Current Perspectives on In Vivo Noninvasive Tracking of Extracellular Vesicles with Molecular Imaging

Clinical and preclinical in vivo tracking of extracellular vesicles (EVs) are a crucial tool for the development and optimization of EV-based diagnosis and treatment. EVs have gained interest due to their unique properties that make them excellent candidates for biological applications. Noninvasive in vivo EV tracking has allowed marked progress towards elucidating the mechanisms and functions of EVs in real time in preclinical and clinical studies. In this review, we summarize several molecular imaging methods that deal with EVs derived from different cells, which have allowed investigations of EV biodistribution, as well as their tracking, delivery, and tumor targeting, to determine their physiological functions and to exploit imaging-derived information for EV-based theranostics.

[1]  Shunsuke Noguchi,et al.  Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[2]  M. Fujimiya,et al.  Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes , 2016, Scientific Reports.

[3]  C. Melief,et al.  B lymphocytes secrete antigen-presenting vesicles , 1996, The Journal of experimental medicine.

[4]  Jacopo Meldolesi,et al.  Shedding microvesicles: artefacts no more. , 2009, Trends in cell biology.

[5]  Yuki Takahashi,et al.  Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. , 2013, Journal of biotechnology.

[6]  B. Cookson,et al.  Membrane Vesicle Release in Bacteria, Eukaryotes, and Archaea: a Conserved yet Underappreciated Aspect of Microbial Life , 2012, Infection and Immunity.

[7]  Dong Soo Lee,et al.  Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using 99mTc-HMPAO , 2015, Scientific Reports.

[8]  Shiquan Wu,et al.  Exosomes from red blood cell units bind to monocytes and induce proinflammatory cytokines, boosting T-cell responses in vitro. , 2014, Blood.

[9]  Jiayin Zhu,et al.  The role of extracellular vesicles in mediating progression, metastasis and potential treatment of hepatocellular carcinoma , 2016, Oncotarget.

[10]  P. Fraker,et al.  Protein and cell membrane iodinations with a sparingly soluble chloroamide, 1,3,4,6-tetrachloro-3a,6a-diphrenylglycoluril. , 1978, Biochemical and biophysical research communications.

[11]  J. Le Pecq,et al.  A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer , 2005, Journal of Translational Medicine.

[12]  Josiah Ochieng,et al.  Detachment of Breast Tumor Cells Induces Rapid Secretion of Exosomes Which Subsequently Mediate Cellular Adhesion and Spreading , 2011, PloS one.

[13]  Christian Pilarsky,et al.  Glypican-1 identifies cancer exosomes and detects early pancreatic cancer , 2015, Nature.

[14]  H. Yamamoto,et al.  Detection of DNA methylation of gastric juice-derived exosomes in gastric cancer , 2014 .

[15]  Daehee Hwang,et al.  Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells , 2009, BMC Genomics.

[16]  T. Anchordoquy,et al.  Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[17]  Yuki Takahashi,et al.  Macrophage-dependent clearance of systemically administered B16BL6-derived exosomes from the blood circulation in mice , 2015, Journal of extracellular vesicles.

[18]  Samuel A Wickline,et al.  Magnetic resonance imaging of melanoma exosomes in lymph nodes , 2015, Magnetic resonance in medicine.

[19]  L. Zitvogel,et al.  Dendritic cell-derived exosomes for cancer therapy. , 2016, The Journal of clinical investigation.

[20]  H. Vidal,et al.  Exosomes participate in the alteration of muscle homeostasis during lipid-induced insulin resistance in mice , 2014, Diabetologia.

[21]  Meg Duroux,et al.  A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy. , 2014, Biochimica et biophysica acta.

[22]  D. Brigstock,et al.  Cellular or Exosomal microRNAs Associated with CCN Gene Expression in Liver Fibrosis. , 2017, Methods in molecular biology.

[23]  C. Luceri,et al.  Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210 , 2016, Cancer biology & therapy.

[24]  Shinobu Ueda,et al.  Systemically Injected Exosomes Targeted to EGFR Deliver Antitumor MicroRNA to Breast Cancer Cells. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[25]  X. Breakefield,et al.  Role of Exosomes/Microvesicles in the Nervous System and Use in Emerging Therapies , 2012, Front. Physio..

[26]  P. Li,et al.  PKH26 can transfer to host cells in vitro and vivo. , 2013, Stem cells and development.

[27]  Andrea Sbarbati,et al.  Magnetic resonance imaging of ultrasmall superparamagnetic iron oxide-labeled exosomes from stem cells: a new method to obtain labeled exosomes , 2016, International journal of nanomedicine.

[28]  Byeong-Cheol Ahn,et al.  In Vivo Cell Tracking with Bioluminescence Imaging , 2015, Nuclear Medicine and Molecular Imaging.

[29]  A. Molinari,et al.  Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells* , 2009, The Journal of Biological Chemistry.

[30]  Hideo Saji,et al.  Quantitative analysis of tissue distribution of the B16BL6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice. , 2015, Journal of pharmaceutical sciences.

[31]  Ralph Weissleder,et al.  Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters , 2015, Nature Communications.

[32]  Krisztián Szigeti,et al.  Radiolabeling of Extracellular Vesicles with (99m)Tc for Quantitative In Vivo Imaging Studies. , 2016, Cancer biotherapy & radiopharmaceuticals.

[33]  G. Raposo,et al.  The complex ultrastructure of the endolysosomal system. , 2014, Cold Spring Harbor perspectives in biology.

[34]  B. Ahn Personalized Medicine Based on Theranostic Radioiodine Molecular Imaging for Differentiated Thyroid Cancer , 2016, BioMed research international.

[35]  Byeong-Cheol Ahn,et al.  Requisites for successful theranostics with radionuclide-based reporter gene imaging , 2014, Journal of drug targeting.

[36]  Y. You,et al.  Regulation of exosomes released from normal ovarian epithelial cells and ovarian cancer cells , 2016, Tumor Biology.

[37]  M. Danhof,et al.  Drug transport across the blood-brain barrier , 1992, Pharmaceutisch Weekblad.

[38]  Laurence Zitvogel,et al.  Exosomes: composition, biogenesis and function , 2002, Nature Reviews Immunology.

[39]  Robert M Hoffman,et al.  Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models. , 2013, Advanced drug delivery reviews.

[40]  V. Dolo,et al.  Extracellular Vesicles in Glioblastoma: Role in Biological Processes and in Therapeutic Applications. , 2017, Current cancer drug targets.

[41]  Andrew F. Hill,et al.  Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper , 2015, Journal of extracellular vesicles.

[42]  R. Hückelhoven,et al.  Do Plant Cells Secrete Exosomes Derived from Multivesicular Bodies? , 2007, Plant signaling & behavior.

[43]  S. Jeong,et al.  Tracking of dendritic cell migration into lymph nodes using molecular imaging with sodium iodide symporter and enhanced firefly luciferase genes , 2015, Scientific Reports.

[44]  S. Emr,et al.  Molecular mechanisms of the membrane sculpting ESCRT pathway. , 2013, Cold Spring Harbor perspectives in biology.

[45]  Jaesung Park,et al.  Generation of nanovesicles with sliced cellular membrane fragments for exogenous material delivery. , 2015, Biomaterials.

[46]  Johan Skog,et al.  Glioblastoma microvesicles transport RNA and protein that promote tumor growth and provide diagnostic biomarkers , 2008, Nature Cell Biology.

[47]  Imre Mäger,et al.  Extracellular vesicles: biology and emerging therapeutic opportunities , 2013, Nature Reviews Drug Discovery.

[48]  Dong Soo Lee,et al.  Illuminating the physiology of extracellular vesicles , 2016, Stem Cell Research & Therapy.

[49]  S. Sidhu,et al.  Papillary thyroid cancer-derived exosomes contain miRNA-146b and miRNA-222. , 2015, The Journal of surgical research.

[50]  Stromal-cell and cancer-cell exosomes leading the metastatic exodus for the promised niche , 2013, Breast Cancer Research.

[51]  Graça Raposo,et al.  Exosomes--vesicular carriers for intercellular communication. , 2009, Current opinion in cell biology.

[52]  Byeong-Cheol Ahn,et al.  Role of pulmonary macrophages in initiation of lung metastasis in anaplastic thyroid cancer , 2016, International journal of cancer.

[53]  Jacco van Rheenen,et al.  In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior , 2015, Cell.

[54]  Hamid Cheshmi Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[55]  M. V. Filatov,et al.  Exosomes are natural carriers of exogenous siRNA to human cells in vitro , 2013, Cell Communication and Signaling.

[56]  Miguel C. Seabra,et al.  Rab27a and Rab27b control different steps of the exosome secretion pathway , 2010, Nature Cell Biology.

[57]  Y. Cho,et al.  Autologous Adipose Tissue-Derived Stem Cells for the Treatment of Crohn's Fistula: A Phase I Clinical Study , 2013, Cell transplantation.

[58]  W. Westbroek,et al.  Exosomes Released from Breast Cancer Carcinomas Stimulate Cell Movement , 2015, PloS one.

[59]  G. Camussi,et al.  Paracrine/endocrine mechanism of stem cells on kidney repair: role of microvesicle-mediated transfer of genetic information , 2010, Current opinion in nephrology and hypertension.

[60]  Mehmet Fatih Bolukbasi,et al.  Genetically Engineered Microvesicles Carrying Suicide mRNA/Protein Inhibit Schwannoma Tumor Growth , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[61]  Olivier Lantz,et al.  Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial , 2005, Journal of Translational Medicine.

[62]  Reint K Jellema,et al.  Mesenchymal Stromal Cell‐Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia‐Ischemia , 2016, Stem cells translational medicine.

[63]  J Ratajczak,et al.  Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication , 2006, Leukemia.

[64]  P. Quesenberry,et al.  Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging , 2014, International journal of molecular medicine.

[65]  Maria Ericsson,et al.  Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. , 2014, ACS nano.

[66]  G. Camussi,et al.  Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. , 2011, Cancer research.

[67]  Petra Schwille,et al.  Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes , 2008, Science.

[68]  Suresh Mathivanan,et al.  ExoCarta 2012: database of exosomal proteins, RNA and lipids , 2011, Nucleic Acids Res..

[69]  Lynda Chin,et al.  Identification of Double-stranded Genomic DNA Spanning All Chromosomes with Mutated KRAS and p53 DNA in the Serum Exosomes of Patients with Pancreatic Cancer* , 2014, The Journal of Biological Chemistry.

[70]  Tae-Young Roh,et al.  Egr-1 Activation by Cancer-Derived Extracellular Vesicles Promotes Endothelial Cell Migration via ERK1/2 and JNK Signaling Pathways , 2014, PloS one.

[71]  T. Whiteside Exosomes and tumor-mediated immune suppression. , 2016, The Journal of clinical investigation.

[72]  Per Sunnerhagen,et al.  Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes , 2012, Nucleic acids research.

[73]  Sascha Keller,et al.  Exosomes: from biogenesis and secretion to biological function. , 2006, Immunology letters.

[74]  Henrik J Johansson,et al.  Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties. , 2015, Nanomedicine : nanotechnology, biology, and medicine.

[75]  Byeong-Cheol Ahn,et al.  Advances in Molecular Imaging Strategies for In Vivo Tracking of Immune Cells , 2016, BioMed research international.

[76]  L. Pulliam,et al.  Human plasma platelet‐derived exosomes: effects of aspirin , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[77]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[78]  Michael Chopp,et al.  Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. , 2013, Cancer letters.

[79]  T. Rasmussen,et al.  Exosomal Proteins as Diagnostic Biomarkers in Lung Cancer , 2016, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[80]  L. O’Driscoll,et al.  Biological properties of extracellular vesicles and their physiological functions , 2015, Journal of extracellular vesicles.

[81]  Francois Lassailly,et al.  "Microenvironmental contaminations" induced by fluorescent lipophilic dyes used for noninvasive in vitro and in vivo cell tracking. , 2010, Blood.

[82]  M. Mittelbrunn,et al.  Editorial: Novel Clinical Applications of Extracellular Vesicles , 2015, Front. Immunol..

[83]  Gema Moreno-Bueno,et al.  Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET , 2012, Nature Medicine.

[84]  G. Camussi,et al.  Human Liver Stem Cell-Derived Microvesicles Inhibit Hepatoma Growth in SCID Mice by Delivering Antitumor MicroRNAs , 2012, Stem cells.

[85]  C. Emiliani,et al.  Signaling Pathways in Exosomes Biogenesis, Secretion and Fate , 2013, Genes.

[86]  M. Goumans,et al.  Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. , 2011, Stem cell research.

[87]  M. Ratajczak,et al.  Exosomes: an overview of biogenesis, composition and role in ovarian cancer , 2014, Journal of Ovarian Research.

[88]  Dongmei Sun,et al.  A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[89]  Pieter Vader,et al.  Extracellular vesicles: emerging targets for cancer therapy. , 2014, Trends in molecular medicine.

[90]  In‐San Kim,et al.  Identification of Developmental Endothelial Locus-1 on Circulating Extracellular Vesicles as a Novel Biomarker for Early Breast Cancer Detection , 2015, Clinical Cancer Research.

[91]  P. Fraker,et al.  PROTEIN AND CELL MEMBRANE IODINATION WITH A SPARINGLY SOLUBLE CHLOROAMIDE , 1978 .

[92]  Cristina Martelli,et al.  In vivo imaging of immune cell trafficking in cancer , 2011, European Journal of Nuclear Medicine and Molecular Imaging.

[93]  D. García-Olmo,et al.  Expanded Adipose-Derived Stem Cells for the Treatment of Complex Perianal Fistula: a Phase II Clinical Trial , 2009, Diseases of the colon and rectum.

[94]  S. Wickline,et al.  Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. , 2011, Cancer research.

[95]  Seena K. Ajit,et al.  Modulation of Immune Responses by Exosomes Derived from Antigen-Presenting Cells , 2016, Clinical medicine insights. Pathology.

[96]  Imre Mäger,et al.  Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting , 2015, Journal of extracellular vesicles.