Shuttle‐Mediated Nanoparticle Delivery to the Blood–Brain Barrier

Abstract

Many therapeutic drugs are excluded from entering the brain due to their lack of transport through the blood-brain barrier (BBB). The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. To overcome this problem, a viral fusion peptide (gH625) derived from the glycoprotein gH of Herpes simplex virus type 1 is developed, which possesses several advantages including high cell translocation potency, absence of toxicity of the peptide itself, and the feasibility as an efficient carrier for delivering therapeutics. Therefore, it is hypothesized that brain delivery of nanoparticles conjugated with gH625 should be efficiently enhanced. The surface of fluorescent aminated polystyrene nanoparticles (NPs) is functionalized with gH625 via a covalent binding procedure, and the NP uptake mechanism and permeation across in vitro BBB models are studied. At early incubation times, the uptake of NPs with gH625 by brain endothelial cells is greater than that of the NPs without the peptide, and their intracellular motion is mainly characterized by a random walk behavior. Most importantly, gH625 peptide decreases NP intracellular accumulation as large aggregates and enhances the NP BBB crossing. In summary, these results establish that surface functionalization with gH625 may change NP fate by providing a good strategy for the design of promising carriers to deliver drugs across the BBB for the treatment of brain diseases.

Peptide gH625 enters into neuron and astrocyte cell lines and crosses the blood–brain barrier in rats

“…31,32 We have previously demonstrated that gH625, a 19-residue peptide, is a membrane-perturbing domain 13 that interacts with model membranes, contributing to their merging 13 and is able to traverse the membrane bilayer and transport a cargo (quantum dots, liposomes, and dendrimers) 16,18,20 into the cytoplasm and across an in vitro model of the BBB. 19 Uptake studies suggested a nonactive translocation mechanism in crossing the lipid bilayer, which may vary depending on the cargo. 15 Penetration by gH625 occurs in a rapid, concentration-dependent fashion that appears to be independent of receptors and transporters and instead is thought to target the lipid bilayer component of the cell membrane.…”

“…15 Further, gH625 has been used extensively for vector-mediated strategies that enable passage of a large variety of small molecules as well as proteins across cell membranes in vitro. [16][17][18][19][20] Conjugation of gH625 to the surface of nanoparticles also enhances their transport across the BBB, as previously demonstrated in an in vitro model of the BBB. 19 Whether or not multifunctional nanodevices, designed and tested in vitro, work properly in vivo in a mammalian host is still not fully understood.…”

“…[16][17][18][19][20] Conjugation of gH625 to the surface of nanoparticles also enhances their transport across the BBB, as previously demonstrated in an in vitro model of the BBB. 19 Whether or not multifunctional nanodevices, designed and tested in vitro, work properly in vivo in a mammalian host is still not fully understood. In vivo studies are necessary to address this issue, thus validating design strategies and facilitating optimization and further functionalization.…”

gH625 is a viral derived peptide for effective delivery of intrinsically disordered proteins

“…In addition, gH625 has been used to efficiently deliver quantum dots in cells, that do not significantly traverse the membrane bilayer on their own; 18 liposomes; 17 dendrimers; 1 or nanoparticles through the blood-brain barrier. 2 Therefore, gH625 can be considered a promising tool to efficiently perform intracellular delivery and may represent an alternative strategy to the use of the well characterized positively charged TAT peptide.…”

“…1,2,17,18 In particular, we recently reported the ability of gH625 peptide to transport quantum dots inside the cytoplasm in an efficient way and only partially involving endocytic pathways; 18 moreover, we reported its ability to enhance intracellular penetration of liposomes functionalized with the peptide on the external leaflet, 17 nanoparticles, 2 and dendrimers. 19 Compared with the TAT peptide, which mainly exploits the endocytic pathway, the viral membranotropic peptide gH625 crosses membrane bilayers mainly through a translocation mechanism.…”