Systemic oxygen delivery by peritoneal perfusion of oxygen microbubbles.

Severe hypoxemia refractory to pulmonary mechanical ventilation remains life-threatening in critically ill patients. Peritoneal ventilation has long been desired for extrapulmonary oxygenation owing to easy access of the peritoneal cavity for catheterization and the relative safety compared to an extracorporeal circuit. Unfortunately, prior attempts involving direct oxygen ventilation or aqueous perfusates of fluorocarbons or hemoglobin carriers have failed, leading many researchers to abandon the method. We attribute these prior failures to limited mass transfer of oxygen to the peritoneum and have designed an oxygen formulation that overcomes this limitation. Using phospholipid-coated oxygen microbubbles (OMBs), we demonstrate 100% survival for rats experiencing acute lung trauma to at least 2 h. In contrast, all untreated rats and rats treated with peritoneal oxygenated saline died within 30 min. For rats treated with OMBs, hemoglobin saturation and heart rate were at normal levels over the 2-h timeframe. Peritoneal oxygenation with OMBs was therefore shown to be safe and effective, and the method requires less equipment and technical expertise than initiating and maintaining an extracorporeal circuit. Further translation of peritoneal oxygenation with OMBs may provide therapy for acute respiratory distress syndrome arising from trauma, sepsis, pneumonia, aspiration, burns and other pulmonary diseases.

Magnetic resonance properties of Gd(III)-bound lipid-coated microbubbles and their cavitation fragments.

Gas-filled microbubbles are potentially useful theranostic agents for magnetic resonance imaging-guided focused ultrasound surgery (MRIgFUS). Previously, MRI at 9.4 T was used to measure the contrast properties of lipid-coated microbubbles with gadolinium (Gd(III)) bound to lipid headgroups, which revealed that the longitudinal molar relaxivity (r(1)) increased after microbubble fragmentation. This behavior was attributed to an increase in water proton exchange with the Gd(III)-bound lipid fragments caused by an increase in the lipid headgroup area that accompanied the lipid shell monolayer-to-bilayer transition. In this article, we explore this mechanism by comparing the changes in r(1) and its transverse counterpart, r(2)*, after the fragmentation of microbubbles consisting of Gd(III) bound to two different locations on the lipid monolayer shell: the phosphatidylethanolamine (PE) lipid headgroup region or the distal region of the poly(ethylene glycol) (PEG) brush. Nuclear magnetic resonance (NMR) at 1.5 T was used to measure the contrast properties of the various microbubble constructs because this is the most common field strength used in clinical MRI. Results for the lipid-headgroup-labeled Gd(III) microbubbles revealed that r(1) increased after microbubble fragmentation, whereas r(2)* was unchanged. An analysis of PEG-labeled Gd(III) microbubbles revealed that both r(1) and r(2)* decreased after microbubble fragmentation. Further analysis revealed that the microbubble gas core enhanced the transverse MR signal (T(2)*) in a concentration-dependent manner but minimally affected the longitudinal (T(1)) signal. These results illustrate a new method for the use of NMR to measure the biomembrane packing structure and suggest that two mechanisms, proton-exchange enhancement by lipid membrane relaxation and magnetic field inhomogeneity imposed by the gas/liquid interface, may be used to detect and differentiate Gd(III)-labeled microbubbles and their cavitation fragments with MRI.

Theranostic Gd(III)-lipid microbubbles for MRI-guided focused ultrasound surgery.

We have synthesized a biomaterial consisting of Gd(III) ions chelated to lipid-coated, size-selected microbubbles for utility in both magnetic resonance and ultrasound imaging. The macrocyclic ligand DOTA-NHS was bound to PE headgroups on the lipid shell of pre-synthesized microbubbles. Gd(III) was then chelated to DOTA on the microbubble shell. The reaction temperature was optimized to increase the rate of Gd(III) chelation while maintaining microbubble stability. ICP-OES analysis of the microbubbles determined a surface density of 7.5 × 10(5) ± 3.0 × 10(5) Gd(III)/µm(2) after chelation at 50 °C. The Gd(III)-bound microbubbles were found to be echogenic in vivo during high-frequency ultrasound imaging of the mouse kidney. The Gd(III)-bound microbubbles also were characterized by magnetic resonance imaging (MRI) at 9.4 T by a spin-echo technique and, surprisingly, both the longitudinal and transverse proton relaxation rates were found to be roughly equal to that of no-Gd(III) control microbubbles and saline. However, the relaxation rates increased significantly, and in a dose-dependent manner, after sonication was used to fragment the Gd(III)-bound microbubbles into non-gas-containing lipid bilayer remnants. The longitudinal (r(1)) and transverse (r(2)) molar relaxivities were 4.0 ± 0.4 and 120 ± 18 mM(-1)s(-1), respectively, based on Gd(III) content. The Gd(III)-bound microbubbles may find application in the measurement of cavitation events during MRI-guided focused ultrasound therapy and to track the biodistribution of shell remnants.