Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits

JOURNAL OF CONTROLLED RELEASE

卷:185

Article

Agyare, Edward K.⁶  Jaruszewski, Kristen M.^1,2,3,4,5  Curran, Geoffry L.^3,4,5  Rosenberg, Jens T.^7,8  Grant, Samuel C.^7,8,9  Lowe, Val J.¹⁰  Ramakrishnan, Subramanian⁹  Paravastu, Anant K.^7,8,9  Poduslo, Joseph F.^3,4,5  Kandimalla, Karunya K.^1,2,3,4,5 

[1] Univ Minnesota, Dept Pharmaceut, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Brain Barriers Res Ctr, Minneapolis, MN 55455 USA

[3] Mayo Clin, Coll Med, Mol Neurobiol Lab, Dept Neurol, Rochester, MN 55905 USA

[4] Mayo Clin, Coll Med, Mol Neurobiol Lab, Dept Neurosci, Rochester, MN 55905 USA

[5] Mayo Clin, Coll Med, Mol Neurobiol Lab, Dept Biochem Mol Biol, Rochester, MN 55905 USA

[6] Florida A&M Univ, Coll Pharm & Pharmaceut Sci, Div Basic Pharmaceut Sci, Tallahassee, FL 32307 USA

[7] Florida State Univ, Tallahassee, FL 32310 USA

[8] Natl High Magnet Field Lab, Tallahassee, FL 32310 USA

[9] Florida State Univ, Florida A&M Univ, Coll Engn, Dept Chem & Biomed Engn, Tallahassee, FL 32310 USA

[10] Mayo Clin, Dept Radiol, Rochester, MN 55905 USA

关键词: Amyloid beta protein;    Alzheimer's disease;    Cerebrovascular amyloid angiopathy;    Theranostic nanoparticles;    Blood brain barrier;    Cerebrovascular inflammation;   

DOI  :  10.1016/j.jconrel.2014.04.010

来源: Elsevier

【 摘 要 】

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid beta (A beta) 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 (R) (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')(2)4.1) 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 (R), CYC, and pF(ab')(2)4.1) 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 (R) 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 A beta challenged blood brain barrier (BBB) endothelium more effectively than the cyclophosphamide alone. (C) 2014 Elsevier B.V. All rights reserved.

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