Ultrasound and microbubble-induced local delivery of MicroRNA-based therapeutics.

MicroRNAs are involved in many pathologic processes and are a promising target for therapeutic intervention. However, successful, localized delivery of microRNA-based therapeutics is lacking. In this study, cationic ultrasound-responsive microbubbles (MBs) were used to deliver microRNA blockers and mimics in vitro and in vivo. Cationic MBs successfully delivered microRNA blockers to human endothelial cells on ultrasound (US) exposure in vitro. This in vitro US protocol did not successfully deliver microRNA mimics to skeletal muscle of mice, whereas an US protocol that is routinely used for contrast imaging did. Additionally, we used cationic MBs and US to locally deliver antimiR and antagomiR molecules with US causing inertial cavitation. Delivery of antimiR to the extracellular compartments of the muscle was only slightly increased, whereas delivery of antagomiR to the capillaries, myocytes and extracellular space was significantly increased. AntagomiR seems to be a more suitable microRNA blocker than antimiR for use in combination with MBs and US for local delivery.

Quantification of myocardial perfusion using intravenous myocardial contrast echocardiography in healthy volunteers: comparison with positron emission tomography.

BACKGROUND: Intravenous myocardial contrast echocardiography (ivMCE) has the potential to evaluate myocardial contraction and perfusion simultaneously. The purpose of this study was to assess quantification of myocardial blood flow (MBF) using ivMCE and to compare this with MBF as measured with positron emission tomography (PET). METHODS: A total of 16 healthy volunteers underwent ivMCE using power pulse inversion and contrast agent microbubbles at rest and during pharmacologically induced vasodilation. Microbubble destruction was achieved with a burst of high-energy ultrasound, followed by imaging of contrast replenishment with low-energy ultrasound. Regions of interest were drawn and time intensity curves were calculated that were fitted to a monoexponential function. An estimate of MBF (perfusion estime) was calculated as the product of the plateau value A and the exponential beta describing the replenishment curve. MBF was measured with PET using oxygen-15-labeled water at rest and during adenosine stress. RESULTS: Significant correlations were found between MBF as measured with PET and perfusion estimate as measured with ivMCE in the left anterior descending coronary artery (r = 0.87, P < .01), right coronary artery (r = 0.66, P < .01), and left circumflex artery (r = 0.75, P < .01) territories. Heterogeneity, however, was significantly larger for ivMCE (coefficient of variation 32 +/- 15%) than for PET (9 +/- 6%) measurements (P < .01). CONCLUSION: Perfusion parameters as measured with ivMCE correlated with PET-derived MBF, but associated heterogeneity was significantly larger. Currently, this heterogeneity precludes true quantification of MBF using ivMCE.

Quantitative evaluation of myocardial perfusion in patients with revascularized myocardial infarction: comparison between intravenous myocardial contrast echocardiography and 99mTc-sestamibi single photon emission computed tomography.

AIMS: This two-center study compared quantitative segmental perfusion mapping by intravenous myocardial contrast echocardiography (ivMCE) and scintigraphy (SPECT) in patients in the subacute phase of myocardial infarction (AMI). METHODS AND RESULTS: Sixteen patients underwent ivMCE using 1:1 intermittent harmonic imaging 24 h after first AMI treated with PTCA and stenting. Apical contrast echocardiograms were obtained after the injections of Sonazoid. Baseline-corrected peak myocardial videointensity (bcPMVI) was determined automatically in 16 segments. Resting 99mTc-sestamibi SPECT was performed within one day after ivMCE. SPECT images were reoriented matching the ivMCE views, and divided into the same segments as in ivMCE, from which mean count rate values were obtained. After exclusion due to artifacts or attenuation, 208/256 (82%) segments remained for analysis. Normalized SPECT count rate and bcPMVI correlated linearly: bcPMVI = 1.237 x SPECT - 35; r = 0.74, p < 0.0001. The relation remained identical in subgroup analysis based on participating center, echocardiographic view, perfusion territory, infarct zone, or function. Using SPECT as reference, mean bcPMVI was 77+/-19% in normal segments, 53+/-29% in mild-moderate defects and 25+/-18% in severe defects (p<0.001 for all comparisons). CONCLUSION: The videointensity increase observed in quantitative ivMCE clearly correlated with SPECT tracer uptake. This further substantiates the use of ivMCE as a valid technique for myocardial perfusion imaging.