Polymeric Microbubbles for Ultrasonic Molecular Imaging and Targeted Therapeutics

Xiong, Xiaoxing; Zhao, Fenglong; Shi, Mengran; Yang, Hong; Liu, Yiyao

doi:10.1163/092050610x540440

Cited by 41 publications

(25 citation statements)

References 45 publications

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“…With the potential to load therapeutic agents [23,24,33–36] and to retain within specific tissue volume [37,38], targeted microbubbles provide a unique opportunity for combined ultrasound imaging and targeted drug delivery with enhanced efficacy and reduced side effects [31,39,40]. We used high speed videomicroscopy to capture the complete dynamic process of the initially cell-bound microbubbles exposed to ultrasound pulses.…”

Section: Introductionmentioning

confidence: 99%

Improving ultrasound gene transfection efficiency by controlling ultrasound excitation of microbubbles

Fan

Chen

Deng

2013

Journal of Controlled Release

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Ultrasound application in the presence of microbubbles has shown great potential for non-viral gene transfection via transient disruption of cell membrane (sonoporation). However, improvement of its efficiency has largely relied on empirical approaches without consistent and translatable results. The goal of this study is to develop a rational strategy based on new results obtained using novel experimental techniques and analysis to improve sonoporation gene transfection. We conducted experiments using targeted microbubbles that were attached to cell membrane to facilitate sonoporation. We quantified the dynamic activities of microbubbles exposed to pulsed ultrasound and the resulting sonoporation outcome and identified distinct regimes of characteristic microbubble behaviors: stable cavitation, coalescence and translation, and inertial cavitation. We found that inertial cavitation generated the highest rate of membrane poration. By establishing direct correlation of ultrasound-induced bubble activities with intracellular uptake and pore size, we designed a ramped pulse exposure scheme for optimizing microbubble excitation to improve sonoporation gene transfection. We implemented a novel sonoporation gene transfection system using an aqueous two phase system (ATPS) for efficient use of reagents and high throughput operation. Using plasmid coding for the green fluorescence protein (GFP), we achieved a sonoporation transfection efficiency in rate aortic smooth muscle cells (RASMCs) of 6.9% ± 2.2% (n = 9), comparable with lipofection (7.5% ± 0.8%, n = 9). Our results reveal characteristic microbubble behaviors responsible for sonoporation and demonstrated a rational strategy to improve sonoporation gene transfection.

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Section: Introductionmentioning

confidence: 99%

Improving ultrasound gene transfection efficiency by controlling ultrasound excitation of microbubbles

Fan

Chen

Deng

2013

Journal of Controlled Release

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“…Various polymeric microbubbles have been investigated for ultrasonic imaging (Forsberg et al 2004; Lavisse et al 2005; Ketterling et al 2007; Grishenkov et al 2009a; Grishenkov et al 2009b; Lu et al 2009; Yang et al 2009; Sciallero et al 2012) and targeted drug delivery/therapeutics (Wheatley et al 2007; Jie et al 2008; Lu et al 2009; Sirsi et al 2009) (see the review by Xiong et al (Xiong et al 2011)). Specifically, PLA as well as PLGA—a block copolymer with varying lactic to co-glycolic acid ratios—has been investigated as an encapsulating material for contrast microbubbles.…”

Section: Introductionmentioning

confidence: 99%

Determination of the Interfacial Rheological Properties of a Poly(DL-lactic acid)-Encapsulated Contrast Agent Using In Vitro Attenuation and Scattering

Paul

Russakow

Rodgers

et al. 2013

Ultrasound in Medicine & Biology

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The stabilizing encapsulation of a microbubble based ultrasound contrast agent (UCA) critically affects its acoustic properties. Polymers, which behave differently from commonly used materials—e.g. lipids or proteins—for the monolayer encapsulation, hold potential for better stability and control over encapsulation properties. Air-filled microbubbles coated with Poly (D, L-lactide) (PLA) are characterized here using in vitro acoustic experiments and several models of encapsulation. The interfacial rheological properties of the encapsulation are determined according to each of these models using attenuation of ultrasound through a suspension of these microbubbles. Then the model predictions are compared with scattered nonlinear—sub- and second harmonic—responses. For this microbubble population (average diameter 1.9 μm), the peak in attenuation measurement indicates a weighted average resonance frequency of 2.5–3 MHz, which, in contrast to other encapsulated microbubbles, is lower than the resonance frequency of a free bubble of similar size (diameter 1.9 μm). This apparently contradictory result stems from the extremely low surface dilatational elasticity (around 0.01–0.07 N/m) and the reduced surface tension of the PLA encapsulation as well as the polydispersity of the bubble population. All models considered here are shown to behave similarly even in the nonlinear regime because of the low value of the surface dilatational elasticity. Pressure dependent scattering measurements at two different excitation frequencies (2.25 and 3 MHz) show strongly non-linear behavior with 25–30 dB and 5–20 dB enhancements in fundamental and second-harmonic responses respectively for a concentration of 1.33 μg/mL of suspension. Subharmonic responses are registered above a relatively low generation threshold of 100–150 kPa with up to 20 dB enhancement beyond that pressure. Numerical predictions from all models show good agreement with the experimentally measured fundamental response, but not with the second harmonic response. The characteristic features of subharmonic response and the steady response beyond the threshold are matched well by model predictions. However, prediction of the threshold value depends on property values and the size distribution. The variation in size distribution from sample to sample leads to variation in estimated encapsulation property values—the lowest estimated value of surface dilatational viscosity better predicts the subharmonic threshold.

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“…One approach is to spatially distribute the drug concentration unevenly such that the local dose to the disease site is elevated while the systematic dose remains low. Microbubbles can behave as a targeted delivery system by loading them with drugs and selectively lysing (fragmenting) them in regions where the drug delivery is desired 138–140…”

Section: Therapeutic Applicationsmentioning

confidence: 99%

Current status and prospects for microbubbles in ultrasound theranostics

Martin¹,

Dayton²

2013

WIREs Nanomed Nanobiotechnol

121

105

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Encapsulated microbubbles have been developed over the past two decades to provide both improvements in imaging as well as new therapeutic applications. Microbubble contrast agents are used currently for clinical imaging where increased sensitivity to blood flow is required, such as echocardiography. These compressible spheres oscillate in an acoustic field, producing nonlinear responses which can be uniquely distinguished from surrounding tissue, resulting in substantial enhancements in imaging signal-to-noise ratio. Furthermore, with sufficient acoustic energy the oscillation of microbubbles can mediate localized biological effects in tissue including the enhancement of membrane permeability or increased thermal energy deposition. Structurally, microbubbles are comprised of two principal components – an encapsulating shell and an inner gas core. This configuration enables microbubbles to be loaded with drugs or genes for additional therapeutic effect. Application of sufficient ultrasound energy can release this payload, resulting in site-specific delivery. Extensive pre-clinical studies illustrate that combining microbubbles and ultrasound can result in enhanced drug delivery or gene expression at spatially selective sites. Thus, microbbubles can be used for imaging, for therapy, or for both simultaneously. In this sense, microbubbles combined with acoustics may be one of the most universal theranostic tools.

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Polymeric Microbubbles for Ultrasonic Molecular Imaging and Targeted Therapeutics

Cited by 41 publications

References 45 publications

Improving ultrasound gene transfection efficiency by controlling ultrasound excitation of microbubbles

Improving ultrasound gene transfection efficiency by controlling ultrasound excitation of microbubbles

Determination of the Interfacial Rheological Properties of a Poly(DL-lactic acid)-Encapsulated Contrast Agent Using In Vitro Attenuation and Scattering

Current status and prospects for microbubbles in ultrasound theranostics

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