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Cited by 72Nanoparticle-Based Drug DeliveryIntracerebral and Subarachnoid Hemorrhage ResearchAdvanced Drug Delivery Systems

Engineering Theranostic Nanovehicles Capable of Targeting Cerebrovascular Amyloid Deposits

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Agyare, Edward K., Jaruszewski, Kristen M., Curran, Geoffry L., Rosenberg, Jens T., Grant, Samuel C., Lowe, Val J., Ramakrishnan, Subramanian, Paravastu, Anant K. +2 more·2014·Journal of Controlled Release
DOI 10.1016/j.jconrel.2014.04.010PMC PMC9039981
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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.

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  • The most common targeting approach is conjugation of Nps with antibodies or their fragments specific to various forms of Aβ.

    “The most common approach is the conjugation of Nps with antibodies or their fragments specific to various forms of Aβ [63,70,71,81].”

    From Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions (2026) · cites this paper as [70]

    The Materials and Methods (Preparation of TNVs; page not supplied) describe conjugating an anti-amyloid antibody fragment to a nanocore, so this paper provides an example of the approach. It does not establish that the approach is the most common or address targeting various forms of Aβ. (LLM, conf=0.85)

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  • Oxidative stress and neuroinflammation rank as key secondary targets (10 studies), with Nps incorporating antioxidants or immunosuppressants.

    “Oxidative stress and neuroinflammation rank as key secondary targets (10 studies), with Nps incorporating antioxidants (CeNCs, tannic acid, curcumin, quercetin) or immunosuppressants (dexamethasone, cyclophosphamide) to prevent neuronal death and attenuate inflammation [58,70,71,78].”

    From Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions (2026) · cites this paper as [70]

    The Results section reports cyclophosphamide-loaded nanovehicles and reduced pro-inflammatory cytokine release in amyloid-challenged endothelial cells, supporting the immunosuppressant and inflammation portion. This paper does not establish an antioxidant effect or prevention of neuronal death; the “10 studies” count is not a finding of this study. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • A number of studies employ multimodal approaches, combining MRI with PET, SPECT, or fluorescence imaging, which compensates for the limitations of each method individually.

    “A number of studies employ multimodal approaches, combining MRI with PET [64], SPECT [70,71], or fluorescence imaging [72,75], which compensates for the limitations of each method individually.”

    From Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions (2026) · cites this paper as [70]

  • A significant portion of studies use MRI with contrast agents based on gadolinium, SPIONs, or manganese ions, reflecting the researchers' desire to create platforms potentially applicable in clinical practice.

    “A significant portion of the studies use MRI with contrast agents based on gadolinium [70,71], SPIONs [58,63,73,83], or manganese ions [72], reflecting the researchers’ desire to create platforms potentially applicable in clinical practice.”

    From Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions (2026) · cites this paper as [70]

  • Many studies include an antioxidant component aimed at reducing ROS and an anti-inflammatory effect via delivery of immunosuppressants.

    “Many studies also include an antioxidant component aimed at reducing the level of ROS [64,72,78,80,83], and an anti-inflammatory effect, implemented through the delivery of immunosuppressants [70,71].”

    From Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions (2026) · cites this paper as [70]

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Authors
Agyare, E. K., Jaruszewski, K. M., Curran, G. L., Rosenberg, J. T., Grant, S. C., Lowe, V. J., Ramakrishnan, S., Paravastu, A. K., Poduslo, J. F., & Kandimalla, K. K.
Affiliations
  • Florida Agricultural and Mechanical University (US)
  • Mayo Clinic (US)
  • Florida State University (US)
  • Florida A&M University - Florida State University College of Engineering (US)
  • University of Minnesota (US)
Corresponding author
Kandimalla, Karunya K.
ORCID
Venue
Journal of Controlled Release
Publisher
Elsevier BV
Published
2014-07
Volume
185
Pages
121-129
ISSN
0168-3659 (ISSN-L)
DOI
10.1016/j.jconrel.2014.04.010
PMC
PMC9039981
OpenAlex
W2020622005
Cited by
71
References
31
Citations by year
2026: 1 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 11 · 2020: 9 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 7 · 2015: 5 · 2014: 3
FWCI
3.03
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Controlled Release (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Minority Health and Health Disparities (P20MD006738, G12MD007582)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords
cerebral amyloid angiopathy, amyloid-beta, chitosan nanoparticles, Gd-DTPA, MRI contrast agents, cyclophosphamide, anti-amyloid antibodies, F(ab')2 fragments, blood-brain barrier, cerebrovascular inflammation, hemorrhagic stroke, drug delivery, sustained drug release, inflammatory cytokines
MeSH terms
Animals, Blood-Brain Barrier, Cell Line, Cyclophosphamide, Gadolinium, Humans, Immunosuppressive Agents, Inflammation, Magnetic Resonance Imaging, Tomography, Emission-Computed, Single-Photon, Amyloid beta-Peptides, Drug Delivery Systems, Cerebral Amyloid Angiopathy, Nanostructures, Mice, Nanoparticles, Plaque, Amyloid

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