Ultrasound Microbubbles for Molecular Diagnosis, Therapy, and Theranostics

Kießling, Fabian; Fokong, Stanley; Koczera, Patrick; Lederle, Wiltrud; Lammers, Twan

doi:10.2967/jnumed.111.099754

Cited by 270 publications

(220 citation statements)

References 36 publications

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“…Over the years, it has undergone significant development from an initial proof of concept to a localized membrane perforation technique with spatio-temporal control [3], and it has achieved early success in facilitating drug delivery [4], gene therapy [5], intracellular biomarker extraction [6] and cancer treatment [7]. In fostering localized induction of sonoporation, one technical advance that has played an important role is the advent of targeted microbubbles with binding affinity to antigen receptors on the cell type of interest [8,9], such as vascular endothelial growth factor (VEGF) receptors expressed on cancerous cells [10] or hypoxic endothelial cells [11]. These targeted microbubbles, often composed of a perfluorocarbon gas core encapsulated within an antibody-conjugated shell material [12], are in effect artificial gas bodies that would cavitate in response to ultrasound excitation, which could be as short as a single pulse firing [13].…”

Section: Introductionmentioning

confidence: 99%

Membrane blebbing as a recovery manoeuvre in site-specific sonoporation mediated by targeted microbubbles

Leow

Wan

2015

J. R. Soc. Interface.

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Site-specific perforation of the plasma membrane can be achieved through ultrasound-triggered cavitation of a single microbubble positioned adjacent to the cell. However, for this perforation approach (sonoporation), the recovery manoeuvres invoked by the cell are unknown. Here, we report new findings on how membrane blebbing can be a recovery manoeuvre that may take place in sonoporation episodes whose pores are of micrometres in diameter. Each sonoporation site was created using a protocol involving single-shot ultrasound exposure (frequency: 1 MHz; pulse length: 30 cycles; peak negative pressure: 0.45 MPa) which triggered inertial cavitation of a single targeted microbubble (diameter: 1-5 mm). Over this process, live confocal microscopy was conducted in situ to monitor membrane dynamics, model drug uptake kinetics and cytoplasmic calcium ion (Ca 2þ ) distribution. Results show that blebbing would occur at a recovering sonoporation site after its resealing, and it may emerge elsewhere along the membrane periphery. The bleb size was correlated with the pre-exposure microbubble diameter, and 99% of blebbing cases at sonoporation sites were inflicted by microbubbles larger than 1.5 mm diameter (analysed over 124 sonoporation episodes). Blebs were not observed at irreversible sonoporation sites or when sonoporation site repair was inhibited via extracellular Ca 2þ chelation. Functionally, the bleb volume was found to serve as a buffer compartment to accommodate the cytoplasmic Ca 2þ excess brought about by Ca 2þ influx during sonoporation. These findings suggest that membrane blebbing would help sonoporated cells restore homeostasis.

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Section: Introductionmentioning

confidence: 99%

Membrane blebbing as a recovery manoeuvre in site-specific sonoporation mediated by targeted microbubbles

Leow

Wan

2015

J. R. Soc. Interface.

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“…The principles of this model may also be adapted to enable quantitative analysis in other imaging methods that suffer from multiple scattering and interference effects, most notably ultrasound and contrast-enhanced ultrasound. 23,24 We would like to acknowledge the funding from the following sources: the United States Air Force (FA9550-15-1-0007), the National Institutes of Health (NIH DP50D012179), the National Science Foundation (NSF 1438340), the Damon Runyon Cancer Research Center (DFS# 06-13), the Susan G. Komen Breast Cancer Foundation (SAB15-00003), the Mary Kay Foundation (017-14), the Donald E. and Delia B. Baxter Foundation, a seed grant from the Center for Cancer Nanotechnology Excellence and Translation (CCNE-T U54CA151459), and a Stanford Bio-X Interdisciplinary Initiative Seed Grant for GNR characterization. Additional thanks to the Cell Sciences Imaging Facility (CSIF), the Stanford Nano Center (SNF), and the Stanford Nanocharacterization Lab (SNL) for access to instruments for GNR characterization.…”

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confidence: 99%

Quantitative contrast-enhanced optical coherence tomography

Winetraub

SoRelle

Liba

et al. 2016

Applied Physics Letters

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We have developed a model to accurately quantify the signals produced by exogenous scattering agents used for contrast-enhanced Optical Coherence Tomography (OCT). This model predicts distinct concentration-dependent signal trends that arise from the underlying physics of OCT detection. Accordingly, we show that real scattering particles can be described as simplified ideal scatterers with modified scattering intensity and concentration. The relation between OCT signal and particle concentration is approximately linear at concentrations lower than 0.8 particle per imaging voxel. However, at higher concentrations, interference effects cause signal to increase with a square root dependence on the number of particles within a voxel. Finally, high particle concentrations cause enough light attenuation to saturate the detected signal. Predictions were validated by comparison with measured OCT signals from gold nanorods (GNRs) prepared in water at concentrations ranging over five orders of magnitude (50 fM to 5 nM). In addition, we validated that our model accurately predicts the signal responses of GNRs in highly heterogeneous scattering environments including whole blood and living animals. By enabling particle quantification, this work provides a valuable tool for current and future contrast-enhanced in vivo OCT studies. More generally, the model described herein may inform the interpretation of detected signals in modalities that rely on coherence-based detection or are susceptible to interference effects. V C 2016 AIP Publishing LLC.

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“…Clinically, however, due to the abovementioned large inter-and intraindividual variability in EPR, the efficacy of passively tumor-targeted nanomedicines is compromised, with often significant improvements in tolerability, but hardly any increases in efficacy [9,10,14]. Consequently, there seems to be a clear need to develop methods to visualize and characterize the EPR effect, in order to preselect patients presenting with sufficiently high levels of EPR, to thereby (pre-) stratify responders and non-responders, and to thereby individualize and improve nano-chemotherapeutic treatments.We here used ~70 kDa-sized near-infrared fluorophore (NIRF) -labeled HPMA copolymers (which are known to efficiently accumulate in subcutaneous CT26 tumors in mice via EPR [29]), hybrid computed tomography-fluorescence molecular tomography (CT-FMT; [30][31][32]) and microbubble (MB) -based contrast-enhanced functional ultrasound (ceUS) imaging [33,34], to demonstrate that the degree of tumor vascularization correlates with the degree of EPR-mediated passive drug targeting. These findings indicate that relatively easily imageable vascular parameters, such as tumor blood volume and tumor blood flow, can be used to characterize EPR, and to on the basis of this preselect patients likely to respond to passively tumor-targeted nanomedicine therapies.…”

mentioning

confidence: 99%

Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging

Theek

Gremse

Kunjachan

et al. 2014

Journal of Controlled Release

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The Enhanced Permeability and Retention (EPR) effect is extensively used in drug delivery research. Taking into account that EPR is a highly variable phenomenon, we have here set out to evaluate if contrast-enhanced functional ultrasound (ceUS) imaging can be employed to characterize EPR-mediated passive drug targeting to tumors. Using standard fluorescence molecular tomography (FMT) and two different protocols for hybrid computed tomographyfluorescence molecular tomography (CT-FMT), the tumor accumulation of a ~10 nm-sized nearinfrared-fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) was evaluated in CT26 tumor-bearing mice. In the same set of animals, two different ceUS techniques (2D MIOT and 3D B-mode imaging) were employed to assess tumor vascularization. Subsequently, the degree of tumor vascularization was correlated with the degree of EPR-mediated drug targeting. Depending on the optical imaging protocol used, the tumor accumulation of the polymeric drug carrier ranged from 5-12% of the injected dose. The degree of tumor vascularization, determined using ceUS, varied from 4-11%. For both hybrid CT-FMT protocols, a good correlation between the degree of tumor vascularization and the degree of tumor accumulation was observed, with in the case of reconstructed CT-FMT, correlation coefficients of ~0.8 and p-values of <0.02. These findings indicate that ceUS can be used to characterize and predict EPR, and potentially also to preselecting patients likely to respond to passively tumor-targeted nanomedicine treatments. KeywordsDrug targeting; Nanomedicine; Theranostics; Cancer; EPR; HPMA; US; FMT; CT The biodistribution of nanomedicine formulations is very different from that of lowmolecular-weight drugs. As the size of nanocarrier materials generally is above the kidney clearance threshold (~5 nm), they tend to circulate for prolonged periods of time, and they are consequently able to exploit the fact that tumor blood vessels are more leaky that healthy blood vessels, resulting in passive, progressive and relatively selective accumulation at the pathological site over time. This phenomenon is known as the Enhanced Permeability and Retention (EPR) effect [7,8], and it is extensively used in drug delivery research. It is increasingly recognized, however, that EPR is a highly variably phenomenon, presenting not only with large differences between different animal models and patient tumors, but also with large inter-and intraindividual differences between tumors of the same sub-type. And even within a single tumor, certain vessels are significantly more leaky than others. Several recent reviews critically describe and comprehensively discuss the validity and the variability of the EPR effect [9][10][11][12][13][14]. To better understand EPR, to predict which animal models or patient tumors are likely to benefit from EPR-mediated passive drug targeting, and to thereby individualize and improve nano-chemotherapeutic treatments, it therefore seems highly important to identify imageable parameters to c...

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Ultrasound Microbubbles for Molecular Diagnosis, Therapy, and Theranostics

Cited by 270 publications

References 36 publications

Membrane blebbing as a recovery manoeuvre in site-specific sonoporation mediated by targeted microbubbles

Membrane blebbing as a recovery manoeuvre in site-specific sonoporation mediated by targeted microbubbles

Quantitative contrast-enhanced optical coherence tomography

Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging

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