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The Effect of Microbubble-Assisted Ultrasound on Molecular Permeability across Cell Barriers.

ABSTRACT: The combination of ultrasound and microbubbles (USMB) has been applied to enhance drug permeability across tissue barriers. Most studies focused on only one physicochemical aspect (i.e., molecular weight of the delivered molecule). Using an in vitro epithelial (MDCK II) cell barrier, we examined the effects of USMB on the permeability of five molecules varying in molecular weight (182 Da to 20 kDa) and hydrophilicity (LogD at pH 7.4 from 1.5 to highly hydrophilic). Treatment of cells with USMB at increasing ultrasound pressures did not have a significant effect on the permeability of small molecules (molecular weight 259 to 376 Da), despite their differences in hydrophilicity (LogD at pH 7.4 from -3.2 to 1.5). The largest molecules (molecular weight 4 and 20 kDa) showed the highest increase in the epithelial permeability (3-7-fold). Simultaneously, USMB enhanced intracellular accumulation of the same molecules. In the case of the clinically relevant anti- C-X-C Chemokine Receptor Type 4 (CXCR4) nanobody (molecular weight 15 kDa), USMB enhanced paracellular permeability by two-fold and increased binding to retinoblastoma cells by five-fold. Consequently, USMB is a potential tool to improve the efficacy and safety of the delivery of drugs to organs protected by tissue barriers, such as the eye and the brain.

SUBMITTER: Rousou C

PROVIDER: S-EPMC8949944 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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The Effect of Microbubble-Assisted Ultrasound on Molecular Permeability across Cell Barriers.

Rousou Charis C de Maar Josanne J Qiu Boning B van der Wurff-Jacobs Kim K Ruponen Marika M Urtti Arto A Oliveira Sabrina S Moonen Chrit C Storm Gert G Mastrobattista Enrico E Deckers Roel R

Pharmaceutics 20220224 3

The combination of ultrasound and microbubbles (USMB) has been applied to enhance drug permeability across tissue barriers. Most studies focused on only one physicochemical aspect (i.e., molecular weight of the delivered molecule). Using an in vitro epithelial (MDCK II) cell barrier, we examined the effects of USMB on the permeability of five molecules varying in molecular weight (182 Da to 20 kDa) and hydrophilicity (LogD at pH 7.4 from 1.5 to highly hydrophilic). Treatment of cells with USMB a ...[more]

PMID: 35335871

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Project description:RationaleMicrobubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld.ObjectiveTo develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging.Methods and resultsMicrobubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab')2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (|r|≥0.8), demonstrating a high degree of non-invasive molecular quantification.ConclusionsTargeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described, may possess properties (i)-(iii) desired for clinical applications.

Project description:The objective of this study was to evaluate the feasibility, safety, and effectiveness of intravenous stem cell delivery utilizing ultrasound-targeted microbubble destruction (UTMD) in a rat model of middle cerebral artery occlusion (MCAO), while investigating the underlying mechanisms. Acute cerebral infarction (ACI) was induced surgically in adult rats to create the MCAO rat model. Intravenous injection of SonoVue microbubbles and bone marrow-derived mesenchymal stem cells (BMSC) was performed concurrently, with or without ultrasound targeting the stroke. The animals were divided into four groups: sham-operated group, ACI-MCAO rats treated with phosphate-buffered saline (ACI+PBS), rats receiving intravenous delivery of BMSC expressing green fluorescent protein (GFP-BMSC; ACI+BMSC), and rats receiving intravenous GFP-BMSC with simultaneous UTMD exposure (ACI+BMSC+UTMD). The efficacy of the treatments was assessed by evaluating the animals' neurological function using the Longa score and examining histopathological changes such as cerebral infarct volume, cerebral edema, and cell apoptosis. A rat cytokine array was utilized to identify the potential cytokines that may be responsible for the therapeutic effect of UTMD-mediated BMSC treatment. Optimal UTMD parameters resulted in an increase in blood-brain barrier (BBB) permeability after 30 min, which returned to baseline 72 h later without causing any residual injury. UTMD application significantly increased the homing of intravenously delivered BMSC, resulting in a 2.2-fold increase in GFP-BMSC cell count on day 3 and a 2.6-fold increase on day 7 compared with intravenous delivery alone. This effect persisted for up to 6 weeks after injection. Intravenous BMSC delivery significantly reduced the volume of cerebral infarct and decreased cerebral edema, leading to a lower Longa score. Furthermore, this effect was further enhanced by UTMD. Acute cerebral infarction induced by MCAO led to elevated matrix metalloproteinase 8 (MMP8) levels in the cerebrospinal fluid, which were significantly reduced following UTMD-mediated BMSC treatment. Ultrasound-targeted microbubble destruction facilitates the migration and homing of BMSC into the brain, possibly by transiently increasing blood-brain barrier (BBB) permeability, thereby improving therapeutic outcomes in an ACI rat model. The observed effect may be partly attributed to modulation of MMP8 levels.Advances in knowledge: UTMD-mediated intravenously delivered BMSC transplantation led to a significant increase in cell homing and reduction of MMP8 levels, resulting in increased therapeutic effect in an acute ischemic cerebral infarction model.

Project description:It is now well established that for tumour growth and survival, tumour vasculature is an important element. Studies have demonstrated that ultrasound-stimulated microbubble (USMB) treatment causes extensive endothelial cell death leading to tumour vascular disruption. The subsequent rapid vascular collapse translates to overall increases in tumour response to various therapies. In this study, we explored USMB involvement in the enhancement of hyperthermia (HT) treatment effects. Human prostate tumour (PC3) xenografts were grown in mice and were treated with USMB, HT, or with a combination of the two treatments. Treatment parameters consisted of ultrasound pressures of 0 to 740 kPa, the use of perfluorocarbon-filled microbubbles administered intravenously, and an HT temperature of 43°C delivered for various times (0-50 minutes). Single and multiple repeated treatments were evaluated. Tumour response was monitored 24 hours after treatments and tumour growth was monitored for up to over 30 days for a single treatment and 4 weeks for multiple treatments. Tumours exposed to USMB combined with HT exhibited enhanced cell death (p<0.05) and decreased vasculature (p<0.05) compared to untreated tumours or those treated with either USMB alone or HT alone within 24 hours. Deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and cluster of differentiation 31 (CD31) staining were used to assess cell death and vascular content, respectively. Further, tumours receiving a single combined USMB and HT treatment exhibited decreased tumour volumes (p<0.05) compared to those receiving either treatment alone when monitored over the duration of 30 days. Additionally, tumour response monitored weekly up to 4 weeks demonstrated a reduced vascular index and tumour volume, increased fibrosis and lesser number of proliferating cells with combined treatment of USMB and HT. Thus in this study, we characterize a novel therapeutic approach that combines USMB with HT to enhance treatment responses in a prostate cancer xenograft model in vivo.

Project description:Microbubble (MB)-assisted ultrasound (US) is a promising physical method to increase non-invasively, transiently, and precisely the permeability of the blood-brain barrier (BBB) to therapeutic molecules. Previous preclinical studies established the innocuity of this procedure using complementary analytical strategies including transcriptomics, histology, brain imaging, and behavioral tests. This cross-sectional study using rats aimed to investigate the metabolic processes following acoustically-mediated BBB opening in vivo using multimodal and multimatrices metabolomics approaches. After intravenous injection of MBs, the right striata were exposed to 1-MHz sinusoidal US waves at 0.6 MPa peak negative pressure with a burst length of 10 ms, for 30 s. Then, the striata, cerebrospinal fluid (CSF), blood serum, and urine were collected during sacrifice in three experimental groups at 3 h, 2 days, and 1 week after BBB opening (BBBO) and were compared to a control group where no US was applied. A well-established analytical workflow using nuclear magnetic resonance spectrometry and non-targeted and targeted high-performance liquid chromatography coupled to mass spectrometry were performed on biological tissues and fluids. In our experimental conditions, a reversible BBBO was observed in the striatum without physical damage or a change in rodent weight and behavior. Cerebral, peri-cerebral, and peripheral metabolomes displayed specific and sequential metabolic kinetics. The blood serum metabolome was more impacted in terms of the number of perturbated metabolisms than in the CSF, the striatum, and the urine. In addition, perturbations of arginine and arginine-related metabolisms were detected in all matrices after BBBO, suggesting activation of vasomotor processes and bioenergetic supply. The exploration of the tryptophan metabolism revealed a transient vascular inflammation and a perturbation of serotoninergic neurotransmission in the striatum. For the first time, we characterized the metabolic signature following the acoustically-mediated BBBO within the striatum and its surrounding biological compartments.

Dataset Information

The Effect of Microbubble-Assisted Ultrasound on Molecular Permeability across Cell Barriers.

Publications

The Effect of Microbubble-Assisted Ultrasound on Molecular Permeability across Cell Barriers.

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