Accelerated Clearance of Ultrasound Contrast Agents Containing Polyethylene Glycol is Associated with the Generation of Anti-Polyethylene Glycol Antibodies

Fix, Samantha M.; Nyankima, A. Gloria; McSweeney, Morgan D.; Tsuruta, James K.; Lai, Samuel K.; Dayton, Paul A.

doi:10.1016/j.ultrasmedbio.2018.02.006

Cited by 41 publications

(31 citation statements)

References 57 publications

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“…The passive release profile of Xe from Xe-OFP-MB could not be assessed in this study because of the limited time resolution of GC/MS measurements. Future studies will assess Xe payload stability using alternate techniques within the first 4 min, consistent with the reported in vivo half-life of a similar lipid-shelled ultrasound contrast agent [66]. The size distributions reported in this study were measured at room temperature.…”

Section: Discussionsupporting

confidence: 68%

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

et al. 2019

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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.

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Section: Discussionsupporting

confidence: 68%

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

et al. 2019

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“…Variable amounts of contrast enhancement were observed in these rats on GdT1w images immediately post sonication such that by W4, it was necessary to increase the PNP from 0.3 MPa to 0.5 MPa in order to obtain BBBD in the cortex or hippocampus ( Figure 3 A ). The increase in PNP was needed possibly due to changes in skull thickness and weight gain that resulted in a decrease in MB/kg concentration in the animals or possibly shortening of Optison TM intravascular half-life from repeated exposures in the rat 44 . pFUS PNP at 0.5 MPa starting at the 4 th sonication was the minimum pressure that resulted in BBBD visible on GdT1w 3 T MRI using the infusion protocol for Optison TM (vide supra) with animals inhaling 100% O 2 .…”

Section: Resultsmentioning

confidence: 99%

MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain

Kovács

Sundby

et al. 2018

Theranostics

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Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound (pFUS) combined with microbubbles (MB) contrast agent infusion has been shown to transiently disrupt the blood-brain barrier (BBBD), increasing the delivery of neurotherapeutics to treat central nervous system (CNS) diseases. pFUS interaction with the intravascular MB results in acoustic cavitation forces passing through the neurovascular unit (NVU), inducing BBBD detected on contrast-enhanced MRI. Multiple pFUS+MB exposures in Alzheimer's disease (AD) models are being investigated as a method to clear amyloid plaques by activated microglia or infiltrating immune cells. Since it has been reported that pFUS+MB can induce a sterile inflammatory response (SIR) [1-5] in the rat, the goal of this study was to investigate the potential long-term effects of SIR in the brain following single and six weekly sonications by serial high-resolution MRI and pathology.Methods: Female Sprague Dawley rats weighing 217±16.6 g prior to sonication received bromo-deoxyuridine (BrdU) to tag proliferating cells in the brain. pFUS was performed at 548 kHz, ultrasound burst 10 ms and initial peak negative pressure of 0.3 MPa (in water) for 120 s coupled with a slow infusion of ~460 µL/kg (5-8×107 MB) that started 30 s before and 30 s during sonication. Nine 2 mm focal regions in the left cortex and four regions over the right hippocampus were treated with pFUS+MB. Serial high-resolution brain MRIs at 3 T and 9.4 T were obtained following a single or during the course of six weekly pFUS+MB resulting in BBBD in the left cortex and the right hippocampus. Animals were monitored over 7 to 13 weeks and imaging results were compared to histology.Results: Fewer than half of the rats receiving a single pFUS+MB exposure displayed hypointense voxels on T2*-weighted (w) MRI at week 7 or 13 in the cortex or hippocampus without differences compared to the contralateral side on histograms of T2* maps. Single sonicated rats had evidence of limited microglia activation on pathology compared to the contralateral hemisphere. Six weekly pFUS+MB treatments resulted in pathological changes on T2*w images with multiple hypointense regions, cortical atrophy, along with 50% of rats having persistent BBBD and astrogliosis by MRI. Pathologic analysis of the multiple sonicated animals demonstrated the presence of metallophagocytic Prussian blue-positive cells in the parenchyma with significantly (p<0.05) increased areas of activated astrocytes and microglia, and high numbers of systemic infiltrating CD68+ macrophages along with BrdU+ cells compared to contralateral brain. In addition, multiple treatments caused an increase in the number of hyperphosphorylated Tau (pTau)-positive neurons containing neurofibrillary tangles (NFT) in the sonicated cortex but not in the hippocampus when compared to contralateral brain, which was confirmed by Western blot (WB) (p<0.04).Conclusions: The repeated SIR following multiple pFUS+MB treatments could contribute to changes on MR imaging including persistent BBBD, co...

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“…Several studies showed that the PEG‐coating of nanotherapeutics could trigger the recognition of PEGylated nanomedicines by the cells of the Mononuclear phagocyte system (MPS), upon repeated administrations. [ 48,49 ] In particular, it was demonstrated that the second administration of PEGylated nanocarriers was rapidly cleared from the blood circulation, when administered at a specific time course after the injection of the first dose. [ 50,51 ] This unexpected pharmacokinetic modification, or accelerated blood clearance (ABC) [ 52,53 ] phenomenon, caused a large accumulation of PEGylated nanocarriers in the liver and it was widely studied by Dams et al.…”

Section: Accelerated Blood Clearance Phenomenonmentioning

confidence: 99%

“…demonstrated that the ABC phenomenon occurs also after 28 days after the first injection of PEGylated microbubble, although the serum level of IgM and IgG decreased significantly at the same incubation time. [ 75 ]…”

Section: Accelerated Blood Clearance Phenomenonmentioning

confidence: 99%

“…The induction of the ABC phenomenon was largely studied using PEGylated liposomes; however, different papers demonstrated that this phenomenon was not only limited to liposomes but it also occurred for PEGylated polymeric nanoparticles, [ 50,76 ] polymeric micelles, [ 95 ] or ultrasound contrast agents. [ 49 ] However, various PEGylated nanocarriers did not show the same severity on immune response in animal models and patients after multiple administrations. Recently, different scientists tested the effect of chemical composition of nanoparticles in the activation of the ABC phenomenon.…”

Section: Accelerated Blood Clearance Phenomenonmentioning

confidence: 99%

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Immunogenicity of Polyethylene Glycol Based Nanomedicines: Mechanisms, Clinical Implications and Systematic Approach

d’Avanzo

Celia

Barone

et al. 2020

Advanced Therapeutics

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PEGylation technique is currently considered the gold standard approach to provide a long and safe circulation of drugs. Although this is the accepted dogma, various clinical reports and animal studies show the occurrence of immunogenic responses against polyethylene glycol (PEG) after systemic injection. These side effects, associated with complement activation and/or anti‐PEG antibody production, result in hypersensitivity reactions and lack of therapeutic efficacy of the drug during clinical protocols. Furthermore, different healthy patients show the presence of anti‐PEG antibodies in their blood stream, even though they have not received PEGylated drugs. The aim of this review is to discuss the main mechanisms based on PEG immunogenicity and its clinical implications and report the most promising approaches to reduce these unexpected side effects.

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Accelerated Clearance of Ultrasound Contrast Agents Containing Polyethylene Glycol is Associated with the Generation of Anti-Polyethylene Glycol Antibodies

Cited by 41 publications

References 57 publications

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

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

MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain

Immunogenicity of Polyethylene Glycol Based Nanomedicines: Mechanisms, Clinical Implications and Systematic Approach

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