title: Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits.
abstract: Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid beta (Aβ) proteins within the walls of the cerebral vasculature with subsequent aggressive vascular inflammation leading to recurrent hemorrhagic strokes. The objective of the study was to develop theranostic nanovehicles (TNVs) capable of a) targeting cerebrovascular amyloid; b) providing magnetic resonance imaging (MRI) contrast for the early detection of CAA; and c) treating cerebrovascular inflammation resulting from CAA. The TNVs comprised of a polymeric nanocore made from Magnevist (MRI contrast agent) conjugated chitosan. The nanocore was also loaded with cyclophosphamide (CYC), an immunosuppressant shown to reduce the cerebrovascular inflammation in CAA. Putrescine modified F(ab')2 fragment of anti-amyloid antibody, IgG4.1 (pF(ab')24.1) was conjugated to the surface of the nanocore to target cerebrovascular amyloid. The average size of the control chitosan nanoparticles (conjugated with albumin and are devoid of Magnevist, CYC, and pF(ab')24.1) was 164±1.2 nm and that of the TNVs was 239±4.1 nm. The zeta potential values of the CCNs and TNVs were 21.6±1.7 mV and 11.9±0.5 mV, respectively. The leakage of Magnevist from the TNVs was a modest 0.2% over 4 days, and the CYC release from the TNVs followed Higuchi's model that describes sustained drug release from polymeric matrices. The studies conducted in polarized human microvascular endothelial cell monolayers (hCMEC/D3) in vitro as well as in mice in vivo have demonstrated the ability of TNVs to target cerebrovascular amyloid. In addition, the TNVs provided contrast for imaging cerebrovascular amyloid using MRI and single photon emission computed tomography. Moreover, the TNVs were shown to reduce pro-inflammatory cytokine production by the Aβ challenged blood brain barrier (BBB) endothelium more effectively than the cyclophosphamide alone.
authors.affiliation: Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1520 S. MLK BLVD, Tallahassee 32307, USA.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Agyare
authors.affiliation: Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota, 308 Harvard St. SE, Room 9-149A WDH, Minneapolis 55455, USA; Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience, and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester 55905, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Jaruszewski
authors.affiliation: Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience, and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester 55905, USA.
authors.forename: Geoffry L
authors.initials: GL
authors.lastname: Curran
authors.affiliation: The Florida State University and National High Magnetic Field Laboratory, 1800 East Paul Dirac Drive, Tallahassee 32310, USA.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Rosenberg
authors.affiliation: The Florida State University and National High Magnetic Field Laboratory, 1800 East Paul Dirac Drive, Tallahassee 32310, USA; Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University College of Engineering, 2525 Pottsdamer Street, Tallahassee 32310, USA.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Grant
authors.affiliation: Nuclear Medicine, Department of Radiology, Mayo Clinic, 200 1st Street SW, Rochester 55905, USA.
authors.forename: Val J
authors.initials: VJ
authors.lastname: Lowe
authors.affiliation: Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University College of Engineering, 2525 Pottsdamer Street, Tallahassee 32310, USA.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: The Florida State University and National High Magnetic Field Laboratory, 1800 East Paul Dirac Drive, Tallahassee 32310, USA; Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University College of Engineering, 2525 Pottsdamer Street, Tallahassee 32310, USA.
authors.forename: Anant K
authors.initials: AK
authors.lastname: Paravastu
authors.affiliation: Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience, and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester 55905, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Poduslo
authors.affiliation: Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota, 308 Harvard St. SE, Room 9-149A WDH, Minneapolis 55455, USA; Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience, and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester 55905, USA. Electronic address: kkandima@umn.edu.
authors.forename: Karunya K
authors.initials: KK
authors.lastname: Kandimalla
mesh_terms: D016229:Amyloid beta-Peptides; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D016657:Cerebral Amyloid Angiopathy / Q000175:diagnosis* / Q000628:therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005682:Gadolinium / Q000008:administration & dosage; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007249:Inflammation / Q000175:diagnosis / Q000628:therapy; D008279:Magnetic Resonance Imaging; D051379:Mice; D053758:Nanoparticles / Q000378:metabolism / Q000627:therapeutic use*; D049329:Nanostructures / Q000627:therapeutic use*; D058225:Plaque, Amyloid / Q000473:pathology*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D016229:Amyloid beta-Peptides; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D005682:Gadolinium
keywords: Alzheimer's disease; Amyloid beta protein; Blood brain barrier; Cerebrovascular amyloid angiopathy; Cerebrovascular inflammation; Theranostic nanoparticles
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