Topical Application of Activity-based Probes for Visualization of Brain Tumor Tissue

Abstract

Several investigators have shown the utility of systemically delivered optical imaging probes to image tumors in small animal models of cancer. Here we demonstrate an innovative method for imaging tumors and tumor margins during surgery. Specifically, we show that optical imaging probes topically applied to tumors and surrounding normal tissue rapidly differentiate between tissues. In contrast to systemic delivery of optical imaging probes which label tumors uniformly over time, topical probe application results in rapid and robust probe activation that is detectable as early as 5 minutes following application. Importantly, labeling is primarily associated with peri-tumor spaces. This methodology provides a means for rapid visualization of tumor and potentially infiltrating tumor cells and has potential applications for directed surgical excision of tumor tissues. Furthermore, this technology could find use in surgical resections for any tumors having differential regulation of cysteine cathepsin activity.

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

“…We and others have previously demonstrated that small-molecule ABPs can be used to topically label active cathepsins in excised tissues (37,38). Two fresh human carotid endarterectomy specimens were split into sections to perform labeling using the optical probe BMV109 (Fig.…”

Microscopic Detection of Quenched Activity-Based Optical Imaging Probes Using an Antibody Detection System: Localizing Protease Activity

“…In particular, fluorescently quenched ABPs (qABPs) have proven to be powerful tools for the noninvasive optical imaging of cancer and subsequent characterization of the target cathepsins on a histological, cellular, and protein level [9,10]. Previously, we have presented an attractive and unique approach to utilize the ability of qABP to elucidate overexpression of tumor-associated cathepsin-L (CTS-L) ex vivo [11]. Utilizing one member of the qABP class of probes, GB119 [9,11], we have shown that topical application of GB119 can rapidly identify active proteases present in the peri-tumor spaces and margins when it was used in an animal model of brain cancer [11].…”

“…Previously, we have presented an attractive and unique approach to utilize the ability of qABP to elucidate overexpression of tumor-associated cathepsin-L (CTS-L) ex vivo [11]. Utilizing one member of the qABP class of probes, GB119 [9,11], we have shown that topical application of GB119 can rapidly identify active proteases present in the peri-tumor spaces and margins when it was used in an animal model of brain cancer [11]. More specifically, such topical administration appears to be more effective than systemic administration for identification of small clumps of tumor cells that presumably have not develop a vasculature [11].…”

Rinsing paired-agent model (RPAM) to quantify cell-surface receptor concentrations in topical staining applications of thick tissues

“…It should be noted, however, that despite these complications, there is a large body of work demonstrating that topical staining can provide significant improvements in tissue identification (Nitin et al , 2009; DaCosta et al , 2005; Foersch et al , 2010; Hsiung et al , 2008; Nguyen and Tsien, 2013; Shin et al , 2010; Barth and Gibbs, 2017; Park et al , 2014). Other work has demonstrated improvements in signal-to-noise achievable with activatable imaging agents (Cutter et al , 2012; Urano et al , 2011) or induced autofluorescence (Leunig et al , 2001), that mitigate problems of non-specific retention (though can still be affected by uneven staining or rinsing). Paired-agent models do not aim to compete with these approaches, rather, they could be adapted to any of them to improve tissue identification.…”