Systemically Administered Brain-Targeted Nanoparticles Transport Peptides across the Blood—Brain Barrier and Provide Neuroprotection

Abstract

Although growth factors and anti-apoptotic peptides have been shown to be neuroprotective in stroke models, translation of these experimental findings to clinic is hampered by limited penetration of peptides to the brain. Here, we show that a large peptide like the basic fibroblast growth factor (bFGF) and a small peptide inhibitor of caspase-3 (z-DEVD-FMK) can effectively be transported to the brain after systemic administration by incorporating these peptides to brain-targeted nanoparticles (NPs). Chitosan NPs were loaded with peptides and then functionalized by conjugating with antibodies directed against the transferrin receptor-1 on brain endothelia to induce receptor-mediated transcytosis across the blood-brain barrier (BBB). Pre-ischemic systemic administration of bFGF- or z-DEVD-FMK-loaded NPs significantly decreased the infarct volume after 2-hour middle cerebral artery occlusion and 22-hour reperfusion in mice. Co-administration of bFGF- or z-DEVD-FMK-loaded NPs reduced the infarct volume further and provided a 3-hour therapeutic window. bFGF-loaded NPs were histologically detected in the brain parenchyma and also restored ischemia-induced Akt dephosphorylation. The neuroprotection was not observed when receptor-mediated transcytosis was inhibited with imatinib or when bFGF-loaded NPs were not conjugated with the targeting antibody, which enables them to cross the BBB. Nanoparticles targeted to brain are promising drug carriers to transport large as well as small BBB-impermeable therapeutics for neuroprotection against stroke.

Cerium oxide nanoparticles promote neurogenesis and abrogate hypoxia-induced memory impairment through AMPK–PKC–CBP signaling cascade

“…Unfortunately, the conventional neuroprotective drugs find limited clinical applications due to limited brain penetration. With the advantages of brain targeting without blood-brain barrier (BBB) disruption 40 and specific coatings for long retention in brain, 25,26,30 nanoparticles are emerging as promising antioxidants as well as drug carriers for neuronal diseases. Using PEG-coated CNPs that are uniform with a size of 3 nm, Kim et al 6,25 have reported protection against ischemic stroke by reducing ROS and apoptosis.…”

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

“…For example, the large neutral amino acid CMT transporter delivers L-3,4-dihydroxyphenylalanine (L-DOPA) to the brain in PD 240 , and the transferrin RMT can deliver therapeutic antibodies to the brain in various neurological conditions 4,241–243 . Other approaches, such as using nanoparticles 244 and/or opening the BBB by focused ultrasound 245,246 to improve the delivery of therapeutic agents to CNS, have been attempted.…”

The role of growth factors as a therapeutic approach to demyelinating disease

“…In a recent report, nanoparticles were conjugated with antibodies directed against transferrin receptor-1, a peptide endogenously expressed on brain endothelial cells. When the nanoparticles were injected to an animal exposed to a stroke model, receptor mediated transcytosis occurs across the blood barrier and FGF-2 is able to enter the brain, resulting in reduction in the size of the injury (Yemisci et al 2015). Additional approaches, such as using glucose transporters (Bonina et al 2003, Patching 2016) or gene therapy with AAV9 (Dayton et al 2012), are also seeking to develop systemic gene delivery strategies to bypass the barrier.…”