligands, like cyclic RGD or E-selectin, on the microbubble shell [66][67][68] , as well as through physical forces such as the application of an external magnetic field 69,70 or ultrasound-induced radiation forces [71][72][73] . Adding targeting moieties to the liposomes could also affect the liposomal uptake through receptor-mediated internalization 74 . Secondly, the lack of an endothelial cell layer in this spheroid model makes it impossible to evaluate the impact of this barrier in the current study.…”

Engineering Theranostic Microbubbles Using Microfluidics for Ultrasound Imaging and Therapy: A Review

“…Progress along these lines of investigation is underway. Park et al (2016) used a microfluidic chip to explore the effect of microbubbles under ultrasound on drug delivery to a solid tumor microvasculature model. The greatest cell toxicity was observed when targeted doxorubicin liposomes were used, in the presence of microbubbles, after exposure to ultrasound under stable cavitation conditions.…”

Fibrin-Targeted Polymerized Shell Microbubbles as Potential Theranostic Agents for Surgical Adhesions

“…For fibrin generation, 50 μ L of thrombin (bovine plasma, Sigma-Aldrich) at 100 units/mL was added to fibrinogen-containing wells. 34 The plates were agitated at room temperature for 1 h, and all wells were washed with PBS buffer. Aliquots of microbubbles (50 μ L, ~10 7 PSM/mL) were added to fibrin- and fibrinogen-coated wells and incubated for 30 min at room temperature.…”