Recent Advances in Receptor-Targeted Fluorescent Probes for In Vivo Cancer Imaging

Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh School of Medicine, 100 Technology Drive Suite 452G, Pittsburgh, PA 15219
Current Medicinal Chemistry (Impact Factor: 3.85). 08/2012; 19(28). DOI: 10.2174/092986712803341467
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Receptor-targeted optical imaging of cancer is emerging as an attractive strategy for early cancer diagnosis and surgical guidance. The success of such strategy depends largely upon the development of receptor-targeted fluorescent probes with high specificity and binding affinity to the target receptors. Recently, a host of such probes have been reported to target cancer-specific receptors, such as somatostatin receptors (SSTRs), integrin receptors, cholecystokinin-2 (CCK2) receptor, gastrin-releasing peptide (GRP) receptor, endothelin A (ETA) receptor, translocator protein (TSPO) receptor, epidermal growth factor (EGF) receptor, human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF) receptor, folate receptor (FR), transferrin receptor (TFR), low-density lipoprotein (LDL) receptors, type I insulin-like growth factor receptor (IGF1R), vasoactive intestinal peptide (VIP) receptors, urokinase plasminogen activator (uPA) and estrogen receptor (ER). This review will describe the recent advances in synthetic targeting optical imaging probes and demonstrate their in vivo imaging potentials. Moreover, current status of near infrared (NIR) fluorescent dyes, targeting moieties and coupling reactions, as well as strategies for designing targeted probes, will also be discussed.

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Available from: Mingfeng Bai,
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    • "Therefore, there is an urgent need to develop reliable imaging tools to answer these important questions about CB 2 R. As a low-cost imaging method with high sensitivity and resolution , fluorescence imaging is widely used to study receptors at the cellular and molecular levels [14e16]. For in vivo imaging studies, near infrared (NIR) light (650e900 nm) is usually adopted, owing to the low tissue absorption and negligible tissue autofluorescence in the NIR region [14]. However, it is difficult to develop CB 2 R-targeted fluorescent probes because conjugating a relatively large fluorescent dye to a CB 2 R ligand could obliterate its binding to CB 2 R [17]. "
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    ABSTRACT: The type 2 cannabinoid receptors (CB2R) have gained much attention recently due to their important regulatory role in a host of pathophysiological processes. However, the exact biological function of CB2R and how this function might change depending on disease progression remains unclear and could be better studied with highly sensitive and selective imaging tools for identifying the receptors. Here we report the first near infrared fluorescence imaging probe (NIR760-XLP6) that binds preferentially to CB2R over the type 1 cannabinoid receptors (CB1R). The selectivity of the probe was demonstrated by fluorescence microscopy using DBT-CB2 and DBT-CB1 cells. Furthermore, in mouse tumor models, NIR760-XLP6 showed significantly higher uptake in DBT-CB2 than that in DBT-CB1 tumors. These findings indicate that NIR760-XLP6 is a promising imaging tool for the study of CB2R regulation. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biomaterials 04/2015; 57:169-178. DOI:10.1016/j.biomaterials.2015.04.018 · 8.56 Impact Factor
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    • "Three main strategies are involved in designing targeted NIRF probes: single coupling between signaling and targeting moieties, target-activatable probes with a turn-on option, and molecular probes with two different targeting sites.103 The interaction between activatable probes and their targets triggers a turn-on effect through oxidation or enzymatic cleavage, which disintegrates the probes into fluorescent dyes. "
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    ABSTRACT: Near-infrared fluorescence (NIRF) imaging is an attractive modality for early cancer detection with high sensitivity and multi-detection capability. Due to convenient modification by conjugating with moieties of interests, NIRF probes are ideal candidates for cancer targeted imaging. Additionally, the combinatory application of NIRF imaging and other imaging modalities that can delineate anatomical structures extends fluorometric determination of biomedical information. Moreover, nanoparticles loaded with NIRF dyes and anticancer agents contribute to the synergistic management of cancer, which integrates the advantage of imaging and therapeutic functions to achieve the ultimate goal of simultaneous diagnosis and treatment. Appropriate probe design with targeting moieties can retain the original properties of NIRF and pharmacokinetics. In recent years, great efforts have been made to develop new NIRF probes with better photostability and strong fluorescence emission, leading to the discovery of numerous novel NIRF probes with fine photophysical properties. Some of these probes exhibit tumoricidal activities upon light radiation, which holds great promise in photothermal therapy, photodynamic therapy, and photoimmunotherapy. This review aims to provide a timely and concise update on emerging NIRF dyes and multifunctional agents. Their potential uses as agents for cancer specific imaging, lymph node mapping, and therapeutics are included. Recent advances of NIRF dyes in clinical use are also summarized.
    International Journal of Nanomedicine 03/2014; 9(1):1347-1365. DOI:10.2147/IJN.S60206 · 4.38 Impact Factor
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    • "Aberrant TSPO levels have been linked to multiple diseases, including cancer, endocrine disorders, brain injury, neurodegeneration, ischemia-reperfusion injury and inflammatory diseases [12] [13] [14] [15]. Thus, for all above mentioned, TSPO has become an extremely attractive subcellular target not only to image disease states overexpressing this protein, but also for a selective mitochondrial drug targeting [16] [17] [18] [19]. Investigation of the functions of this protein in vitro and in vivo has been mainly carried out using high-affinity drug ligands, such as isoquinoline carboxamides (e.g. "
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    ABSTRACT: Mitochondria represents an attractive subcellular target due to its function particularly important for oxidative damage, calcium metabolism and apoptosis. However, the concept of mitochondrial targeting has been a neglected area so far. The translocator protein (TSPO), represents an interesting subcellular target not only to image disease states overexpressing this protein, but also for a selective mitochondrial drug targeting. Recently, we have delivered in vitro and in vivo small molecule imaging agents into cells overexpressing TSPO by using a family of high-affinity conjugable ligands characterized by 2-phenyl-imidazo[1,2-a]pyridine acetamide structure. As an extension, in the present work we studied the possibility to target and image TSPO with dendrimers. These nano-platforms have unique features, in fact, are prepared with a level of control not reachable with most linear polymers, leading to nearly monodisperse, globular macromolecules with a large number of peripheral groups. As a consequence, they are an ideal delivery vehicle candidate for explicit study of the effects of polymer size, charge, composition, and architecture on biologically relevant properties such as lipid bilayer interactions, cytotoxicity, cellular internalization, and subcellular compartments and organelles interactions. Here, we present the synthesis, characterization, cellular internalization, and mitochondria labeling of a TSPO targeted fourth generation [G(4)-PAMAM] dendrimer nanoparticle labeled with the organic fluorescent dye fluorescein. We comprehensively studied the cellular uptake behavior of these dendrimers, into glioma C6 cell line, under the influence of various endocytosis inhibitors. We found that TSPO targeted-G(4)-PAMAM-FITC dendrimer is quickly taken up by these cells by endocytosis pathways, and moreover specifically targets the mitochondria as evidenced from subcellular fractionation experiments and co-localization studies performed with CAT (Confocal-AFM-TIRF) microscopy.
    Journal of Controlled Release 10/2013; 172(3). DOI:10.1016/j.jconrel.2013.09.024 · 7.71 Impact Factor
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