Phospholipid/carbocyanine dye-shelled microbubbles as ultrasound-modulated fluorescent contrast agents

Benchimol, Michael; Hsu, Mark J.; Schutt, Carolyn E.; Hall, D.; Mattrey, Robert F.; Esener, Sadik C.

doi:10.1039/c2sm26900g

Cited by 24 publications

(35 citation statements)

References 32 publications

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“…[1][2][3][4][5] One of its unique features is that it can provide tissue fluorescent contrast with ultrasound resolution. [1][2][3][4] The concept of UMF is similar to ultrasound-modulated optical tomography, which has been widely studied.…”

Section: Introductionmentioning

confidence: 99%

“…1 Microbubbles have been investigated to improve the modulation depth of UMF. 2,5,19 Theoretically, because a microbubble can significantly oscillate in size when activated by an ultrasonic wave, the surface concentration of the fluorophores can be dramatically modulated. Thus, the quenching efficiency and the fluorescence intensity can be modulated at the ultrasound frequency, which generates the UMF signal.…”

Section: Introductionmentioning

confidence: 99%

“…2 Recently, a significant UMF signal was also observed from microbubbles whose phospholipid shell was embedded with a type of lipophilic carbocyanine fluorophore (DiI). 5 Although significant progress has been made during the past years, there is a great deal of fundamental work that should be investigated to push this technique toward real biomedical applications. For example, (1) the synthesis of UMF contrast agents should be simple, and the selection of fluorophores should be flexible so they can be widely used in the field; (2) how many fluorophores should be labeled on microbubbles to achieve high-modulation efficiency should be quantitatively investigated; (3) how the UMF signal is quantitatively related to microbubble oscillation and therefore ultrasound pressure should be experimentally studied; and (4) sensitive systems should be developed to detect weak UMF signals in optically scattering media.…”

Section: Introductionmentioning

confidence: 99%

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Ultrasound-modulated fluorescence based on fluorescent microbubbles

et al. 2014

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Abstract. Ultrasound-modulated fluorescence (UMF) imaging has been proposed to provide fluorescent contrast while maintaining ultrasound resolution in an optical-scattering medium (such as biological tissue). The major challenge is to extract the weakly modulated fluorescent signal from a bright and unmodulated background. UMF was experimentally demonstrated based on fluorophore-labeled microbubble contrast agents. These contrast agents were produced by conjugating N-hydroxysuccinimide (NHS)-ester-attached fluorophores on the surface of amine-functionalized microbubbles. The fluorophore surface concentration was controlled so that a significant self-quenching effect occurred when no ultrasound was applied. The intensity of the fluorescent emission was modulated when microbubbles were oscillated by ultrasound pulses, presented as UMF signal. Our results demonstrated that the UMF signals were highly dependent on the microbubbles' oscillation amplitude and the initial surface fluorophore-quenching status. A maximum of ∼42% UMF modulation depth was achieved with a single microbubble under an ultrasound peak-to-peak pressure of 675 kPa. Further, UMF was detected from a 500-μm tube filled with contrast agents in water and scattering media with ultrasound resolution. These results indicate that ultrasound-modulated fluorescent microbubble contrast agents can potentially be used for fluorescence-based molecular imaging with ultrasound resolution in the future.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ultrasound-modulated fluorescence based on fluorescent microbubbles

et al. 2014

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“…[1][2][3][4][5][6][7][8][9] The idea is that the fluorescence photons are modulated by a focused ultrasound beam. By specifically analyzing the modulated fluorescence photons, we can quantify the fluorescent properties at the ultrasound focal volume.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, more sensitive UMF contrast agents based on fluorophore-labeled microbubbles have been developed to significantly improve the modulation efficiency through a quenching effect. 7,8,[12][13][14][15] One research group has designed a microbubble whose phospholipid shell was embedded with a type of lipophilic dye. 7,15 Recently, we developed a contrast agent by conjugating a type of NHS-ester-attached fluorophore on the surfaces of amine-functionalized microbubbles.…”

Section: Introductionmentioning

confidence: 99%

Ultrasound-modulated fluorescence based on donor-acceptor-labeled microbubbles

et al. 2015

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Abstract. A fluorescence resonance energy transfer (FRET)-based microbubble contrast agent system was designed to experimentally demonstrate the concept of ultrasound-modulated fluorescence (UMF). Microbubbles were simultaneously labeled with donor and acceptor fluorophores on the surface to minimize self-quenching and maximize FRET. In response to ultrasound, the quenching efficiency was greatly modulated by changing the distance between the donor and acceptor molecules through microbubble size oscillations. Both donors and acceptors exhibited UMF on individual microbubbles. The UMF strength of the donor was more significant compared to that of the acceptor. Furthermore, the UMF of the donor was observed from a microbubble solution in a turbid media. This study exploits the feasibility of donor-acceptor labeled microbubbles as UMF contrast agents.

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Manipulating Nanoscale Features on the Surface of Dye‐Loaded Microbubbles to Increase Their Ultrasound‐Modulated Fluorescence Output

Schutt

Benchimol

Hsu

et al. 2014

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The nanoscale surface features of lipid-coated microbubbles can dramatically affect how the lipids interact with one another as the microbubble diameter expands and contracts under the influence of ultrasound. During microbubble manufacturing, the different lipid shell species naturally partition forming concentrated lipid islands. In this study the dynamics of how these nanoscale islands accommodate the expansion of the microbubbles are monitored by measuring the fluorescence intensity changes that occur as self-quenching lipophilic dye molecules embedded in the lipid layer change their distance from one another. It was found that when the dye molecules were concentrated in islands, less than 5% of the microbubbles displayed measurable fluorescence intensity modulation indicating the islands were not able to expand sufficiently for the dye molecules to separate from one another. When the microbubbles were heated and cooled rapidly through the lipid transition temperature the islands were melted creating an even distribution of dye about the surface. This resulted in over 50% of the microbubbles displaying the fluorescence-modulated signal indicating that the dye molecules could now separate sufficiently to change their self-quenching efficiency. The separation of the surface lipids in these different formations has significant implications for microbubble development as ultrasound and optical contrast agents.

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Phospholipid/carbocyanine dye-shelled microbubbles as ultrasound-modulated fluorescent contrast agents

Cited by 24 publications

References 32 publications

Ultrasound-modulated fluorescence based on fluorescent microbubbles

Ultrasound-modulated fluorescence based on fluorescent microbubbles

Ultrasound-modulated fluorescence based on donor-acceptor-labeled microbubbles

Manipulating Nanoscale Features on the Surface of Dye‐Loaded Microbubbles to Increase Their Ultrasound‐Modulated Fluorescence Output

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