Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles

Eisenbrey, John R.; Shraim, Rawan; Liu, Ji‐Bin; Li, Jingzhi; Stanczak, Maria; Oeffinger, Brian; Leeper, Dennis B.; Keith, Scott W.; Jablonowski, Lauren J.; Forsberg, Flemming; O’Kane, Patrick; Wheatley, Margaret A.

doi:10.1016/j.ijrobp.2018.01.042

Cited by 90 publications

(87 citation statements)

References 38 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the interaction of NO with dissolved oxygen and the rapid degradation of NO made the assessment of the passive release profile challenging. MB stabilized with other types of shell materials, such as polymers (McEwan et al, 2014), dextran (Cavalli et al, 2009a), surfactants (Eisenbrey et al, 2015;Eisenbrey et al, 2018), or chitosan (Cavalli et al, 2009b) shells, may increase the timescale of gas diffusion across the shell, with or without the addition of osmotic gases for payload stabilization. The efficacy and biocompatibility of such agents for encapsulating NO could also be compared to lipid-shelled MB.…”

Section: Discussionmentioning

confidence: 99%

Bactericidal Activity of Lipid-Shelled Nitric Oxide-Loaded Microbubbles

Lafond¹,

Shekhar²,

Panmanee³

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

The global pandemic of antibiotic resistance is an ever-burgeoning public health challenge, motivating the development of adjunct bactericidal therapies. Nitric oxide (NO) is a potent bioactive gas that induces a variety of therapeutic effects, including bactericidal and biofilm dispersion properties. The short half-life, high reactivity, and rapid diffusivity of NO make therapeutic delivery challenging. The goal of this work was to characterize NO-loaded microbubbles (MB) stabilized with a lipid shell and to assess the feasibility of antibacterial therapy in vitro. MB were loaded with either NO alone (NO-MB) or with NO and octafluoropropane (NO-OFP-MB) (9:1 v/v and 1:1 v/v). The size distribution and acoustic attenuation coefficient of NO-MB and NO-OFP-MB were measured. Ultrasound-triggered release of the encapsulated gas payload was demonstrated with 3-MHz pulsed Doppler ultrasound. An amperometric microelectrode sensor was used to measure NO concentration released from the MB and compared to an NO-OFP-saturated solution. The effect of NO delivery on the viability of planktonic (free living) Staphylococcus aureus (SA) USA 300, a methicillin-resistant strain, was evaluated in a 96 well-plate format. The co-encapsulation of NO with OFP increased the total volume and attenuation coefficient of MB. The NO-OFP-MB were destroyed with a clinical ultrasound scanner with an output of 2.48 MPa peak negative pressure (in situ MI of 1.34) but maintained their echogenicity when exposed to 0.02 MPa peak negative pressure (in situ MI of 0.01. The NO dose in NO-MB and NO-OFP-MB was more than 2-fold higher than the NO-OFPsaturated solution. Delivery of NO-OFP-MB increased bactericidal efficacy compared to the NO-OFP-saturated solution or air and OFP-loaded MB. These results suggest that encapsulation of NO with OFP in lipid-shelled MB enhances payload delivery. Furthermore, these studies demonstrate the feasibility and limitations of NO-OFP-MB for antibacterial applications.

show abstract

Section: Discussionmentioning

confidence: 99%

Bactericidal Activity of Lipid-Shelled Nitric Oxide-Loaded Microbubbles

Lafond¹,

Shekhar²,

Panmanee³

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…However, future large animal and human studies (in which the recirculation time is longer) will be necessary to assess whether intravenous administration of Xe-OFPloaded microbubbles provides neuroprotection during ischemia. Recent reports with microbubbles stabilized with surfactants [28,62], dextran [63], polymer [64], or chitosan shells [65] show promise for reducing gas diffusion across the shell, even without co-encapsulating perfluorocarbon gases. In the future, the performance and biocompatibility of such agents should be compared against lipid-shelled microbubbles for Xe delivery.…”

Section: Discussionmentioning

confidence: 99%

“…Up to 34% of the Xe-ELIP payload exists in dissolved form in the lipid bilayer [17], which enables a biphasic release profile [19]. Shelled microbubbles have been investigated for the delivery of bioactive gases such as oxygen, nitric oxide, and hydrogen sulfide [24][25][26][27][28][29]. The volume of microbubbles is almost entirely composed of gas, which enables ultrasound-triggered release and enhancement of payload delivery.…”

Section: Introductionmentioning

confidence: 99%

Characterization and Imaging of Lipid-Shelled Microbubbles for Ultrasound-Triggered Release of Xenon

et al. 2019

View full text Add to dashboard Cite

Xenon (Xe) is a bioactive gas capable of reducing and stabilizing neurologic injury in stroke. The goal of this work was to develop lipid-shelled microbubbles for xenon loading and ultrasound-triggered release. Microbubbles loaded with either xenon (Xe-MB) or xenon and octafluoropropane (Xe-OFP-MB) (9:1 v/v) were synthesized by high-shear mixing. The size distribution and the frequency-dependent attenuation coefficient of Xe-MB and Xe-OFP-MB were measured using a Coulter counter and a broadband acoustic attenuation spectroscopy system, respectively. The Xe dose was evaluated using gas chromatography/mass spectrometry. The total Xe doses in Xe-MB and Xe-OFP-MB were 113.1 ± 13.5 and 145.6 ± 25.5 μl per mg of lipid, respectively. Co-encapsulation of OFP increased the total xenon dose, attenuation coefficient, microbubble stability (in an undersaturated solution), and shelf life of the agent. Triggered release of gas payload was demonstrated with 6-MHz duplex Doppler and 220-kHz pulsed ultrasound. These results constitute the first step toward the use of lipid-shelled microbubbles for applications such as neuroprotection in stroke.

show abstract

“…In 2018, Fix et al showed that intra-tumoral injection lipid-coated OMB Ivyspring International Publisher can increase tumor oxygen levels and tumor control in a fibrosarcoma rat model [4]. In the same year, Eisenbrey et al showed that intravenous injection of surfactant-coated OMB can increase tumor oxygen and control in a breast cancer model [5,6]. These studies have demonstrated the promise of ultrasound-guided OMB for treating hypoxic tumors.…”

Section: Introductionmentioning

confidence: 99%

Phospholipid Oxygen Microbubbles for Image-Guided Therapy

Reusser¹,

Song²,

Ramirez³

et al. 2020

Nanotheranostics

View full text Add to dashboard Cite

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.

show abstract

Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles

Abstract: Our findings demonstrate the potential advantages of ultrasound-triggered oxygen delivery to solid tumors and warrant future efforts into clinical translation of the microbubble platform.

Cited by 90 publications

References 38 publications

Bactericidal Activity of Lipid-Shelled Nitric Oxide-Loaded Microbubbles

Bactericidal Activity of Lipid-Shelled Nitric Oxide-Loaded Microbubbles

Characterization and Imaging of Lipid-Shelled Microbubbles for Ultrasound-Triggered Release of Xenon

Phospholipid Oxygen Microbubbles for Image-Guided Therapy

Contact Info

Product

Resources

About