Ultrasound molecular imaging: Moving toward clinical translation

Abou‐Elkacem, Lotfi; Bachawal, Sunitha V.; Willmann, Jürgen K.

doi:10.1016/j.ejrad.2015.03.016

Cited by 173 publications

(177 citation statements)

References 66 publications

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“…In contrast, we found that the expression of the pro-angiogenic marker proteins VEGFR-2 and α v ß 3 integrin differed significantly between breast cancer, pre-invasive cancerous lesions and benign breast lesions. In line with preclinical studies, our histopathological in situ findings support the notion that VEGFR-2 and α v ß 3 integrin may be suitable molecular imaging targets for tumor diagnosis and characterization in the breast [5,6,[10][11][12][23][24][25].…”

Section: Endothelial Vegfr-2 Levels But Not Vascular Area Fractionssupporting

confidence: 71%

“…S4+5). [5,6,[10][11][12][23][24][25]. However, besides a pilot phase study on breast cancer patients using radiolabeled α V ß 3 -targeted RGD peptides and PET demonstrating a significant probe uptake in the primary lesion and in the metastases [19], clinical studies comparing the diagnostic power of functional vs. molecular imaging for differentiating (mammographically) suspect tumors or for monitoring recurrent lesions upon breast cancer surgery have not yet been reported.…”

Section: Endothelial Vegfr-2 Levels But Not Vascular Area Fractionsmentioning

confidence: 99%

“…In this regard, angiogenesisassociated proteins expressed on the endothelial cell layer such as VEGFR-2 and α v ß 3 integrin have been identified as promising targets for monitoring (anti-)angiogenesis using molecularly-targeted microbubbles in combination with ultrasound imaging in preclinical tumor models [5,6]. Whereas the transmembrane receptor tyrosine kinase VEGFR-2, which activates the PI3K/Akt/mTOR pathway and mediates endothelial cell proliferation, is mainly expressed on activated endothelium, the cell adhesion molecule α v ß 3 integrin, which binds to arginine-glycine-aspartic acid (RGD)-containing proteins and peptides, is up-regulated on tumor endothelium and on interstitial and tumor cells [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

et al. 2016

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Vascular endothelial growth factor receptor 2 (VEGFR-2) and α v ß 3 integrin are the most frequently addressed targets in molecular imaging of tumor angiogenesis. In preclinical studies, molecular imaging of angiogenesis has shown potential to detect and differentiate benign and malignant lesions of the breast. Thus, in this retrospective clinical study employing patient tissues, the diagnostic value of VEGFR-2, α v ß 3 integrin and vascular area fraction for the diagnosis and differentiation of breast neoplasia was evaluated. To this end, tissue sections of breast cancer (n=40), pre-invasive ductal carcinoma in situ (DCIS; n=8), fibroadenoma (n=40), radial scar (n=6) and normal breast tissue (n=40) were used to quantify (i) endothelial VEGFR-2, (ii) endothelial α v ß 3 integrin and (iii) total α v ß 3 integrin expression, as well as (iv) the vascular area fraction.Sensitivity and specificity to differentiate benign from malignant lesions were calculated for each marker by receiver operating characteristics (ROC) analyses. Whereas vessel density, as commonly used, did not significantly differ between benign and malignant lesions (AUROC: 0.54), VEGFR-2 and α v ß 3 integrin levels were gradually up-regulated in carcinoma vs. fibroadenoma vs. healthy tissue. The highest diagnostic accuracy for differentiating carcinoma from fibroadenoma was found for total α v ß 3 integrin expression (AUROC: 0.76), followed by VEGFR-2 (AUROC: 0.71) and endothelial α v ß 3 integrin expression (AUROC: 0.68). In conclusion, total α v ß 3 integrin expression is the best discriminator between breast cancer, fibroadenoma and normal breast tissue. With respect to vascular targeting and molecular imaging

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Section: Endothelial Vegfr-2 Levels But Not Vascular Area Fractionssupporting

confidence: 71%

Section: Endothelial Vegfr-2 Levels But Not Vascular Area Fractionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

et al. 2016

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“…The most successful of these is the BR55, which targets VEGFR and has been reported in tumor diagnosis and evaluations of anti-vascular therapy. 34,35 In the ultrasound molecular imaging of tumor parenchyma, targeted ultrasound microbubbles at the micron scale cannot penetrate tumor blood vessels to enter tumor tissues; therefore, there are fewer relevant studies on the direct specific binding between ultrasound microbubbles and tumor cells to achieve targeted imaging.…”

mentioning

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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“…14.15. The physical system formed by the capsule, the oil and the surrounding water obeys the following set of equations: 5) with the substitutionT = rT , as before. In the equations, the subscript p refers to the polymer, w to the water and oil to the oil.…”

Section: Methodsmentioning

confidence: 99%

Ultrasound contrast agents: bubbles drops and particles

Lajoinie¹

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The research described in this thesis is part of the research program NanoNextNL, a micro and nanotechnology consortium of the Government of the Netherlands and 130 partners. This thesis was carried out at the Physics of Fluids group of the Faculty of Science and Technology of the University of Twente. Cover design:As a representation of a crucial goal of this work, the cover depicts a confocal microscopy image showing cells selectively porated by loaded microbubbles upon ultrasound exposure. The porated cells take up a blue fluorescent probe. By Ine Lentacker, Ine De Cock and Guillaume Lajoinie. Guide through the thesisIn this thesis, we investigate different types of innovative agents, designed for biomedical use in a context of molecular imaging. In Chapter 1, we review the agents that arouse the interest of the scientific community, most of them at the research stage of development, together with the experimental methods that can be used to study their interaction with cells. Such in vitro investigations are necessary to test on short scales the impact of the various agents on biological structures.We separate the agents in three main categories. The first group consists of stabilized microbubbles, usually by means of phospholipids that fill up the interfacial area between the gas core and the surrounding liquid (water). Such bubbles are clinically used for 40 years as contrast agents for ultrasound owing to their unique resonance behavior. When irradiated with an ultrasound pulse, a bubble experiences volumetric oscillations, that reemit an ultrasound wave back to the transducer. This process makes them unchallenged ultrasound scatterers. The role of these stable microbubbles in new biomedical research directions is discussed in Chapters 2 to 9.Phospholipid coatings were developed in the last decade to do much more than just prevent bubble dissolution. They are now a crucial tool to enrich the microbubbles with specific markers or drug payloads. In Chapter 2, we investigate the behavior of this coating when the microbubbles are subjected to an ultrasound field. We show that the coating is shed away from the microbubble, which is of major interest for molecular imaging combined with drug delivery using microbubbles. We pursue the idea in Chapter 3 where we investigate how a bubble payload, here liposomes labeled with a fluorescent dye, is released under ultrasound exposure. In Chapter 4, we link these direct observations of shedding of the previous Chapters to the subsequent dissolution of the microbubbles, no longer protected by a phospholipid shell. This dissolution, visible in the ultrasound scatter spectrum can be used to remotely quantify the effect of the microbubbles. In support of these observations, we dedicate the next Chapter (Chapter 5) to physically understand the mechanisms underlying the behavior of the phospholipid coating. The application of these findings in practice requires the production a sufficiently high production rate and with great control of such microbubbles. In Chapter 6, we th...

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Ultrasound molecular imaging: Moving toward clinical translation

Cited by 173 publications

References 66 publications

In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

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

Ultrasound contrast agents: bubbles drops and particles

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