Microfluidic Fabrication of Perfluorohexane-Shelled Double Emulsions for Controlled Loading and Acoustic-Triggered Release of Hydrophilic Agents Wynter J. Duncanson, †,§,⊥ Laura R. Arriaga, †,⊥ W. Lloyd Ung, † Jonathan A. Kopechek, ‡,∥ Tyrone M. Porter, ‡ and David A. Weitz* ,† † School of Engineering and Applied Sciences and Department of Physics, Harvard University, Cambridge, Massachusetts, United States ‡ Department of Mechanical Engineering, Boston University, Boston, Massachusetts, United States * S Supporting Information ABSTRACT: The ability of low boiling point liquid perfluorocarbons (PFCs) to undergo a phase change from a liquid to a gas upon ultrasound irradiation makes PFC-based emulsions promising vehicles for triggered delivery of payloads. However, loading hydrophilic agents into PFC-based emulsions is difficult due to their insolubility in PFC. Here, we address this challenge by taking advantage of microfluidic technologies to fabricate double emulsions consisting of large aqueous cores and a perfluorohexane (PFH) shell, thus yielding high loading capacities for hydrophilic agents. Using this technology, we efficiently encapsulate a model hydrophilic agent within the emulsions and study its response to ultrasound irradiation. Using a combination of optical and acoustic imaging methods, we observe payload release upon acoustic vaporization of PFH. Our work demonstrates the utility of microfluidic techniques for controllably loading hydrophilic agents into PFH-based emulsions, which have great potential for acoustically triggered release. ■ INTRODUCTION An important goal of advanced drug delivery is to controllably supply drugs to specific sites in the body, which often requires the use of carrier vehicles that efficiently encapsulate payloads and release them in response to an external trigger; examples of such triggers include light, magnetic fields, and ultrasound. 1−4 Ultrasound is, in fact, an ideal trigger because it provides both spatial and temporal control over the transmission of thermal and mechanical energy; 5,6 this enables highly-localized heating or mechanical disruption of carrier vehicles 1,2,4 and hence rapid release of entrapped payloads. Carrier vehicles for ultrasound drug delivery often contain small gas bubbles; these serve as cavitating bodies that concentrate acoustic pressure waves to facilitate disruption of the carrier vehicles. Unfortunately, such vehicles have limited shelf-lives due to the inherent instability of gas bubbles. A promising alternative is to utilize emulsion drops composed of low boiling point liquid perfluorocarbons (PFCs); these undergo a liquid-to-gas phase transition when insoni- fied. 7−16 These drops have a longer shelf life than bubbles, can circulate in blood for hours rather than minutes, 17 and can extravasate through leaky tumor vasculature. 17,18 In addition to imaging applications, these PFC drops can be combined with ultrasound for highly localized delivery of payloads. 7,11 Conventionally, PFC emulsion drops are coated using polymers or lipids; these not only provide stability to the emulsion drops but also allow for drug loading. 19 Payloads can either be dissolved in the emulsion drop or embedded in its coatings. However, due to the poor solubility of hydrophilic agents in both amphiphilic coatings and PFCs, the utility of these emulsion drops as carrier vehicles is restricted to hydrophobic or amphiphilic payloads. To address this limitation, hydrophilic agents are predissolved in water and subsequently emulsified with PFCs through high shear mixing; 20−24 unfortunately, this strategy leads to wide distributions in both loading capacities and drop sizes. Microfluidic technologies enable the encapsu- lation of these mixtures into micron-sized droplets with narrow size distributions; 25 however, this strategy still results in uncontrolled loading capacities. These issues severely limit the utility of PFC-based emulsions as acoustically-activated vehicles for controlled delivery of hydrophilic payloads. It is therefore essential to develop an approach for the production of PFC-based emulsions with uniform sizes and controlled loading capacity for hydrophilic agents. In this work, we report a microfluidic technique for the production of perfluorohexane (PFH)-shelled double emulsion drops with uniform sizes and controlled loading capacities for Received: June 24, 2014 Revised: October 14, 2014 Published: October 23, 2014 Article pubs.acs.org/Langmuir © 2014 American Chemical Society 13765 dx.doi.org/10.1021/la502473w | Langmuir 2014, 30, 13765−13770