Material Properties, Dissolution and Time Evolution of PEGylated Lipid-Shelled Microbubbles: Effects of the Polyethylene Glycol Hydrophilic Chain Configurations

Azami, Roozbeh Hassanzadeh; Aliabouzar, Mitra; Osborn, Jenna; Kumar, Krishna N.; Forsberg, Flemming; Eisenbrey, John R.; Mallik, Sanku; Sarkar, Kausik

doi:10.1016/j.ultrasmedbio.2022.04.216

Cited by 8 publications

(4 citation statements)

References 54 publications

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“…Interestingly, we found that PEG-MBs with 2 mol % exhibited a 1.5-fold higher concentration compared to 5 and 10 mol %. This observed concentration trend aligns with the findings reported by Azami et al in their study involving polydisperse DPPC: DPPE-PEG 2000 MB suspensions. It is worth noting that some studies have suggested an optimal concentration of 5% DSPE-PEG 2000 for achieving maximum MB concentration .…”

Section: Resultssupporting

confidence: 92%

Effect of Poly(ethylene glycol) Configuration on Microbubble Pharmacokinetics

Navarro-Becerra,

Castillo,

Borden

2024

ACS Biomater. Sci. Eng.

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Microbubbles (MBs) hold substantial promise for medical imaging and therapy; nonetheless, knowledge gaps persist between composition, structure, and in vivo performance, especially with respect to pharmacokinetics. Of particular interest is the role of the poly(ethylene glycol) (PEG) layer, which is thought to shield the MB against opsonization and rapid clearance but is also known to cause an antibody response upon multiple injections. The goal of this study was, therefore, to elucidate the role of the PEG layer in circulation persistence of MBs in the nai ̈ve animal (prior to an adaptive immune response). Here, we directly observe the number and size of individual MBs obtained from blood samples, unifying size and concentration into the microbubble volume dose (MVD) parameter. This approach enables direct evaluation of the pharmacokinetics of intact MBs, comprising both the lipid shell and gaseous core, rather than separately assessing the lipid or gas components. We examined the in vivo circulation persistence of 3 μm diameter phospholipid-coated MBs with three different mPEG 2000 content: 2 mol % (mushroom), 5 mol % (intermediate), and 10 mol % (brush). MB size and concentration in the blood were evaluated by a hemocytometer analysis over 30 min following intravenous injections of 20 and 40 μL/kg MVD in Sprague−Dawley rats. Interestingly, pharmacokinetic analysis demonstrated that increasing PEG concentration on the MB surface resulted in faster clearance. This was evidenced by a 1.6-fold reduction in half-life and area under the curve (AUC) (p < 0.05) in the central compartment. Conversely, the AUC in the peripheral compartment increased with PEG density, suggesting enhanced MB trapping by the mononuclear phagocyte system. This was supported by an in vitro assay, which showed a significant rise in complement C3a activation with a higher PEG content. In conclusion, a minimal PEG concentration on the MB shell (mushroom configuration) was found to prolong circulation and mitigate immunogenicity.

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Section: Resultssupporting

confidence: 92%

Effect of Poly(ethylene glycol) Configuration on Microbubble Pharmacokinetics

Navarro-Becerra,

Castillo,

Borden

2024

ACS Biomater. Sci. Eng.

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“…SonoVue® and Definity® microbubbles rely on a phospholipid shell containing either SF 6 or C 3 F 8 , respectively, with a primary difference in shell composition being the PEGylated phospholipids present on Definity® microbubbles. The presence of these large PEG chains protect microbubbles from their surroundings through steric hindrance, effectively preventing coalescence and macromolecule adsorption, improving circulation, and minimising immunogenicity 133 . Comparatively, Optison™ microbubbles use an albumin shell, aimed at reducing the immunogenicity of their microbubbles by utilising a protein commonly produced in the body (Table 6 ).…”

Section: Resultsmentioning

confidence: 99%

A systematic review of ultrasound-mediated drug delivery to the eye and critical insights to facilitate a timely path to the clinic

Rad,

Chapman,

Tupally

et al. 2023

Theranostics

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Ultrasound has long been identified as a promising, non-invasive modality for improving ocular drug delivery across a range of indications. Yet, with 20 years of learnings behind us, clinical translation remains limited. To help address this, and in accordance with PRISMA guidelines, the various mechanisms of ultrasound-mediated ocular drug delivery have been appraised, ranging from first principles to emergent applications spanning both ex vivo and in vivo models. The heterogeneity of study methods precluded meta-analysis, however an extensive characterisation of the included studies allowed for semi-quantitative and qualitative assessments. Methods: In this review, we reflected on study quality of reporting, and risk of bias (RoB) using the latest Animal Research: Reporting of In Vivo Experiments (ARRIVE 2.0) guidelines, alongside the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) RoB tools. Literature studies from 2002 to 2022 were initially characterised according to methods of ultrasound application, ultrasound parameters applied, animal models employed, as well as safety and efficacy assessments. This exercise contributed to developing a comprehensive understanding of the current state of play within ultrasound-mediated ocular drug delivery. The results were then synthesised and processed into a guide to aid future study design, with the goal of improving the reliability of data, and to support efficient and timely translation to the clinic. Results: Key attributes identified as hindering translation included: poor reporting quality and high RoB, skewed use of animals unrepresentative of the human eye, and the over reliance of reductionist safety assessments. Ex vivo modelling studies were often unable to have comprehensive safety assessments performed on them, which are imperative to determining treatment safety, and represent a pre-requisite for clinical translation. Conclusion:With the use of our synthesised guide, and a thorough understanding of the underlying physicochemical interactions between ultrasound and ocular biology provided herein, this review offers a firm foundation on which future studies should ideally be built, such that ultrasound-mediated ocular drug delivery can be translated from concept to the coalface where it can provide immense clinical benefit.

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“…As stated above, however, the shell composition greatly affects its viscoelasticity, that is, causing a shift in the resonance frequency, damping of the oscillation amplitude, and changing the destruction propensity. These effects have been investigated theoretically and experimentally. − The acoustic characteristics of the commercial microbubbles Sonazoid (Daiichi Sankyo, GE Healthcare, Tokyo, Japan), Definity (Lantheus, North Billerica, MA, USA), and SonoVue (Bracco, Milan, Italy) have been investigated by measuring the attenuation of acoustic pulse waves, and the dilatational viscoelasticity values of these shells have been estimated using a theoretical model. − More precisely, phospholipids with carbon chains of various lengths were used as the shell and their effects were examined. , Poloxamer surfactants are often used to prepare laboratory-made and commercial phospholipid-based microbubbles. , The acoustic properties of bubbles coated with shells containing various ratios of lipids and poloxamer surfactants have been reported in several studies. ,,, However, there are few reports on the acoustic properties of bubbles coated with poloxamer surfactants used as the only shell material. In addition, the relationships between the adsorption properties of the shell material and its dilatational viscoelasticity have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

“…28,34 The acoustic properties of bubbles coated with shells containing various ratios of lipids and poloxamer surfactants have been reported in several studies. 28,34,36,37 However, there are few reports on the acoustic properties of bubbles coated with poloxamer surfactants used as the only shell material. In addition, the relationships between the adsorption properties of the shell material and its dilatational viscoelasticity have not been investigated.…”

Section: ■ Introductionmentioning

confidence: 99%

Concentration-Dependent Viscoelasticity of Poloxamer-Shelled Microbubbles

et al. 2022

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The oscillation of shelled microbubbles during exposure to ultrasound is influenced by the mechanical properties of the shell components. The oscillation behavior of bubbles coated with various phospholipids and other amphiphiles has been studied. However, there have been few investigations of how the adsorption conditions of the shell molecules relate to the viscoelastic properties of the shell and influence the oscillation behavior of the bubbles. In the present study, we investigated the oscillation characteristics of microbubbles coated with a poloxamer surfactant, that is, Pluronic F-68, at several concentrations after the adsorption kinetics of the surfactant at the gas−water interface had reached equilibrium. The dilatational viscoelasticity of the shell during exposure to ultrasound was analyzed in the frequency domain from the attenuation characteristics of the acoustic pulses propagated in the bubble suspension. At Pluronic F-68 concentrations lower than 2.0 × 10 −2 mol L −1 , the attenuation characteristics typically exhibited a sharp peak. At concentrations higher than 2.0 × 10 −2 mol L −1 , the peak flattened. The dilatational elasticity and viscosity of the shell were estimated by fitting the theoretical model to the experimental values, which revealed that both the elasticity and viscosity increased markedly at approximately 2.0 × 10 −2 mol L −1 . This suggests that the adsorption properties of Pluronic F-68 strongly affect the oscillation characteristics of microbubbles of a size suitable for medical ultrasound diagnostics.

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Material Properties, Dissolution and Time Evolution of PEGylated Lipid-Shelled Microbubbles: Effects of the Polyethylene Glycol Hydrophilic Chain Configurations

Cited by 8 publications

References 54 publications

Effect of Poly(ethylene glycol) Configuration on Microbubble Pharmacokinetics

Effect of Poly(ethylene glycol) Configuration on Microbubble Pharmacokinetics

A systematic review of ultrasound-mediated drug delivery to the eye and critical insights to facilitate a timely path to the clinic

Concentration-Dependent Viscoelasticity of Poloxamer-Shelled Microbubbles

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