Microbubble-mediated intravascular ultrasound imaging and drug delivery

Dixon, Adam J.; Kilroy, Joseph P.; Dhanaliwala, Ali H.; Chen, Johnny L.; Phillips, Linsey C.; Ragosta, Michael; Klibanov, Alexander L.; Wamhoff, Brian R.; Hossack, John A.

doi:10.1109/tuffc.2015.007143

Cited by 16 publications

(8 citation statements)

References 143 publications

(201 reference statements)

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“…3 However, current studies about ultrasound molecular imaging are mainly applied in targeted ultrasound diagnosis of thrombosis, inflammation, and tumors. [4][5][6][7] The newly emerging lipid ultrasound nanobubble (NB) is a UCA with a particle size smaller than 1,000 nm, which can overcome the limitations of traditional ultrasound microbubbles exclusively in blood vessels. 8 Nano-scale UCAs in tumor tissues can utilize the permeability and retention effects of tumors, such as larger endothelial gaps, lack of a basement membrane, and poor lymph drainage in tumors, to enter extravascular spaces to achieve imaging of tumor parenchyma.…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles

Fan

Guo

Wang

et al. 2016

IJN

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In this study, the lipid targeted nanobubble carrying the A10-3.2 aptamer against prostate specific membrane antigen was fabricated, and its effect in the ultrasound imaging of prostate cancer was investigated. Materials including 2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and polyethyleneglycol-2000 were for mechanical oscillation, and nanobubbles were obtained through the centrifugal flotation method. After mice were injected with nanobubbles, abdominal color Doppler blood flow imaging significantly improved. Through left ventricular perfusion with normal saline to empty the circulating nanobubbles, nanobubbles still existed in tumor tissue sections, which demonstrated that nanobubbles could enter tissue spaces via the permeability and retention effect. Fluorinated A10-3.2 aptamers obtained by chemical synthesis had good specificity for PSMA-positive cells, and were linked with carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid molecules from the outer shell of nanobubbles via amide reaction to construct targeted nanobubbles. Gel electrophoresis and immunofluorescence confirmed that targeted nanobubbles were fabricated successfully. Next, targeted nanobubbles could bind with PSMA-positive cells (C4-2 cells), while not with PSMA-negative cells (PC-3 cells), using in vitro binding experiments and flow cytometry at the cellular level. Finally, C4-2 and PC-3 xenografts in mice were used to observe changes in parameters of targeted and non-targeted nanobubbles in the contrast-enhanced ultrasound mode, and the distribution of Cy5.5-labeled targeted nanobubbles in fluorescent imaging of live small animals. Comparison of ultrasound indicators between targeted and non-targeted nanobubbles in C4-2 xenografts showed that they had similar peak times ( P >0.05), while the peak intensity, half time of peak intensity, and area under the curve of ½ peak intensity were significantly different ( P <0.05). In PC-3 xenografts, there were no differences in these four indicators. Fluorescent imaging indicated that targeted nanobubbles had an aggregation ability in C4-2 xenograft tumors. In conclusion, targeted nanobubbles carrying the anti-PSMA A10-3.2 aptamer have a targeted imaging effect in prostate cancer.

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Section: Introductionmentioning

confidence: 99%

Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles

Fan

Guo

Wang

et al. 2016

IJN

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“…Unlike sonothrombolysis performed using a systemic injection of small-diameter, long-circulating MBs, 6–8 the MBs evaluated in this work are intended to be administered from a catheter placed in close proximity to or embedded within the blood clot. 20,27 While this approach is more invasive than intravenous therapies, it is consistent with existing catheter-directed interventions for venous thromboembolism 4 and investigational therapies for ischemic stroke 28 . Further, focal delivery also ensures that the majority of MBs reach the therapeutic target site and permits the use of MBs that otherwise could not be administered systemically.…”

Section: Discussionmentioning

confidence: 53%

“…17 While this study primarily focused on the efficacy of the microbubble formulation for enhancing thrombolysis, it must be noted that significant effort is still required to miniaturize the FFMD to human-compatible dimensions for future intravascular deployment on a catheter. 27…”

Section: Discussionmentioning

confidence: 99%

In Vitro Sonothrombolysis Enhancement by Transiently Stable Microbubbles Produced by a Flow-Focusing Microfluidic Device

et al. 2017

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Therapeutic approaches that enhance thrombolysis by combining recombinant tissue plasminogen activator (rtPA), ultrasound, and/or microbubbles (MBs) are known as sonothrombolysis techniques. To date, sonothrombolysis approaches have primarily utilized commercially available MB formulations (or derivatives thereof) with diameters in the range 1-4 µm and circulation lifetimes between 5 and 15 min. The present study evaluated the in vitro sonothrombolysis efficacy of large diameter MBs (d ≥ 10 µm) with much shorter lifetimes that were produced on demand and in close proximity to the blood clot using a flow-focusing microfluidic device. MBs with a N gas core and a non-crosslinked bovine serum albumin shell were produced with diameters between 10 and 20 µm at rates between 50 and 950 × 10 per second. Use of these large MBs resulted in approximately 4.0-8.8 fold increases in thrombolysis rates compared to a clinical rtPA dose and approximately 2.1-4.2 fold increases in thrombolysis rates compared to sonothrombolysis techniques using conventional MBs. The results of this study indicate that the large diameter microbubbles with transient stability are capable of significantly enhanced in vitro sonothrombolysis rates when delivered directly to the clot immediately following production by a flow focusing microfluidic device placed essentially in situ adjacent to the clot.

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“…46 The present study focused on ischemic stroke, but a multi-function sonothrombolysis catheter could find application in stroke, deep vein thrombosis, myocardial infarction, and other thrombosis-related conditions including those pertaining to the microvasculature. [47][48][49][50][51] Overall, the peak production rate of approximately 100 × 10 3 MB/s achieved by the PDMS catheter-based FFMD is probably sufficient for future translation, with the possibility of increased production rates achievable by using a more robust design.…”

Section: Miniaturization Of Ffmds To Human-compatible Dimensionsmentioning

confidence: 99%

Efficacy of Sonothrombolysis Using Microbubbles Produced by a Catheter-Based Microfluidic Device in a Rat Model of Ischemic Stroke

Dixon

Rickel

et al. 2019

Ann Biomed Eng

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Limitations of existing thrombolytic therapies for acute ischemic stroke have motivated the development of catheter-based approaches that utilize no or low doses of thrombolytic drugs combined with a mechanical action to either dissolve or extract the thrombus. Sonothrombolysis accelerates thrombus dissolution via the application of ultrasound combined with microbubble contrast agents and low doses of thrombolytics to mechanically disrupt the fibrin mesh. In this work, we studied the efficacy of catheter-directed sonothrombolysis in a rat model of ischemic stroke. Microbubbles of 10-20 μm diameter with a nitrogen gas core and a non-crosslinked albumin shell were produced by a flow-focusing microfluidic device in real time. The microbubbles were dispensed from a catheter located in the internal carotid artery for direct delivery to the thrombus-occluded middle cerebral artery, while ultrasound was administered through the skull and recombinant tissue plasminogen activator (rtPA) was infused via a tail vein catheter. The results of this study demonstrate that flow focusing microfluidic devices can be miniaturized to dimensions compatible with human catheterization and that large-diameter microbubbles comprised of high solubility gases can be safely administered intraarterially to deliver a sonothrombolytic therapy. Further, sonothrombolysis using intraarterial delivery of large microbubbles reduced cerebral infarct volumes by approximately 50% versus no therapy, significantly improved functional neurological outcomes at 24 hrs, and permitted rtPA dose reduction of 3.3 (95% C.I. 1.8-3.8) fold when compared to therapy with intravenous rtPA alone. Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1 Author Contributions Statement AJD, JAH, ZZ conceived of study. AJD wrote main manuscript text. AJD, JMRR, JL conducted experiments and analyzed data. JAH, ALK, and ZZ supervised the study and all authors reviewed the manuscript.

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Microbubble-mediated intravascular ultrasound imaging and drug delivery

Cited by 16 publications

References 143 publications

Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles

Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles

In Vitro Sonothrombolysis Enhancement by Transiently Stable Microbubbles Produced by a Flow-Focusing Microfluidic Device

Efficacy of Sonothrombolysis Using Microbubbles Produced by a Catheter-Based Microfluidic Device in a Rat Model of Ischemic Stroke

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