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Commercially available microbubbles such as Definity contain octafluoropropane encapsulated in a lipid shell. This perfluorocarbon can be compressed into liquid nanodroplets at room temperatures and activated with transthoracic diagnostic ultrasound. The aim of this study was to determine the size range and acoustic characteristics of Definity nanodroplets (DNDs) compared with Definity microbubbles (DMBs).An in vitro flow system was used with a diagnostic ultrasound transducer (S5-1, iE33). DMBs were prepared using package insert instructions. DNDs were prepared by cooling DMBs in a -10°C to -15°C isopropyl alcohol bath before hand-pressurizing the solution. The formed DNDs were sized, diluted to 1% solutions, and infused continuously into a phosphate-buffered saline solution running within Silastic tubing. Acoustic intensity (AI) was compared with equivalent dilutions of DMBs at different mechanical indices (MIs) ranging from 0.2 to 1.4 (n = 6 comparisons at each MI) using real-time 56-Hz and triggered 2-Hz frame rates (FRs). A 3-cm-thick tissue-mimicking phantom was used to simulate transthoracic attenuation. In vivo transthoracic studies were performed in four normal pigs infused with 10% intravenous infusions of DMBs or DNDs at real-time and triggered end-systolic FRs to compare differences in myocardial and left ventricular cavity AI.DNDs were smaller than DMBs and ranged in size from 50 to 1,000 nm. In vitro studies revealed that at an MI of 0.2 and an FR of 56 Hz, DMBs had high AI (37 ± 2 dB), but AI dropped to 25 ± 2 dB at an MI of 1.0 (P .001, analysis of variance). In comparison, DNDs had virtually no AI at MIs of 0.2 to 0.6 at both triggered and 56-Hz FRs (1 ± 0 dB), but AI increased to 34 ± 2 dB at an MI of 1.4 using an FR of 56 Hz (P .001 vs MI of 0.2). AI also persisted longer at 56 Hz with DNDs when using higher MIs. In vivo studies demonstrated higher myocardial AI for DNDs at higher MIs when using real-time FR, most likely from microvascular nanodroplet activation.These data indicate significant differences in acoustic responses of the commercially available DMBs when administered as an equivalent number of DNDs. The DND formulation may render them more useful for high-MI real-time imaging and other targeted transthoracic diagnostic applications.