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WIREs Nanomed Nanobiotechnol
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Status and trends in the development of clinical diagnostic agents

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Contrast agents (CA) are routinely used in clinical practice to improve the diagnosis of diseases and to monitor therapy response. The majority of CA comprises small molecules accumulating at pathological sites due to vascular abnormalities, such as changes in perfusion and permeability. For many diseases, high diagnostic accuracy can be achieved with contrast‐enhanced imaging. This means that new CA will only succeed in translation if they either show superior performance with respect to diagnostic accuracy, safety and cost, support a new imaging modality, or are directly linked to the refinement of therapy, e.g., as a companion diagnostic. Unfortunately, these basic demands are often not carefully considered by the scientific community, leading to concepts with low chances of clinical translation. Thus, it is not surprising that, despite steadily increasing numbers of publications, there is quite the opposite trend when it comes to the clinical approval of new diagnostics. As a matter of fact, except for PET tracers, in the last decade, only a handful of CA received FDA or EMA approval. Furthermore, several approved products were discontinued by the manufacturers because of low market potential, a competitive own product, suboptimal clinical performance, or safety concerns. This review article discusses the current status of approved diagnostic probes for clinical imaging modalities, with a focus on new trends in CA development. In this context, molecularly targeted diagnostics or probes for emerging fields, such as image‐guided surgery, nanomedicine, or theranostics, will be introduced and discussed with regard to their clinical translation. WIREs Nanomed Nanobiotechnol 2017, 9:e1441. doi: 10.1002/wnan.1441 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Scheme of the CA development pipeline and important factors that will impact the chances for successful clinical translation. CA development should be motivated by the clinical need, also considering new therapies and alternative diagnostic strategies. The feasibility to develop new CA should be estimated with regard to drug design and attainable production, acceptance by users, and estimated commercial benefit. In this manner, selected CA can be subjected to further preclinical and clinical trials. (Copyright: http://www.servier.com/Powerpoint‐image‐bank)
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Examples of the application of emerging contrast agents. (a) T2‐weighted image and overlays of hyperpolarized [1‐13C]lactate/ [1‐13C]pyruvate, showing enhanced metabolism (red/violet) in two cancerous regions (Reprinted with permission from Ref. Copyright 2013 The American Association for the Advancement of Science). (b) US image of a breast cancer xenograft before (left) and after (right) injection of BR55, showing strong enhancement due to binding of BR55 to VEGFR2 (Reprinted with permission from Ref. Copyright 2011 Springer). (c) T1‐weighted MRI scan of a murine brain after BBB opening with MB‐enhanced US and subsequent Gd‐injection, showing enhanced signals in the treated areas. (d) PET/CT scan of a prostate cancer patient with increasing PSA level after 68Ga‐PSMA‐HBED‐CC (left), 18F‐DCFPyL (middle), and without additional injection (right), showing an additional bone metastasis after application of the 18F tracer (Reprinted with permission from Ref. Copyright 2015 Springer). (e) Intraoperative image of the peritoneum of an ovarian cancer patient after injection of a folate receptor‐α‐targeted fluorescent probe (left) and the corresponding fluorescence image (right) (Reprinted with permission from Ref. Copyright 2011 Nature Publishing Group) [Figure (c) and (d) were released under the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), all credits belong to the authors.]
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Risk sites for CA accumulation. Gd CA were shown to lead to Gd accumulation in bones and brain. Iodine CA accumulate in the thyroid gland, while peptides accumulate in the kidneys. Accumulation sites for nanoparticles are liver and spleen, while iron oxide nanoparticles also shown accumulation in bones (Copyright: http://www.servier.com/Powerpoint‐image‐bank).
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Phases in the development of a novel product. Comparison of time, cost, and annual revenue between therapeutic drug and CA. Lower ratio between developmental costs and revenues is reported for the development of CA as compared to therapeutic drugs (Modified from Figure 4 of FDA's critical path initiative).
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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