The impact of vaporized nanoemulsions on ultrasound-mediated ablation

BACKGROUND: The clinical feasibility of using high-intensity focused ultrasound (HIFU) for ablation of solid tumors is limited by the high acoustic pressures and long treatment times required. The presence of microbubbles during sonication can increase the absorption of acoustic energy and accelerate heating. However, formation of microbubbles within the tumor tissue remains a challenge. Phase-shift nanoemulsions (PSNE) have been developed as a means for producing microbubbles within tumors. PSNE are emulsions of submicron-sized, lipid-coated, and liquid perfluorocarbon droplets that can be vaporized into microbubbles using short (5 MPa) acoustic pulses. In this study, the impact of vaporized phase-shift nanoemulsions on the time and acoustic power required for HIFU-mediated thermal lesion formation was investigated in vitro. METHODS: PSNE containing dodecafluoropentane were produced with narrow size distributions and mean diameters below 200 nm using a combination of sonication and extrusion. PSNE was dispersed in albumin-containing polyacrylamide gel phantoms for experimental tests. Albumin denatures and becomes opaque at temperatures above 58°C, enabling visual detection of lesions formed from denatured albumin. PSNE were vaporized using a 30-cycle, 3.2-MHz, at an acoustic power of 6.4 W (free-field intensity of 4,586 W/cm(2)) pulse from a single-element, focused high-power transducer. The vaporization pulse was immediately followed by a 15-s continuous wave, 3.2-MHz signal to induce ultrasound-mediated heating. Control experiments were conducted using an identical procedure without the vaporization pulse. Lesion formation was detected by acquiring video frames during sonication and post-processing the images for analysis. Broadband emissions from inertial cavitation (IC) were passively detected with a focused, 2-MHz transducer. Temperature measurements were acquired using a needle thermocouple. RESULTS: Bubbles formed at the HIFU focus via PSNE vaporization enhanced HIFU-mediated heating. Broadband emissions detected during HIFU exposure coincided in time with measured accelerated heating, which suggested that IC played an important role in bubble-enhanced heating. In the presence of bubbles, the acoustic power required for the formation of a 9-mm(3) lesion was reduced by 72% and the exposure time required for the onset of albumin denaturation was significantly reduced (by 4 s), provided that the PSNE volume fraction in the polyacrylamide gel was at least 0.008%. CONCLUSIONS: The time or acoustic power required for lesion formation in gel phantoms was dramatically reduced by vaporizing PSNE into bubbles. These results suggest that PSNE may improve the efficiency of HIFU-mediated thermal ablation of solid tumors; thus, further investigation is warranted to determine whether bubble-enhanced HIFU may potentially become a viable option for cancer therapy.R21 EB009493 - NIBIB NIH HH

High fat diet deviates PtC-specific B1 B cell phagocytosis in obese mice

Phagocytosis had been attributed predominantly to "professional" phagocytes such as macrophages, which play critical roles in adipose tissue inflammation. However, recently, macrophage-like phagocytic activity has been reported in B1 B lymphocytes. Intrigued by the long-established correlation between high fat diet (HFD)-induced obesity and immune dysfunction, we investigated how HFD affects B1 B cell phagocytosis. A significant number of B1 B cells recognize phosphatidylcholine (PtC), a common phospholipid component of cell membrane. We report here that unlike macrophages, B1 B cells have a unique PtC-specific phagocytic function. In the presence of both PtC-coated and non-PtC control fluorescent nano-particles, B1 B cells from healthy lean mice selectively engulfed PtC-coated beads, whereas B1 B cells from HFD-fed obese mice non-discriminately phagocytosed both PtC-coated and control beads. Morphologically, B1 B cells from obese mice resembled macrophages, displaying enlarged cytosol and engulfed more beads. Our study suggests for the first time that HFD can affect B1 B cell phagocytosis, substantiating the link of HFD-induced obesity and immune deviation.R21 AR063387 - NIAMS NIH HHS; R25 CA153955 - NCI NIH HHS; UL1 TR000157 - NCATS NIH HH

Being there: a preliminary study examining the role of presence in Internet Gaming Disorder

Internet Gaming Disorder (IGD) has been introduced as an emerging mental health condition requiring further study. Associations between IGD and gaming presence (i.e., absorption in the virtual environment) have been implied. The aim of the present study was twofold: (a) to evaluate the extent to which presence contributes to IGD severity and, (b) to examine longitudinal differences in IGD according to the initial level of presence experienced. The participants comprising 125 emerging adults aged 18 to 29 years completed either: (i) three face-to-face assessments (one month apart, over three months) or (ii) a cross-sectional, online assessment. IGD was assessed with the nine-item IGD Scale Short Form and presence was assessed using the Presence Questionnaire. Regression and latent growth modelling analyses were conducted. Findings demonstrated that the level of gaming presence related to IGD severity but not to linear change in severity over a three-month period. The study shows that emergent adults who play internet games may be at a high risk of IGD given a more salient sense of being present within the gaming environment. Clinical implications considering prevention and intervention initiatives are discussed

Effect of flow on targeting and penetration of angiopep-decorated nanoparticles in a microfluidic model blood-brain barrier.

The blood-brain barrier (BBB) limits transport of nanoparticles from the circulation to the brain parenchyma. Angiopep-2, a peptide which functions as a brain transport vector, can be coupled to nanoparticles in order to facilitate binding and internalization by brain endothelial cells (ECs), and subsequent BBB penetration. This multi-step process may be affected by blood flow over brain ECs, as flow influences endothelial cell phenotype as well as interactions of nanoparticles with ECs. In the present study a microfluidic BBB model was constructed to evaluate binding and internalization by brain ECs, as well as BBB penetration of Angiopep-2 coupled liposomes (Ang2-Liposomes) in static and flow conditions. Ang2 conjugation to liposomes markedly improved binding relative to unconjugated liposomes. Ang2-Liposomes bound and were internalized efficiently by brain endothelial cells after static incubation or with 1 dyne/cm2 of fluid shear stress (FSS), while binding was reduced at a FSS of 6 dyne/cm2. Penetration of the model microfluidic BBB by Ang2-Liposomes was higher at a FSS of 1 dyne/cm2 and 6 dyne/cm2 than with static incubation. Analysis of barrier function and control experiments for receptor-mediated penetration provided insight into the magnitude of transcellular versus paracellular transport at each tested FSS. Overall, the results demonstrate that flow impacted the binding and BBB penetration of Ang2-functionalized nanoparticles. This highlights the relevance of the local flow environment for in vitro modeling of the performance of nanoparticles functionalized with BBB penetrating ligands

Accumulation of Phase-Shift Nanoemulsions to Enhance MR-Guided Ultrasound-Mediated Tumor Ablation In Vivo

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is being explored as a non-invasive technology to treat solid tumors. However, the clinical use of HIFU for tumor ablation applications is currently limited by the long treatment times required. Phase-shift nanoemulsions (PSNE), consisting of liquid perfluorocarbon droplets that can be vaporized into microbubbles, are being developed to accelerate HIFU-mediated heating. The purpose of this study was to examine accumulation of PSNE in intramuscular rabbit tumors in vivo. MR images were acquired before and after intravenous injection of gadolinium-containing PSNE. MR signal enhancement was observed in rabbit tumors up to six hours after injection, indicating that PSNE accumulated in the tumors. In addition, PSNE vaporization was detected in the tumor with B-mode ultrasound imaging, and MR thermometry measurements indicated that PSNE accelerated the rate of HIFU-mediated heating. These results suggest that PSNE could dramatically improve the efficiency and clinical feasibility of MRgHIFU

High fat diet deviates PtC‐specific B1 B cell phagocytosis in obese mice

Phagocytosis had been attributed predominantly to "professional" phagocytes such as macrophages, which play critical roles in adipose tissue inflammation. However, recently, macrophage-like phagocytic activity has been reported in B1 B lymphocytes. Intrigued by the long-established correlation between high fat diet (HFD)-induced obesity and immune dysfunction, we investigated how HFD affects B1 B cell phagocytosis. A significant number of B1 B cells recognize phosphatidylcholine (PtC), a common phospholipid component of cell membrane. We report here that unlike macrophages, B1 B cells have a unique PtC-specific phagocytic function. In the presence of both PtC-coated and non-PtC control fluorescent nano-particles, B1 B cells from healthy lean mice selectively engulfed PtC-coated beads, whereas B1 B cells from HFD-fed obese mice non-discriminately phagocytosed both PtC-coated and control beads. Morphologically, B1 B cells from obese mice resembled macrophages, displaying enlarged cytosol and engulfed more beads. Our study suggests for the first time that HFD can affect B1 B cell phagocytosis, substantiating the link of HFD-induced obesity and immune deviation.R21 AR063387 - NIAMS NIH HHS; R25 CA153955 - NCI NIH HHS; UL1 TR000157 - NCATS NIH HH