Design of Protease Activated Optical Contrast Agents That Exploit a Latent Lysosomotropic Effect for Use in Fluorescence-Guided Surgery

Ofori, Leslie O.; Withana, Nimali P.; Prestwood, Tyler R.; Verdoes, Martijn; Brady, Jennifer J.; Winslow, Monte M.; Sorger, Jonathan M.; Bogyo, Matthew

doi:10.1021/acschembio.5b00205

Cited by 109 publications

(148 citation statements)

References 49 publications

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“…54 Cathepsin activatable probes also were used to image different solid tumors, and when used with the NIR Cy5.5 fluorophore, are able to label lung, colorectal and breast cancers in mouse models. 55 To date, GB119 has not been tested in humans.…”

Section: Targeted Fluorescent Molecular Imaging Agentsmentioning

confidence: 99%

Fluorescent-Guided Surgical Resection of Glioma with Targeted Molecular Imaging Agents: A Literature Review

et al. 2016

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The median life expectancy following a diagnosis of glioblastoma (GBM) is 15 months. While chemotherapeutics may someday cure GBM by killing the highly dispersive malignant cells, the most important contribution that clinicians can currently offer to improve survival is by maximizing the extent of resection and providing concurrent chemo-radiation, which has become standard. Strides have been made in this area with the advent and implementation of methods of improved intraoperative tumor visualization. One of these techniques, optical fluorescent imaging with targeted molecular imaging agents, allows the surgeon to view fluorescently labeled tumor tissue during surgery with the use of special microscopy – thereby highlighting where to resect, and indicating when tumor-free margins have been obtained. This advantage is especially important at the difficult to observe margins where tumor cells infiltrate normal tissue. Targeted fluorescent agents also may be valuable for identifying tumor versus non-tumor tissue. In this review, we briefly summarize non-targeted fluorescent tumor imaging agents before discussing several novel targeted fluorescent agents being developed for glioma imaging in the context of fluorescent guided surgery or live molecular navigation. Many of these agents are currently undergoing preclinical testing. As the agents become available, however, it is necessary to understand the strengths and weaknesses of each.

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Section: Targeted Fluorescent Molecular Imaging Agentsmentioning

confidence: 99%

Fluorescent-Guided Surgical Resection of Glioma with Targeted Molecular Imaging Agents: A Literature Review

et al. 2016

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“…For example, cathepsin S has been shown to colocalize with a major protein of the extracellular matrix, elastin, in the arterial medium of atheromas (27), especially in regions of elastin breaks (28). Several cysteine cathepsin-specific probes have been developed for both optical and PET imaging of tumor progression and lung inflammation (29)(30)(31). However, cathepsin protease probes equipped with both optical and PET tracers have never been tested in models of atherosclerosis.…”

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confidence: 99%

Dual-Modality Activity-Based Probes as Molecular Imaging Agents for Vascular Inflammation

Withana

Saito

et al. 2016

J Nucl Med

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Macrophages are cellular mediators of vascular inflammation and are involved in the formation of atherosclerotic plaques. These immune cells secrete proteases such as matrix metalloproteinases and cathepsins that contribute to disease formation and progression. Here, we demonstrate that activity-based probes (ABPs) targeting cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes can also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. Methods: Macrophage-rich carotid lesions were induced in FVB mice fed on a high-fat diet by streptozotocin injection followed by ligation of the left common carotid artery. Mice with carotid atherosclerotic plaques were injected with the optical or dual-modality probes BMV109 and BMV101, respectively, via the tail vein and noninvasively imaged by optical and small-animal PET/CT at different time points. After noninvasive imaging, the murine carotid arteries were imaged in situ and ex vivo, followed by immunofluorescence staining to confirm target labeling. Additionally, human carotid plaques were topically labeled with the probe and analyzed by both sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunofluorescence staining to confirm the primary targets of the probe. Results: Quantitative analysis of the signal intensity from both optical and PET/CT imaging showed significantly higher levels of accumulation of BMV109 and BMV101 (P , 0.005 and P , 0.05, respectively) in the ligated left carotid arteries than the right carotid or healthy arteries. Immunofluorescence staining for macrophages in cross-sectional slices of the murine artery demonstrated substantial infiltration of macrophages in the neointima and adventitia of the ligated left carotid arteries compared with the right. Analysis of the human plaque tissues by sodium dodecyl sulfate polyacrylamide gel electrophoresis confirmed that the primary targets of the probe were cathepsins X, B, S, and L. Immunofluorescence labeling of the human tissue with the probe demonstrated colocalization of the probe with CD68, elastin, and cathepsin S, similar to that observed in the experimental carotid inflammation murine model. Conclusion: We demonstrate that ABPs targeting the cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes could also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. Therefore, ABPs targeting the cysteine cathepsins are potentially valuable new reagents for rapid and noninvasive imaging of atherosclerotic disease progression and plaque vulnerability.

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“…This latent lysosomotropic effect (LLE) has been used to design quenched cathepsin protease probes that produce fluorescent fragments with long half-lives after cleavage. One such probe, 6QCNIR (Figure 5B), produced rapid fluorescent signals in cancers of the lung, breast and colon, and was compatible with the FDA-approved da Vinci ® imaging system equipped with the Firefly detection system (Ofori, et al, 2015). Therefore, this class of probes could be readily advanced into clinical studies.…”

Section: Substrate and Activity-based Probesmentioning

confidence: 99%

A Bright Future for Precision Medicine: Advances in Fluorescent Chemical Probe Design and Their Clinical Application

Garland

Yim

Bogyo

2016

Cell Chemical Biology

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The Precision Medicine Initiative aims to use advances in basic and clinical research to develop therapeutics that selectively target and kill cancer cells. Under the same doctrine of precision medicine, there is an equally important need to visualize these diseased cells to enable diagnosis, facilitate surgical resection and monitor therapeutic response. Therefore, there is a great opportunity for chemists to develop chemically tractable probes that can image cancer in vivo. This review focuses on recent advances in the development of optical probes as well as their current and future applications in the clinical management of cancer. The progress in probe development described here suggests that optical imaging is an important and rapidly developing field of study that encourages continued collaboration between chemists, biologists and clinicians to further refine these tools for interventional surgical imaging, as well as for diagnostic and therapeutic applications.

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Design of Protease Activated Optical Contrast Agents That Exploit a Latent Lysosomotropic Effect for Use in Fluorescence-Guided Surgery

Cited by 109 publications

References 49 publications

Fluorescent-Guided Surgical Resection of Glioma with Targeted Molecular Imaging Agents: A Literature Review

Fluorescent-Guided Surgical Resection of Glioma with Targeted Molecular Imaging Agents: A Literature Review

Dual-Modality Activity-Based Probes as Molecular Imaging Agents for Vascular Inflammation

A Bright Future for Precision Medicine: Advances in Fluorescent Chemical Probe Design and Their Clinical Application

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