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Advances in imaging strategies for in vivo tracking of exosomes

Advanced Review

Oshra Betzer, Eran Barnoy, Tamar Sadan, Idan Elbaz, Cara Braverman, Zhuang Liu, Rachela Popovtzer

Published Online: Dec 15 2019

DOI: 10.1002/wnan.1594

Full article on Wiley Online Library: HTML PDF

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Abstract Exosomes have many biological functions as short‐ and long distance nanocarriers for cell‐to‐cell communication. They allow the exchange of complex information between cells, and thereby modulate various processes such as homeostasis, immune response and angiogenesis, in both physiological and pathological conditions. In addition, due to their unique abilities of migration, targeting, and selective internalization into specific cells, they are promising delivery vectors. As such, they provide a potentially new field in diagnostics and treatment, and may serve as an alternative to cell‐based therapeutic approaches. However, a major drawback for translating exosome treatment to the clinic is that current understanding of these endogenous vesicles is insufficient, especially in regards to their in vivo behavior. Tracking exosomes in vivo can provide important knowledge regarding their biodistribution, migration abilities, toxicity, biological role, communication capabilities, and mechanism of action. Therefore, the development of efficient, sensitive and biocompatible exosome labeling and imaging techniques is highly desired. Recent studies have developed different methods for exosome labeling and imaging, which have allowed for in vivo investigation of their bio‐distribution, physiological functions, migration, and targeting mechanisms. These improved imaging capabilities are expected to greatly advance exosome‐based nanomedicine applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

(a) Longitudinal in vivo computed tomography (CT) imaging of homing and accumulation of exosomes within the brain. (b–d) Healthy mice. CT signal, indicating presence of gold nanoparticle‐labeled exosomes, is found mainly in the olfactory bulb at 1 hr, and cleared by 24 hr. (f–h) Stroke model: the exosomes CT signal was located in mouse striatum up to 96 hr. (j–l) Parkinson's disease model: exosomes signal was located in the striatum at 96 hr. (n–p) Alzheimer's model: exosomes signal was located in the hippocampus up to 96 hr. (r–t) Autism model: exosomes signal was located in the cerebellum and prefrontal cortex up to 96 hr. (a, e, i, m, q). Brain section images adopted from Allen Mouse Brain 3D atlas, showing the lesioned/pathological area in green (Reprinted with permission from Perets et al. (). Copyright 2019 American Chemical Society)

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In vivo MRI of SPION5 loaded melanoma exosomes. (a) Free SPION5 and (b) SPION5 loaded exosome migrated to ipsilateral (left, L) and contralateral (right, R) popliteal lymph nodes (PLN) as visualized by T1‐weighted images with R2* mapping of PLN ipsilateral to the injection site (Reprinted with permission from Hu et al. (). Copyright 2015 Creative Commons Attribution 4.0 International License)

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In vivo single‐photon emission computed tomography/computed tomography (SPECT/CT) images of ^99mTc‐HMPAO labeled exosomes postintravenous injection. Images were acquired at 30 min, 3, and 5 hr in BALB/c mice. The SPECT/CT imaging shows a significant uptake of radiolabeled exosomes in the liver, salivary glands and intestine up to 5 hr postadministration (Reprinted with permission from Hwang et al. (). Copyright 2015 Creative Commons Attribution 4.0 International License)

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Kinetics of GLuc after intravenous injection of GL‐labeled B16‐BL6 exosomes into mice. Balb/c mice received intravenous injections of exosomes collected from pCMV‐gLuc‐lactadherin‐transfected B16BL6 cells. B16‐BL6 exosomes expressing gLuc were imaged 10, 30, 60, and 240 min postexosome injection through a bolus intravenous injection of Coelenterazine (Reprinted with permission from Takahashi et al. (). Copyright 2013 Elsevier)

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Kinetics of breast‐cancer‐cell‐derived exosomes 24 hr postexosomes injection. (a) Mice following intravenous injections of fluorescently labeled MCF‐7‐, MDA‐MB‐231‐, and HS578T‐derived exosomes. (b) Biodistribution of exosomes, analyzed and quantified by recoding the photons/second/steradian (ph/s/sr) of each organ, normalized to the injected dose fluorescence intensity. The results are expressed as the means ± SD (n = 3) (Reprinted with permission from Zhang et al. (). Copyright 2018 American Chemical Society)

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Photoacoustic imaging (PAI) of primary tumor growth and axillary lymph‐nodes metastasis following intravenous (iv) injection of cancer cell‐derived exosomes in triple‐negative breast cancer models. (a) and (b) Representative ultrasound‐guided PAI of mice that were injected iv with phosphated‐buffered saline or exosomes before, 4 and 24 hr after intratumor injection of anti–EGFR‐GN. (c and d) PA signals (mean ± SE) measured from primary tumors (c) and axillary lymph‐nodes (d). Exosomes reached the tumor area and promoted its growth (Reprinted with permission from Piao et al. (). Copyright 2018 Creative Commons Attribution License 3.0)

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