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.
Bibliographical noteFunding Information:
The authors acknowledge the financial assistance provided by the Alzheimer's Association grant NIRG-09-133017 (KKK), RCMI 5G12MD007582-30 and NIH P20 MD006738 , and the Minnesota Partnership for Biotechnology and Medical Genomics (KKK/JFP). The sponsor had no role in the study design, collection, data analysis and data interpretation, and played no role in the decision to submit this paper for publication. The authors would like to thank James Ahlschwede for his assistance in designing the graphical abstract.
- Alzheimer's disease
- Amyloid beta protein
- Blood brain barrier
- Cerebrovascular amyloid angiopathy
- Cerebrovascular inflammation
- Theranostic nanoparticles