1. Signature Effects of Vector-Guided Systemic Nano Bioconjugate Delivery Across Blood-Brain Barrier of Normal, Alzheimer's, and Tumor Mouse Models
- Author
-
Liron L. Israel, Anna Galstyan, Alysia Cox, Ekaterina S. Shatalova, Tao Sun, Mohammad-Harun Rashid, Zachary Grodzinski, Antonella Chiechi, Dieu-Trang Fuchs, Rameshwar Patil, Maya Koronyo-Hamaoui, Keith L. Black, Julia Y. Ljubimova, and Eggehard Holler
- Subjects
Mice ,Amyloid beta-Peptides ,Blood-Brain Barrier ,Alzheimer Disease ,Polymers ,General Engineering ,General Physics and Astronomy ,Animals ,General Materials Science ,Nanoconjugates ,Transcytosis ,Peptides - Abstract
The ability to cross the blood-brain barrier (BBB) is critical for targeted therapy of the central nerve system (CNS). Six peptide vectors were covalently attached to a 50 kDa poly(β-l-malic acid)-trileucine polymer forming P/LLL(40%)/vector conjugates. The vectors were Angiopep-2 (AP2), B6, Miniap-4 (M4), and d-configurated peptides D1, D3, and ACI-89, with specificity for transcytosis receptors low-density lipoprotein receptor-related protein-1 (LRP-1), transferrin receptor (TfR), bee venom-derived ion channel, and Aβ/LRP-1 related transcytosis complex, respectively. The BBB-permeation efficacies were substantially increased ("boosted") in vector conjugates of P/LLL(40%). We have found that the copolymer group binds at the endothelial membrane and, by an allosterically membrane rearrangement, exposes the sites for vector-receptor complex formation. The specificity of vectors is indicated by competition experiments with nonconjugated vectors. P/LLL(40%) does not function as an inhibitor, suggesting that the copolymer binding site is eliminated after binding of the vector-nanoconjugate. The two-step mechanism, binding to endothelial membrane and allosteric exposure of transcytosis receptors, is supposed to be an integral feature of nanoconjugate-transcytosis pathways.
- Published
- 2022