Phospholipid Oxygen Microbubbles for Image-Guided Therapy

Abstract

In recent work, oxygen microbubbles (OMB) have been shown to oxygenate hypoxic tumors, increase radio-sensitivity and improve tumor control by radiation therapy. Compared to intra-tumoral injection, intravenous delivery of adjuvant agents such as OMBs for radiotherapy offers an attractive means of achieving true theranostic function in a minimally invasive manner via contrast-enhanced ultrasound (CEUS), while reducing the risk of injury, infection or displacing tumor cells. However, short intravascular circulation times with conventional DSPC-lipid OMBs may lead to premature off-target dissolution of OMBs with an associated reduction in tumoral oxygen delivery. Prior work on microbubble stability and gas exchange suggests that increasing phospholipid acyl-chain length of the encapsulating shell and OMB size may increase circulation persistence, delivery and dissolved oxygen content. In the following studies, we investigate the effect of two phospholipid shell compositions, DSPC (C18:0) and DBPC (C22:0), as well as three size distributions (0.5-2 µm, 2-10 µm and polydisperse) on OMB circulation persistence utilizing CEUS in the kidneys of live C57B1/6 male and female mice, six weeks of age. DBPC OMB formulations demonstrated increased circulation half-lives versus DSPC formulations (2.4 ± 1.0 vs. 0.6 ± 0.5 s, p<0.01 for 2-10 µm), as well as an increased maximum intensity by over tenfold (p<0.01). Size-dependent effects remained consistent across both formulations with larger 2-10 µm microbubbles demonstrating significantly increased half-lives (2.4 ± 1.0 vs. 0.3 ± 0.2 s, p < 0.01) compared to smaller 0.5-2 µm formulations of DBPC. These studies indicate that DBPC 2-10 µm OMBs may be improved adjuvant agents for radiotherapy with significant potential for CEUS interrogation.

Magnetic Resonance Detection of Gas Microbubbles via HyperCEST: A Path Toward Dual Modality Contrast Agent

“…The overarching goal of hyperCEST is molecular imaging, requiring functionalization of the cage molecule in order to target different disease sites. MB have been functionalized with binding ligands to increase their targeting specificity and they have been used for in vivo diagnostics and targeted delivery of therapeutic payloads, such as gases [12][13][14][15] or drugs. [7][8][9][10][11] Next steps should focus on MB functionalization through molecular targeting [5,6,55] for hyperCEST imaging, similar to how GV were previously used to image breast cancer cells in vitro.…”

“…They are extremely echogenic and provide enhanced ultrasound (US) image contrast in clinical applications [1–4] . MB can also be functionalized to enhance their molecular specificity, [5,6] and can be guided or locally ruptured on command by US waves to deliver a payload of drugs [7–11] or gases, such as oxygen [12–15] …”

“…[1][2][3][4] MB can also be functionalized to enhance their molecular specificity, [5,6] and can be guided or locally ruptured on command by US waves to deliver a payload of drugs [7][8][9][10][11] or gases, such as oxygen. [12][13][14][15] MB have also been proposed as a contrast agent for magnetic resonance imaging (MRI). [16,17] However, the susceptibility difference at the gas-liquid interface does not provide significant spin dephasing when compared to other MRI relaxation agents.…”

Ultrasound-triggered oxygen-loaded nanodroplets enhance and monitor cerebral damage from sonodynamic therapy

“…However, since the droplet shell reduces diffusion of dissolved gases 43 , and the presence of DFB slows the diffusion of oxygen 44 , we anticipate that additional oxygen at the ultrasound focus plays a role in enhancing SDT. Future work will look at how oxygen diffusion may be slowed further by optimizing lipid chain length 45 , and how using an implanted oxygen probe 46 or measuring oxygen relaxation rate through T1-weighted MR imaging 47 could be used to measure in vivo oxygen content at the target site.…”

Effect of Gambogic Acid–Loaded Porous-Lipid/PLGA Microbubbles in Combination With Ultrasound-Triggered Microbubble Destruction on Human Glioma

“…However, conventional lipid-based MBs have poor drug encapsulation efficiency, and polymer-based MBs show a weak capability in contrast imaging and US-triggered drug release. Common phospholipid microbubbles have a good imaging effect in vivo , but the drug-loading rate is very low ( Reusser et al, 2020 ). PLGA microbubbles have high drug-loading efficiency, but the imaging effect in vivo is poor ( Nigam et al, 2019 ).…”