Purpose. To design a smart nano-vehicle (SNV) capable of permeating the blood-brain barrier (BBB) to target cerebrovascular amyloid formed in both Alzheimer's disease (AD) and cerebrovascular amyloid angiopathy (CAA). Methods. SNV consists of a chitosan polymeric core prepared through ionic gelation with tripolyphosphate. A polyamine modified F(ab') portion of IgG4.1, an anti-amyloid antibody, was coated as a biosensor on the SNV surface. A similar polymeric core coated with bovine serum albumin (BSA) served as a control nano-vehicle (CNV). The BBB uptake of 125I-SNVs and 125I-CNVs was evaluated in mice. The uptake and transcytosis of SNVs and CNVs across bovine brain microvascular endothelial cells (BBMECs) was evaluated using flow cytometry and confocal microscopy. Results. Plasma clearance of 125I-SNVs was nine times higher than that of the 125I- CNVs. However, the uptake of 125I-SNVs in various brain regions was about 8 to 11 times higher than that of 125I-CNVs. The uptake of FITC-BSA loaded SNVs in BBMECs was twice the uptake of FITC-BSA loaded CNVs. Confocal micrographs demonstrated the uptake and transcytosis of Alexa Fluor 647 labeled SNVs, but not CNVs, across the BBMEC monolayer. Conclusions. SNVs are capable of carrying a payload of model protein across the BBB to target cerebral amyloid.
Bibliographical noteFunding Information:
This work was supported by grants from NIH/NIGMS/ MBRS 3S06GM008111-35S1—(Minority Biomedical Research Support); NIH/NCRR/RCMI G12RR03020—(Research centers in Minority Institutions) faculty development grant in drug delivery; the Neuroscience Cores for MR Studies of the Brain from NINDS (NS057091); NIH R01 AG22034; and the Minnesota Partnership for Biotechnology and Medical Genomics.
- Alzheimer's disease
- Blood brain barrier
- Brain delivery
- Cerebral amyloid angiopathy
- Chitosan nanoparticles