In Vivo Therapeutic Gas Delivery for Neuroprotection With Echogenic Liposomes

Britton, George; Kim, Hyunggun; Kee, Patrick; Aronowski, Jaroslaw; Holland, Christy K.; McPherson, David D.; Huang, Shaoling

doi:10.1161/circulationaha.109.879338

Cited by 65 publications

(78 citation statements)

References 42 publications

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“…Despite the detection of strong cavitation at this acoustic pressure, the precise mechanism of NO release and delivery remains unclear. Smith et al describe acoustically driven diffusion at moderate acoustic pressures, 56,57 and other investigators 7,58,59 have postulated that the lipid shell of microbubbles must first be ruptured before cavitation nucleation can occur, liberating encapsulated gas during rapid fragmentation. At a 0.34 MPa pressure exposure, it is likely that NO was released from the bubble liposomes gradually over a number of acoustic cycles.…”

Section: Ultrasound Exposure and Cavitationmentioning

confidence: 99%

Pulsed ultrasound enhances the delivery of nitric oxide from bubble liposomes to ex vivo porcine carotid tissue

Sutton¹,

Raymond²,

Verleye³

et al. 2014

IJN

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Ultrasound-mediated drug delivery is a novel technique for enhancing the penetration of drugs into diseased tissue beds noninvasively. By encapsulating drugs into microsized and nanosized liposomes, the therapeutic can be shielded from degradation within the vasculature until delivery to a target site by ultrasound exposure. Traditional in vitro or ex vivo techniques to quantify this delivery profile include optical approaches, cell culture, and electrophysiology. Here, we demonstrate an approach to characterize the degree of nitric oxide (NO) delivery to porcine carotid tissue by direct measurement of ex vivo vascular tone. An ex vivo perfusion model was adapted to assess ultrasound-mediated delivery of NO. This potent vasodilator was coencapsulated with inert octafluoropropane gas to produce acoustically active bubble liposomes. Porcine carotid arteries were excised post mortem and mounted in a physiologic buffer solution. Vascular tone was assessed in real time by coupling the artery to an isometric force transducer. NO-loaded bubble liposomes were infused into the lumen of the artery, which was exposed to 1 MHz pulsed ultrasound at a peak-to-peak acoustic pressure amplitude of 0.34 MPa. Acoustic cavitation emissions were monitored passively. Changes in vascular tone were measured and compared with control and sham NO bubble liposome exposures. Our results demonstrate that ultrasound-triggered NO release from bubble liposomes induces potent vasorelaxation within porcine carotid arteries (maximal relaxation 31%±8%), which was significantly stronger than vasorelaxation due to NO release from bubble liposomes in the absence of ultrasound (maximal relaxation 7%±3%), and comparable with relaxation due to 12 μM sodium nitroprusside infusions (maximal relaxation 32%±3%). This approach is a valuable mechanistic tool for assessing the extent of drug release and delivery to the vasculature caused by ultrasound.

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Section: Ultrasound Exposure and Cavitationmentioning

confidence: 99%

Pulsed ultrasound enhances the delivery of nitric oxide from bubble liposomes to ex vivo porcine carotid tissue

Sutton¹,

Raymond²,

Verleye³

et al. 2014

IJN

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“…In a previous study, we have shown intravenous injection of this ELIP formulation with ultrasound release over the carotid artery resulted in an enhanced effect using another bioactive gas encapsulated ELIP. 26 Lipids (5 mg) were mixed in chloroform and vaporized with argon in a 50°C water bath to form a thin film on a glass vial wall. The lipid film was placed under high vacuum (,100 Torr) for 4-6 hours to remove the solvent completely.…”

Section: Preparation Of No-elipmentioning

confidence: 99%

“…We have demonstrated that both pulsed diagnostic ultrasound and continuous ultrasound can be utilized to enhance therapeutic release from ELIP. [25][26][27] In this study, we evaluated NO-ELIP for ultrasoundfacilitated site-specific NO delivery to produce vasodilation affecting vasospasm following subarachnoid hemorrhage. We investigated the vasodilative effects of NO released from NO-ELIP following ultrasound exposure in in vitro, ex vivo, and in vivo models.…”

Section: Introductionmentioning

confidence: 99%

“…31 Neurologic assessment was performed 24 hours after subarachnoid hemorrhage using three different behavioral tests. 26,32 All behavioral tests were conducted in a quiet and low-lit room by an observer blinded with respect to the treatment groups. Each animal was tested for motor function and neurologic outcomes by recording their ability to perform limb placing, beam walking, and grid walking on the day following subarachnoid hemorrhage.…”

mentioning

confidence: 99%

“…Each animal was tested for motor function and neurologic outcomes by recording their ability to perform limb placing, beam walking, and grid walking on the day following subarachnoid hemorrhage. 26 Following the behavioral tests, a second dose of NO-ELIP (confirmation of vasodilation) was administered for 10 minutes via the tail vein. Ultrasound was again used for additive NO release in group 4 (NO-ELIP with ultrasound exposure).…”

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confidence: 99%

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Nitric oxide-loaded echogenic liposomes for treatment of vasospasm following subarachnoid hemorrhage

Kim¹,

Britton²,

Peng³

et al. 2013

IJN

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Delayed cerebral vasospasm following subarachnoid hemorrhage causes severe ischemic neurologic deficits leading to permanent neurologic dysfunction or death. Reduced intravascular and perivascular nitric oxide (NO) availability is a primary pathophysiology of cerebral vasospasm. In this study, we evaluated NO-loaded echogenic liposomes (NO-ELIP) for ultrasound-facilitated NO delivery to produce vasodilation for treatment of vasospasm following subarachnoid hemorrhage. We investigated the vasodilative effects of NO released from NO-ELIP both ex vivo and in vivo. Liposomes containing phospholipids and cholesterol were prepared, and NO was encapsulated. The encapsulation and release of NO from NO-ELIP were determined by the syringe/vacuum method and ultrasound imaging. The ex vivo vasodilative effect of NO-ELIP was investigated using rabbit carotid arteries. Arterial vasodilation was clearly observed with NO-ELIP exposed to Doppler ultrasound whereas there was little vasodilative effect without exposure to Doppler ultrasound in the presence of red blood cells. Penetration of NO into the arterial wall was determined by fluorescent microscopy. The vasodilative effects of intravenously administered NO-ELIP in vivo were determined in a rat subarachnoid hemorrhage model. NO-ELIP with ultrasound activation over the carotid artery demonstrated effective arterial vasodilation in vivo resulting in improved neurologic function. This novel methodology for ultrasound-controlled delivery of NO has the potential for therapeutic treatment of vasospasm following subarachnoid hemorrhage. This ultrasound-controlled release strategy provides a new avenue for targeted bioactive gas and therapeutic delivery for improved stroke treatment.

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Ultrasound Responsive Noble Gas Microbubbles for Applications in Image‐Guided Gas Delivery

Chattaraj

Hwang

Zemerov

et al. 2020

Adv Healthcare Materials

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Noble gases, especially xenon (Xe), have been shown to have antiapoptotic effects in treating hypoxia ischemia related injuries. Currently, in vivo gas delivery is systemic and performed through inhalation, leading to reduced efficacy at the injury site. This report provides a first demonstration of the encapsulation of pure Xe, Ar, or He in phospholipid‐coated sub‐10 µm microbubbles, without the necessity of stabilizing perfluorocarbon additives. Optimization of shell compositions and preparation techniques show that distearoylphosphatidylcholine (DSPC) with DSPE‐PEG5000 can produce stable microbubbles upon shaking, while dibehenoylphosphatidylcholine (DBPC) blended with either DSPE‐PEG2000 or DSPE‐PEG5000 produces a high yield of microbubbles via a sonication/centrifugation method. Xe and Ar concentrations released into the microbubble suspension headspace are measured using GC‐MS, while Xe released directly in solution is detected by the fluorescence quenching of a Xe‐sensitive cryptophane molecule. Bubble production is found to be amenable to scale‐up while maintaining their size distribution and stability. Excellent ultrasound contrast is observed in a phantom for several minutes under physiological conditions, while an intravenous administration of a bolus of pure Xe microbubbles provides significant contrast in a mouse in pre‐ and post‐lung settings (heart and kidney, respectively), paving the way for image‐guided, localized gas delivery for theranostic applications.

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In Vivo Therapeutic Gas Delivery for Neuroprotection With Echogenic Liposomes

Cited by 65 publications

References 42 publications

Pulsed ultrasound enhances the delivery of nitric oxide from bubble liposomes to ex vivo porcine carotid tissue

Pulsed ultrasound enhances the delivery of nitric oxide from bubble liposomes to ex vivo porcine carotid tissue

Nitric oxide-loaded echogenic liposomes for treatment of vasospasm following subarachnoid hemorrhage

Ultrasound Responsive Noble Gas Microbubbles for Applications in Image‐Guided Gas Delivery

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