Thrombin-Activatable Microbubbles as Potential Ultrasound Contrast Agents for the Detection of Acute Thrombosis

Lux, Jacques; Vezeridis, Alexander; Hoyt, Kenneth; Adams, Stephen; Armstrong, A. M.; Sirsi, Shashank R.; Mattrey, Robert F.

doi:10.1021/acsami.7b10592

Cited by 31 publications

(21 citation statements)

References 59 publications

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“…The stimulus-responsive MB increased the CEUS signal five-fold in presence of clots and even small lesions that were not visible by non-specific UCA were detected. Another group proposed MB with thrombin-sensitive activatable cell-penetrating peptides (ACPP) [ 97 ]. In this case, thrombin cleaved ACPP making the UCA positively charged.…”

Section: Targeted Contrast Agentsmentioning

confidence: 99%

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Molecular Ultrasound Imaging

2020

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In the last decade, molecular ultrasound imaging has been rapidly progressing. It has proven promising to diagnose angiogenesis, inflammation, and thrombosis, and many intravascular targets, such as VEGFR2, integrins, and selectins, have been successfully visualized in vivo. Furthermore, pre-clinical studies demonstrated that molecular ultrasound increased sensitivity and specificity in disease detection, classification, and therapy response monitoring compared to current clinically applied ultrasound technologies. Several techniques were developed to detect target-bound microbubbles comprising sensitive particle acoustic quantification (SPAQ), destruction-replenishment analysis, and dwelling time assessment. Moreover, some groups tried to assess microbubble binding by a change in their echogenicity after target binding. These techniques can be complemented by radiation force ultrasound improving target binding by pushing microbubbles to vessel walls. Two targeted microbubble formulations are already in clinical trials for tumor detection and liver lesion characterization, and further clinical scale targeted microbubbles are prepared for clinical translation. The recent enormous progress in the field of molecular ultrasound imaging is summarized in this review article by introducing the most relevant detection technologies, concepts for targeted nano- and micro-bubbles, as well as their applications to characterize various diseases. Finally, progress in clinical translation is highlighted, and roadblocks are discussed that currently slow the clinical translation.

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Section: Targeted Contrast Agentsmentioning

confidence: 99%

“…Targeted MB give specific signal only in the presence of thrombin. Reproduced with permission from [ 97 ]. Copyright American Chemical Society, 2017.…”

Section: Figurementioning

confidence: 99%

Molecular Ultrasound Imaging

2020

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“…Thrombin-activatable peptide, which can only be cleaved by thrombin, is a good choice for a thrombosis-responsive imaging system. In 2017, Lux et al [ 57 ] constructed a kind of thrombin-sensitive activatable cell-penetrating peptide (ACPP) containing thrombin-sensitive peptide fragment and cell-penetrating peptide sequence. The peptide was further conjugated to US molecular perfluorobutane-filled microbubbles (MBs).…”

Section: Nanoparticle-based Diagnosismentioning

confidence: 99%

Nano-Medicine for Thrombosis: A Precise Diagnosis and Treatment Strategy

Dai

Chen³

et al. 2020

Nano-Micro Lett.

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HIGHLIGHTS • Recent advances in diagnosis and treatment of thrombosis using nano-medicine are summarized in this review. • The diagnosis system based on biomarkers and imaging nanoprobes could enable the detection in early state of thrombosis. • The targeted drug delivery nanosystems serve as clinically translatable theranostics for thrombosis treatment with minor side effects. ABSTRACT Thrombosis is a global health issue and one of the leading factors of death. However, its diagnosis has been limited to the late stages, and its therapeutic window is too narrow to provide reasonable and effective treatment. In addition, clinical thrombolytics suffer from a short half-life, allergic reactions, inactivation, and unwanted tissue hemorrhage. Nano-medicines have gained extensive attention in diagnosis, drug delivery, and photo/sound/magnetic-theranostics due to their convertible properties. Furthermore, diagnosis and treatment of thrombosis using nano-medicines have also been widely studied. This review summarizes the recent advances in this area, which revealed six types of nanoparticle approaches: (1) in vitro diagnostic kits using "synthetic biomarkers"; (2) in vivo imaging using nano-contrast agents; (3) targeted drug delivery systems using artificial nanoparticles; (4) microenvironment responsive drug delivery systems; (5) drug delivery systems using biological nanostructures; and (6) treatments with external irradiation. The investigations of nano-medicines are believed to be of great significance, and some of the advanced drug delivery systems show potential applications in clinical theranotics.

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“…In this in vitro study, the contrast agent was able to detect thrombin successfully while retaining 91.7% of the signal. This contrast agent could potentially be used to more accurately distinguish acute from chronic thrombus which is currently a challenge when using non-molecular ultrasound [62].…”

Section: Venous Thrombosismentioning

confidence: 99%

Applications in Molecular Ultrasound Imaging: Present and Future

Thumar¹,

Liu²,

Eisenbrey³

2019

Advanced Ultrasound in Diagnosis and Therapy

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Molecular ultrasound imaging or targeted contrast-enhanced ultrasound (CEUS) is a relatively new technique that has varied applications to augment both diagnostics and therapeutics. Ultrasound contrast agents are conjugated to ligands that bind with specific biomarkers in the areas of interest which can then be quantified using ultrasound technology. This technique has numerous clinical applications including studying pathophysiology of disease, improving diagnostic sensitivity and specificity, and improving localized drug delivery. This technology, most notably, has proven useful in numerous oncologic and cardiovascular applications. Given ultrasound's advantages over other radiographic studies including its low cost, lack of ionizing radiation, portability, ability to provide real-time imaging, and non-invasiveness, recent investigations have expanded the utility of molecular ultrasound. In this review, we briefly review targeted ultrasound contrast agents and explore the current applications of molecular ultrasound as well as future applications based on the currently published literature.

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Thrombin-Activatable Microbubbles as Potential Ultrasound Contrast Agents for the Detection of Acute Thrombosis

Cited by 31 publications

References 59 publications

Molecular Ultrasound Imaging

Molecular Ultrasound Imaging

Nano-Medicine for Thrombosis: A Precise Diagnosis and Treatment Strategy

Applications in Molecular Ultrasound Imaging: Present and Future

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