Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits

Edward K. Agyare, Kristen M. Jaruszewski, Geoffry L. Curran, Jens T. Rosenberg, Samuel C. Grant, Val Lowe, Subramanian Ramakrishnan, Anant K. Paravastu, Joseph F. Poduslo, Karunya K. Kandimalla

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)121-129
Number of pages9
JournalJournal of Controlled Release
Volume185
Issue number1
DOIs
StatePublished - Jul 10 2014

Fingerprint

Amyloid Plaques
Cerebral Amyloid Angiopathy
Amyloid
Cyclophosphamide
Gadolinium DTPA
Magnetic Resonance Imaging
Chitosan
Inflammation
Theranostic Nanomedicine
Serum Amyloid A Protein
Putrescine
Amyloid beta-Peptides
Immunosuppressive Agents
Single-Photon Emission-Computed Tomography
Blood-Brain Barrier
Nanoparticles
Contrast Media
Endothelium
Blood Vessels
Anti-Idiotypic Antibodies

Keywords

  • Alzheimer's disease
  • Amyloid beta protein
  • Blood brain barrier
  • Cerebrovascular amyloid angiopathy
  • Cerebrovascular inflammation
  • Theranostic nanoparticles

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Medicine(all)

Cite this

Agyare, E. K., Jaruszewski, K. M., Curran, G. L., Rosenberg, J. T., Grant, S. C., Lowe, V., ... Kandimalla, K. K. (2014). Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits. Journal of Controlled Release, 185(1), 121-129. https://doi.org/10.1016/j.jconrel.2014.04.010

Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits. / Agyare, Edward K.; Jaruszewski, Kristen M.; Curran, Geoffry L.; Rosenberg, Jens T.; Grant, Samuel C.; Lowe, Val; Ramakrishnan, Subramanian; Paravastu, Anant K.; Poduslo, Joseph F.; Kandimalla, Karunya K.

In: Journal of Controlled Release, Vol. 185, No. 1, 10.07.2014, p. 121-129.

Research output: Contribution to journalArticle

Agyare, EK, Jaruszewski, KM, Curran, GL, Rosenberg, JT, Grant, SC, Lowe, V, Ramakrishnan, S, Paravastu, AK, Poduslo, JF & Kandimalla, KK 2014, 'Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits', Journal of Controlled Release, vol. 185, no. 1, pp. 121-129. https://doi.org/10.1016/j.jconrel.2014.04.010
Agyare, Edward K. ; Jaruszewski, Kristen M. ; Curran, Geoffry L. ; Rosenberg, Jens T. ; Grant, Samuel C. ; Lowe, Val ; Ramakrishnan, Subramanian ; Paravastu, Anant K. ; Poduslo, Joseph F. ; Kandimalla, Karunya K. / Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits. In: Journal of Controlled Release. 2014 ; Vol. 185, No. 1. pp. 121-129.
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