title: In vivo theranostics at the peri-infarct region in cerebral ischemia.
abstract: The use of theranostics in neurosciences has been rare to date because of the limitations imposed on the free delivery of substances to the brain by the blood-brain barrier. Here we report the development of a theranostic system for the treatment of stroke, a leading cause of death and disability in developed countries. We first performed a series of proteomic, immunoblotting and immunohistological studies to characterize the expression of molecular biomarkers for the so-called peri-infarct tissue, a key region of the brain for stroke treatment. We confirmed that the HSP72 protein is a suitable biomarker for the peri-infarct region, as it is selectively expressed by at-risk tissue for up to 7 days following cerebral ischemia. We also describe the development of anti-HSP72 vectorized stealth immunoliposomes containing imaging probes to make them traceable by conventional imaging techniques (fluorescence and MRI) that were used to encapsulate a therapeutic agent (citicoline) for the treatment of cerebral ischemia. We tested the molecular recognition capabilities of these nano-platforms in vitro together with their diagnostic and therapeutic properties in vivo, in an animal model of cerebral ischemia. Using MRI, we found that 80% of vectorized liposomes were located on the periphery of the ischemic lesion, and animals treated with citicoline encapsulated on these liposomes presented lesion volumes up to 30% smaller than animals treated with free (non-encapsulated) drugs. Our results show the potential of nanotechnology for the development of effective tools for the treatment of neurological diseases.
authors.affiliation: 1. Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, E-15706 Santiago de Compostela, Spain. ; 2. Research Unit, University Hospital of Salamanca and Institute of Health Sciences of Castilla and Leon, E-37007 Salamanca, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Agulla
authors.affiliation: 1. Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, E-15706 Santiago de Compostela, Spain. ; 3. Cellular and Molecular Neurobiology Research Group and Grup de Recerça en Neurociencies del IGTP, Department of Neurosciences, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias I Pujol-Universitat Autónoma de Barcelona, E-08916 Badalona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Brea
authors.affiliation: 1. Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, E-15706 Santiago de Compostela, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Campos
authors.affiliation: 1. Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, E-15706 Santiago de Compostela, Spain.
authors.forename: Tomás
authors.initials: T
authors.lastname: Sobrino
authors.affiliation: 1. Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, E-15706 Santiago de Compostela, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Argibay
authors.affiliation: 4. Single Molecule Fluorescence Research Unit, Department of Physical Chemistry, Faculty of Science, University of Santiago de Compostela, E-27002 Lugo, Spain.
authors.forename: Wajih
authors.initials: W
authors.lastname: Al-Soufi
authors.affiliation: 1. Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, E-15706 Santiago de Compostela, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Blanco
authors.affiliation: 1. Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, E-15706 Santiago de Compostela, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Castillo
authors.affiliation: 1. Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, E-15706 Santiago de Compostela, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Ramos-Cabrer
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003566:Cytidine Diphosphate Choline / Q000493:pharmacokinetics / Q000627:therapeutic use; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D008081:Liposomes / Q000493:pharmacokinetics / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D053769:Nanocapsules / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D061848:Optical Imaging / Q000379:methods; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; D050884:HSP72 Heat-Shock Proteins; D008081:Liposomes; D053769:Nanocapsules; D018697:Nootropic Agents; D020543:Proteome; D003566:Cytidine Diphosphate Choline
keywords: Drug delivery.; MRI; Theranostics; cerebral ischemia; peri-infarct region