An evaluation of the sonoporation potential of low-boiling point phase-change ultrasound contrast agents in vitro

Abstract Background Phase-change ultrasound contrast agents (PCCAs) offer a solution to the inherent limitations associated with using microbubbles for sonoporation; they are characterized by prolonged circulation lifetimes, and their nanometer-scale sizes may allow for passive accumulation in solid tumors. As a first step towards the goal of extravascular cell permeabilization, we aim to characterize the sonoporation potential of a low-boiling point formulation of PCCAs in vitro. Methods Parameters to induce acoustic droplet vaporization and subsequent microbubble cavitation were optimized in vitro using high-speed optical microscopy. Sonoporation of pancreatic cancer cells in suspension was then characterized at a range of pressures (125–600 kPa) and pulse lengths (5–50 cycles) using propidium iodide as an indicator molecule. Results We achieved sonoporation efficiencies ranging from 8 ± 1% to 36 ± 4% (percent of viable cells), as evidenced by flow cytometry. Increasing sonoporation efficiency trended with increasing pulse length and peak negative pressure. Conclusions We conclude that PCCAs can be used to induce the sonoporation of cells in vitro, and our results warrant further investigation into the use of PCCAs as extravascular sonoporation agents in vivo

Oxygen Microbubbles Improve Radiotherapy Tumor Control in a Rat Fibrosarcoma Model – A Preliminary Study

Cancer affects 39.6% of Americans at some point during their lifetime. Solid tumor microenvironments are characterized by a disorganized, leaky vasculature that promotes regions of low oxygenation (hypoxia). Tumor hypoxia is a key predictor of poor treatment outcome for all radiotherapy (RT), chemotherapy and surgery procedures, and is a hallmark of metastatic potential. In particular, the radiation therapy dose needed to achieve the same tumor control probability in hypoxic tissue as in normoxic tissue can be up to 3 times higher. Even very small tumors (<2–3 mm3) comprise 10–30% of hypoxic regions in the form of chronic and/or transient hypoxia fluctuating over the course of seconds to days. We investigate the potential of recently developed lipid-stabilized oxygen microbubbles (OMBs) to improve the therapeutic ratio of RT. OMBs, but not nitrogen microbubbles (NMBs), are shown to significantly increase dissolved oxygen content when added to water in vitro and increase tumor oxygen levels in vivo in a rat fibrosarcoma model. Tumor control is significantly improved with OMB but not NMB intra-tumoral injections immediately prior to RT treatment and effect size is shown to depend on initial tumor volume on RT treatment day, as expected

A Mobile Health Tool for Peer Support of Individuals Reentering Communities After Incarceration

Individuals just released from prison, or returning citizens (RCs), face high mortality rates during the reentry period, with cardiovascular disease (CVD) being a leading cause. Peer mentors can support RCs\u27 health, but they traditionally work in person, which may not always be feasible, particularly during pandemic outbreaks such as COVID-19. We used human-centered design to build a prototype of RCPeer, a web/mobile application (app) to support peer-led reentry efforts through CVD risk screening, action planning, linkage to resources addressing reintegration needs (e.g., housing, transportation), and goal-setting. We assessed feasibility, acceptability, and usability of RCPeer using mixed-methods. System Usability Scale (SUS) scores were 68 for peers and 66 for RCs, indicating good usability. Qualitative data suggests that RCPeer can support reentry tasks through RCs and peers sharing data, strengthen RC-peer relationships, and facilitate RCs meeting their goals. Future work is needed to enhance usability for RCs with limited technology experience

Experimental procedures.

<p>a) Schematic of the experimental set-up used for in-vivo hypoxia modulation measurements using the Zenascope system. b) Schematic of tumor volume assessment via B-mode ultrasound imaging. Two cross-sectional images were acquired and lengths a, b and c were used to calculate tumor volume. c) Radiotherapy pre and post-imaging experimental protocol.</p

Oxygen microbubbles improve radiotherapy tumor control in a rat fibrosarcoma model – A preliminary study

<div><p>Cancer affects 39.6% of Americans at some point during their lifetime. Solid tumor microenvironments are characterized by a disorganized, leaky vasculature that promotes regions of low oxygenation (hypoxia). Tumor hypoxia is a key predictor of poor treatment outcome for all radiotherapy (RT), chemotherapy and surgery procedures, and is a hallmark of metastatic potential. In particular, the radiation therapy dose needed to achieve the same tumor control probability in hypoxic tissue as in normoxic tissue can be up to 3 times higher. Even very small tumors (<2–3 mm³) comprise 10–30% of hypoxic regions in the form of chronic and/or transient hypoxia fluctuating over the course of seconds to days. We investigate the potential of recently developed lipid-stabilized oxygen microbubbles (OMBs) to improve the therapeutic ratio of RT. OMBs, but not nitrogen microbubbles (NMBs), are shown to significantly increase dissolved oxygen content when added to water in vitro and increase tumor oxygen levels in vivo in a rat fibrosarcoma model. Tumor control is significantly improved with OMB but not NMB intra-tumoral injections immediately prior to RT treatment and effect size is shown to depend on initial tumor volume on RT treatment day, as expected.</p></div

A single oxygen microbubble administration alone does not influence tumor control.

<p>No significant difference was found between the no treatment and oxygen microbubble group in the absence of any radiotherapy (n = 4 per group). Box-and-whisker plots represent all data from the No treatment and OMB alone controls.</p

In vitro oxygen microbubble characterization.

<p>a) Measured oxygen microbubble size distribution, displayed with a diameter bin size of 0.032 μm, as mean ± standard deviation (gray area) from 3 independent samples; b) Measured change in oxygen % saturation in vitro after 300 μL OMB (n = 3) or NMB (n = 3) injection into 70 mL partially degassed water (p<0.05).</p

Plot of gain in tumor control time against initial tumor volume, the confounding variable.

<p>An on/off effect (threshold) is observed around 0.5 cm³ initial tumor volume. Below this size, tumors are controlled for 31 days with RT alone. Above this size, tumors are large enough that RT alone cannot control them for 31 days, and therefore, OMB administration can provide a substantial improvement in tumor control time. Additionally, the benefit offered by OMB administration diminishes as initial tumor volume exceeds ~2 cm³. Given our study design, the slope describing the inverse relationship between improvement in tumor control and initial tumor volume (above the threshold value of 0.5 cm³) could in theory guide optimal OMB dosing with respect to tumor volume (confounder) in order to maximize tumor control benefit for a given RT dose.</p

(Color online) example of acoustic angiography maximum intensity projections around tumors (tumor size denoted with dashed yellow lines) in a rat fibrosarcoma allograft, with tortuous angiogenesis extending beyond the tumor margins (red arrows).

<p>The small tumor (a) is also shown to be more enhanced, denoting its higher perfusion compared to the larger tumor (b).</p

Tumor control time comparison between RT groups.

<p>OMB significantly improve RT outcome, whereas NMB as controls do not (n = 6 per group). Box-and-whisker plots show all data from the three radiotherapy treatment groups.</p