Imaging of Differential Protease Expression in Breast Cancers for Detection of Aggressive Tumor Phenotypes

Bremer, Christoph; Tung, Ching–Hsuan; Bogdanov, Alex; Weissleder, Ralph

doi:10.1148/radiol.2223010812

Cited by 147 publications

(93 citation statements)

References 22 publications

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“…From a molecular-imaging perspective, ACPPDs have several advantages over other targeted fluorescent probes previously described in the literature for use in a surgical system (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Molecular fluorescence-guided surgery demands that a given probe (a), works for a wide variety of tumor types (b), offers ample signal with low background (c), binds tightly to the tumor, and (d), is not affected by the physical trauma of surgery.…”

Section: Discussionmentioning

confidence: 99%

“…These probes are applicable to a wide range of tumors but are limited by contrast and nonspecificity. Other options that offer similar fluorescence contrast to ACPPD are the dequenching probes designed by Weissleder's group (19,20), peptide-based probes that target an abundant ligand such as the αvβ3 integrin (21), or 5-aminolevulinic acid (5-ALA) and derivatives, which get converted to fluorescent protoporphyrin IX in many tumors (22,23). All of these alternatives are limited to fluorescence readout, whereas ACPPD also allows MRI, whose noninvasive depth penetration and tomographic accuracy are ideally complementary to the high spatial resolution, real-time capability, and surgical compatibility of fluorescence.…”

Section: Discussionmentioning

confidence: 99%

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Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival

Nguyen

Olson

Aguilera

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

445

310

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The completeness of tumor removal during surgery is dependent on the surgeon's ability to differentiate tumor from normal tissue using subjective criteria that are not easily quantifiable. A way to objectively assess tumor margins during surgery in patients would be of great value. We have developed a method to visualize tumors during surgery using activatable cell-penetrating peptides (ACPPs), in which the fluorescently labeled, polycationic cell-penetrating peptide (CPP) is coupled via a cleavable linker to a neutralizing peptide. Upon exposure to proteases characteristic of tumor tissue, the linker is cleaved, dissociating the inhibitory peptide and allowing the CPP to bind to and enter tumor cells. In mice, xenografts stably transfected with green fluorescent protein show colocalization with the Cy5-labeled ACPPs. In the same mouse models, Cy5-labeled free ACPPs and ACPPs conjugated to dendrimers (ACPPDs) delineate the margin between tumor and adjacent tissue, resulting in improved precision of tumor resection. Surgery guided by ACPPD resulted in fewer residual cancer cells left in the animal after surgery as measured by Alu PCR. A single injection of ACPPD dually labeled with Cy5 and gadolinium chelates enabled preoperative wholebody tumor detection by MRI, intraoperative guidance by real-time fluorescence, intraoperative histological analysis of margin status by fluorescence, and postoperative MRI tumor quantification. Animals whose tumors were resected with ACPPD guidance had better long-term tumor-free survival and overall survival than animals whose tumors were resected with traditional bright-field illumination only.intraoperative fluorescence imaging | molecular navigation | long-term survival | molecular imaging | surgical margin

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival

Nguyen

Olson

Aguilera

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

445

310

View full text Add to dashboard Cite

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“…An example of the signal sensitivity that can be achieved using these agents is the visualization of MMP-2 activity [50], [51], and [52]. In vitro, the authors observed an 850% increase in NIR fl uorescence intensity when the probe was cleaved and specifi c activation could be blocked by MMP-2 inhibitors.…”

Section: Activatable Probesmentioning

confidence: 99%

“…For in vivo imaging applications, the dye/protein ratio of the conjugate may affect biological or biochemical activity of the protein, signal-to-background ratio, clearance, and biodistribution [52]. The optimal ratio of coupling is unique to each targeting agent.…”

Section: Conjugating Probes With Nir Dyesmentioning

confidence: 99%

A systematic approach to the development of fluorescent contrast agents for optical imaging of mouse cancer models

Kovar

Simpson

Schutz-Geschwender

et al. 2007

Analytical Biochemistry

141

142

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“…Alternatively, specificity might be enhanced by designing smart fluorescence probes, which are activated by interaction with the target tissue (e.g., enzymatic cleavage or oxidation) [113]. Bremer et al, for instance, showed in a mouse model that enzymatic activation of fluorescent probes induces up to 1.5 times higher fluorescence in undifferentiated breast cancer compared with well differentiated cancer [115,116].…”

Section: Discussionmentioning

confidence: 99%

Near‐infrared imaging of breast cancer using optical contrast agents

Poellinger

2012

Journal of Biophotonics

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Breast cancer is the most common malignancy in women worldwide and the second leading cause of cancer death. On the basis of three studies performed by our group, this article reviews the current status of optical breast imaging using extrinsic contrast agents. To date, only two contrast agents have been applied in human studies, indocyanine green (ICG) and omocianine. Both contrast media were used for absorption and fluorescence imaging. Generally speaking, malignant breast lesions exhibited higher absorption contrast as well as higher fluorescence contrast compared to benign lesions or non‐diseased breast tissue. Some groups consider early enhancement characteristics helpful for differentiation between malignant and benign lesions. Late fluorescence ICG imaging – capitalizing on the extravasation of the dye through the wall of tumorous vessels – seems to be a promising technique to distinguish malignant from benign breast lesions. (© 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)

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Imaging of Differential Protease Expression in Breast Cancers for Detection of Aggressive Tumor Phenotypes

Abstract: Cathepsin-B enzyme activity can be determined in vivo with NIRF optical imaging, while differences in tumoral expression may correlate with tumor aggressiveness.

Cited by 147 publications

References 22 publications

Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival

Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival

A systematic approach to the development of fluorescent contrast agents for optical imaging of mouse cancer models

Near‐infrared imaging of breast cancer using optical contrast agents

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