Pharmacodynamics of Streptavidin-Coated Cyanoacrylate Microbubbles Designed for Molecular Ultrasound Imaging

Palmowski, Moritz; Morgenstern, Bernd; Hauff, Peter; Reinhardt, Michaël; Huppert, Jochen; Mäurer, Mathias; Woenne, Eva C.; Doerk, Sebastian; Ladewig, Gesa; Jenne, Juergen; Delorme, Stefan; Grenacher, Lars; Hallscheidt, Peter; Kauffmann, G. W.; Semmler, Willi; Kießling, Fabian

doi:10.1097/rli.0b013e31815a251b

Cited by 58 publications

(60 citation statements)

References 25 publications

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“…In this study, we were able to show the specificity of targeted microbubbles, which accumulated significantly within tumor vessels compared with unspecific ones. In a previous study about the pharmacokinetic behavior of cyanoacrylate microbubbles, we were further able to show that 1.5 min after injection the blood concentrations of microbubbles in mice already decreased to less than 2% of the maximum peak enhancement (24). Commensurate with these findings, this study also found no relevant replenishment of microbubbles in control scans following the diagnostic scan done 7 min after microbubble injection.…”

Section: Discussionsupporting

confidence: 70%

“…Subsequently, 50 AL of 0.9% NaCl were injected to clear the catheter from microbubbles. Imaging was done 7 min after microbubble administration as suggested by prior studies in which timing variables had been optimized (18,24). The initial ultrasound scan of the whole tumor volume was followed by three control scans.…”

Section: Synthesis and Characterization Of Target-specific Microbubblesmentioning

confidence: 99%

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Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects

Palmowski

Huppert

Ladewig

et al. 2008

Molecular Cancer Therapeutics

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Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric ''multitarget quantification'' and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and A v B 3 integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and A v B 3 integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and A v B 3 integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and A v B 3 integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo.

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Section: Discussionsupporting

confidence: 70%

Section: Synthesis and Characterization Of Target-specific Microbubblesmentioning

confidence: 99%

Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects

Palmowski

Huppert

Ladewig

et al. 2008

Molecular Cancer Therapeutics

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158

113

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“…This plateau can be explained by the heterogeneous in vivo stability of the microbubbles within one charge (e.g., due to differences in size, wall thickness, and wall homogeneity; ref. 30). The sum of injected particles causes the initial peak of the enhancement curve.…”

Section: Discussionmentioning

confidence: 99%

Vessel Fractions in Tumor Xenografts Depicted by Flow- or Contrast-Sensitive Three-Dimensional High-Frequency Doppler Ultrasound Respond Differently to Antiangiogenic Treatment

et al. 2008

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High-frequency volumetric Power Doppler ultrasound (HF-VPDU) captures flow-dependent signals in blood vessels and can be used to assess antiangiogenic therapy effects in rodent tumors. However, the sensitivity is limited to vessels larger than capillaries. Contrast-enhanced HF-VPDU reveals all perfused vessels by assessing stimulated acoustic emissions from disintegrating microbubbles. Thus, we investigated whether flow-sensitive and contrast-enhanced HF-VPDU can depict different vessel fractions and assess their early response to antiangiogenic therapy. Mice with A431 tumors were scanned before and after administration of polybutylcyanoacrylate microbubbles by HF-VPDU. Animals received either antiangiogenic treatment (SU11248) or a control substance and were imaged repeatedly over 9 days. At each time point, tumors were removed for immunohistochemical analysis. During growth of untreated tumors, vascularization decreased correspondingly on flow-sensitive and contrast-enhanced scans. Treated tumors showed a significantly (P < 0.05) stronger decline in vascularization than controls, which was more pronounced in contrast-enhanced scans. Surprisingly, whereas vascularization remained low in contrast-enhanced scans, flow-sensitive ultrasound indicated a reincrease after day 6 with a higher vascularization than the controls at day 9. Histologic evaluation indicated that immature vessels degraded markedly on therapy, whereas large mature vessels on the tumor periphery were more therapy resistant and drew closer due to tumor shrinkage. In conclusion, contrast-enhanced HF-VPDU and flow-sensitive HF-VPDU are both capable of assessing the effects of antiangiogenic therapy. Because contrast-sensitive ultrasound is more sensitive for small immature vessels and flow-sensitive ultrasound mostly captures large vessels at the tumor periphery, the combination of both methods can provide evidence of vascular maturity in tumors. [Cancer Res 2008;68(17):7042-9]

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“…Ultrasound contrast agents containing encapsulated microbubbles are mainly used to increase the diagnostic imaging of tumors. McCarville et al [18] showed that gray-scale US measurements of microbubble contrast agent flow can be used to detect the functional consequences of antiangiogenic therapy for tumors and to assess angiogenesis inhibitors that act through different mechanisms [19][20][21][22][23] . Recently, lymphangiogenesis has become a new research frontier [10] .…”

Section: Discussionmentioning

confidence: 99%

Assessment of hepatic VX2 tumors with combined percutaneous transhepatic lymphosonography and contrast-enhanced ultrasonographic imaging

Liu

Liang²,

Wang³

et al. 2008

WJG

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CONCLUSION: PTL is a novel method for the detection of tumor lymphangiogenesis in hepatic VX 2 of rabbits. Combined PTL and contrast-enhanced ultrasonographic imaging can improve the diagnosis of liver cancer.© 2008 The WJG Press. All rights reserved. Key words:Percutaneous transhepatic lymphosonography; Ultrasound; Contrast-enhanced ultrasonographic imaging; Ultrasound contrast media; VX 2 tumor Peer reviewer: Gianluigi Giannelli, MD, Dipartimento di Clinica Medica, Immunologia e Malattie Infettive, Sezione di Medicina Interna, Policlinico, Piazza G. Cesare 11, Bari 70124, Italy Liu C, Liang P, Wang Y, Zhou P, Li X, Han ZY, Liu SP. Assessment of hepatic VX 2 tumors with combined percutaneous transhepatic lymphosonography and contrast-enhanced ultrasonographic imaging.

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Pharmacodynamics of Streptavidin-Coated Cyanoacrylate Microbubbles Designed for Molecular Ultrasound Imaging

Abstract: The pharmacokinetic behavior of streptavidin-coated cyanoacrylate MBs has been studied. In this context, the low amount of MBs in tumors after >5 minutes is beneficial for specific targeting of angiogenesis.

Cited by 58 publications

References 25 publications

Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects

Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects

Vessel Fractions in Tumor Xenografts Depicted by Flow- or Contrast-Sensitive Three-Dimensional High-Frequency Doppler Ultrasound Respond Differently to Antiangiogenic Treatment

Assessment of hepatic VX2 tumors with combined percutaneous transhepatic lymphosonography and contrast-enhanced ultrasonographic imaging

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