Dendrimer Functionalization with a Membrane‐Interacting Domain of Herpes Simplex Virus Type 1: Towards Intracellular Delivery

Abstract

A poly(amide)-based dendrimer was synthesized and functionalized with the membrane-interacting peptide gH(625-644) (gH625) derived from the herpes simplex virus type 1 (HSV-1) envelope glycoprotein H, which has previously been shown to assist in delivering large cargoes across the cellular membrane. We demonstrate that the attachment of the gH625 peptide sequence to the termini of a dendrimer allows the conjugate to penetrate into the cellular matrix, whereas the unfunctionalized dendrimer is excluded from translocation. The peptide-functionalized dendrimer is rapidly taken into the cells mainly through a non-active translocation mechanism. Our results suggest that the presented peptidodendrimeric scaffold may be a promising material for efficient drug delivery.

<em>Daphnia magna</em> and<em> Xenopus laevis</em> as in vivo models to probe toxicity and uptake of quantum dots functionalized with gH625

“…7,8 The coupling of cell-penetrating peptides to MNPs provides a good strategy for a substantial improvement of cellular uptake, enabling them to deliver a large variety of cargo molecules for therapy and diagnosis.…”

“…10,11 This peptide has proved to exhibit exceptional vector properties 9 and has been shown to be essentially internalized by a nonendocytic pathway avoiding endosomal entrapment. 7,[12][13][14][15][16][17] In recent studies, it was also shown to be able to cross the blood-brain barrier in vitro and in vivo. 18 gH625 is, therefore, a very good delivery vector 9 and its coupling to NPs may be exploited to change their internalization mechanism and in case of MNPs, to avoid or reduce their toxicity.…”

Peptide gH625 enters into neuron and astrocyte cell lines and crosses the blood&ndash;brain barrier in&nbsp;rats

“…The presence of advanced technologies for peptide identification and modification further supports the extensive application of peptides in the field of theranostics research. 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 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.…”

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

“…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.…”