An <i>In Vivo</i> Evaluation of the Effect of Repeated Administration and Clearance of Targeted Contrast Agents on Molecular Imaging Signal Enhancement

Streeter, Jason E.; Dayton, Paul A.

doi:10.7150/thno.5341

Cited by 12 publications

(9 citation statements)

References 25 publications

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“…It has also been reported that multiple injections of targeted MBs within 60 minutes do not block sufficient binding sites to bias molecular imaging data [34], which allows for imaging sessions with consecutive targeted MB injections. However, insonation of targeted MBs can reduce blood flow for up to 40 minutes with a frequency of 5 MHz and peak-negative pressure of 2 or 4 MPa [20].…”

Section: Discussionmentioning

confidence: 99%

“…Selective targeting is usually created by conjugating ligands, antibodies [14, 35–40] or short peptides [20, 24, 25, 31, 41–48] onto the surface of the contrast agent. Methods for conjugation include biological interaction (e.g., biotin-avidin [14, 20, 35–40, 44, 45]) and covalent bonds [24, 25, 31, 34, 42, 46–48]. The immunogenicity of short peptides is less than that of antibodies and is also reduced by covalent coupling rather than biotin-avidin interactions.…”

Section: Discussionmentioning

confidence: 99%

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Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble

et al. 2015

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Ultrasound molecular imaging has great potential to impact early disease diagnosis, evaluation of disease progression and the development of target-specific therapy. In this paper, two neuropilin-1 (NRP) targeted peptides, CRPPR and ATWLPPR, were conjugated onto the surface of lipid microbubbles (MBs) to evaluate molecular imaging of tumor angiogenesis in a breast cancer model. Development of a molecular imaging agent using CRPPR has particular importance due to the previously demonstrated internalizing capability of this and similar ligands. In vitro, CRPPR MBs bound to an NRP-expressing cell line 2.6 and 15.6 times more than ATWLPPR MBs and non-targeted (NT) MBs, respectively, and the binding was inhibited by pretreating the cells with an NRP antibody. In vivo, the backscattered intensity within the tumor, relative to nearby vasculature, increased over time during the ~6 min circulation of the CRPPR-targeted contrast agents providing high contrast images of angiogenic tumors. Approximately 67% of the initial signal from CRPPR MBs remained bound after the majority of circulating MBs had cleared (8 min), 8 and 4.5 times greater than ATWLPPR and NT MBs, respectively. Finally, at 7–21 days after the first injection, we found that CRPPR MBs cleared faster from circulation and tumor accumulation was reduced likely due to a complement-mediated recognition of the targeted microbubble and a decrease in angiogenic vasculature, respectively. In summary, we find that CRPPR MBs specifically bind to NRP-expressing cells and provide an effective new agent for molecular imaging of angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble

et al. 2015

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“…Streeter et al [176] performed 3D UMI of tumours expressing a v b 3 integrin by mechanically stepping the transducer across the tumour in 800 mm increments. In another study it was shown that multiple injections of tMBs did not block sufficient binding sites to bias molecular imaging data in serial studies [177], which is an important finding. Using the clinically promising BR55 agent, 3D UMI was shown to be very well suited in depicting the angiogenic activity in very small breast lesions, suggesting its potential for detecting and characterising these lesions at very early stages [178].…”

Section: Three Dimensional Umimentioning

confidence: 96%

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

Rooij

Daeichin

Skachkov

et al. 2015

International Journal of Hyperthermia

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Ultrasound contrast agents (UCAs) are used routinely in the clinic to enhance contrast in ultrasonography. More recently, UCAs have been functionalised by conjugating ligands to their surface to target specific biomarkers of a disease or a disease process. These targeted UCAs (tUCAs) are used for a wide range of pre-clinical applications including diagnosis, monitoring of drug treatment, and therapy. In this review, recent achievements with tUCAs in the field of molecular imaging, evaluation of therapy, drug delivery, and therapeutic applications are discussed. We present the different coating materials and aspects that have to be considered when manufacturing tUCAs. Next to tUCA design and the choice of ligands for specific biomarkers, additional techniques are discussed that are applied to improve binding of the tUCAs to their target and to quantify the strength of this bond. As imaging techniques rely on the specific behaviour of tUCAs in an ultrasound field, it is crucial to understand the characteristics of both free and adhered tUCAs. To image and quantify the adhered tUCAs, the state-of-the-art techniques used for ultrasound molecular imaging and quantification are presented. This review concludes with the potential of tUCAs for drug delivery and therapeutic applications.

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“…Potential targeting ligands include antibodies [22, 53–55], peptides [10, 26, 30, 31, 56], or engineered scaffold ligands [57, 58]. Methods to conjugate ligands onto the surface of contrast agents have included biotin-avidin coupling [22, 43, 53–55] and covalent bonds [10, 26, 30, 56, 59]. In this paper, a peptide was displayed on the surface of the MB by including a lipo-PEG-peptide during self-assembly.…”

Section: Discussionmentioning

confidence: 99%

In vitro characterization and in vivo ultrasound molecular imaging of nucleolin-targeted microbubbles

et al. 2017

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Nucleolin (NCL) plays an important role in tumor vascular development. An increased endothelial expression level of NCL has been related to cancer aggressiveness and prognosis and has been detected clinically in advanced tumors. Here, with a peptide targeted to NCL (F3 peptide), we created an NCL-targeted microbubble (MB) and compared the performance of F3-conjugated MBs with non-targeted (NT) MBs both in vitro and in vivo. In an in vitro study, F3-conjugated MBs bound 433 times more than NT MBs to an NCL-expressing cell line, while pretreating cells with 0.5 mM free F3 peptide reduced the binding of F3-conjugated MBs by 84%, n=4, p<0.001. We then set out to create a method to extract both the tumor wash-in and wash-out kinetics and tumor accumulation following a single injection of targeted MBs. In order to accomplish this, a series of ultrasound frames (a clip) was recorded at the time of injection and subsequent time points. Each pixel within this clip was analyzed for the minimum intensity projection (MinIP) and average intensity projection (AvgIP). We found that the MinIP robustly demonstrates enhanced accumulation of F3-conjugated MBs over the range of tumor diameters evaluated here (2 to 8 mm), and the difference between the AvgIP and the MinIP quantifies inflow and kinetics. The inflow and clearance were similar for unbound F3-conjugated MBs, control (non-targeted) and scrambled control agents. Targeted agent accumulation was confirmed by a high amplitude pulse and by a two-dimensional Fourier Transform technique. In summary, F3-conjugated MBs provide a new imaging agent for ultrasound molecular imaging of cancer vasculature, and we have validated metrics to assess performance using low mechanical index strategies that have potential for use in human molecular imaging studies.

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An In Vivo Evaluation of the Effect of Repeated Administration and Clearance of Targeted Contrast Agents on Molecular Imaging Signal Enhancement

Cited by 12 publications

References 25 publications

Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble

Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

In vitro characterization and in vivo ultrasound molecular imaging of nucleolin-targeted microbubbles

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