Targeted nonviral delivery vehicles to neural progenitor cells in the mouse subventricular zone

Abstract

Targeted gene therapy can potentially minimize undesirable off-target toxicity due to specific delivery. Neuron-specific gene delivery in the central nervous system is challenging because neurons are non-dividing and also outnumbered by glial cells. One approach is to transfect dividing neural stem and progenitor cells (NSCs and NPCs, respectively). In this work, we demonstrate cell-specific gene delivery to NPCs in the brains of adult mice using a peptide-modified polymeric vector. Tet1, a 12-amino acid peptide which has been shown to bind specifically to neuronal cells, was utilized as a neuronal targeting ligand. The cationic polymer polyethylenimine (PEI) was covalently modified with polyethylene glycol (PEG) for in vivo salt stability and Tet1 for neuron targeting to yield a Tet1-PEG-PEI conjugate. When plasmid DNA encoding the reporter gene luciferase was complexed with Tet1-PEG-PEI and delivered in vivo via an injection into the lateral ventricle, Tet1-PEG-PEI complexes mediated increased luciferase expression levels in brain tissue when compared to unmodified PEI-PEG complexes. In addition, cells transfected by Tet1-PEG-PEI complexes were found to be exclusively adult NPCs whereas untargeted PEG-PEI complexes were found to transfect a heterogenous population of cells. Thus, we have demonstrated targeted, nonviral delivery of nucleic acids to adult NPCs using the Tet1 targeting ligand. These materials could potentially be used to deliver therapeutic genes for the treatment of neurodegenerative diseases.

Targeted delivery of Tet1 peptide functionalized polymersomes to the rat cochlear nerve

“…17,18 In addition, gene expression in the lateral ventricle was reported after administration of Tet1-PEG-b-polyethylenimine containing plasmid DNA. 6 This indicated that the PMs might release their cargos in the distal axon compartment, which could then penetrate separately into the cell body compartment of the neuron. Thus, Tet1-PMs could target the neurofilament of the CN; however, whether they effectively release their cargo into the cytoplasm needs further investigation.…”

“…Modification of nanoparticles with the Tet1 peptide has resulted in improved targeted gene delivery to neurons both in vitro and in vivo. 6,7 We hypothesized that SGCs or CN targeted drug delivery could be achieved by using PEG-b-PCL PMs functionalized with the Tet1 peptide. In our previous study, unlabelled PMs that were delivered onto the round window membrane (RWM) did not appear in SGCs and spiral ganglion satellite cells.…”

A dual brain-targeting curcumin-loaded polymersomes ameliorated cognitive dysfunction in intrahippocampal amyloid-β_1–42-injected mice

“…17 The phage display test revealed that a 12-amino acid peptide, Tet-1, possesses a high affinity for GT1B receptor. 18,19 When plasmid DNA encoding luciferase was condensed with Tet1-polyethylene glycol (PEG)-polyethyleneimine and delivered via intracerebroventricular injection to mice, the GT1B-positive stain of transfected nerve cells was observed after delivery of Tet1-mediated vector (58%) as compared to untargeted vector (13%). 18 In most studies, two ligands modified the nanoparticles were used for cancer therapy; these ligands identified the receptors on the tumor cells so as to achieve a sequential targeting action.…”

“…18,19 When plasmid DNA encoding luciferase was condensed with Tet1-polyethylene glycol (PEG)-polyethyleneimine and delivered via intracerebroventricular injection to mice, the GT1B-positive stain of transfected nerve cells was observed after delivery of Tet1-mediated vector (58%) as compared to untargeted vector (13%). 18 In most studies, two ligands modified the nanoparticles were used for cancer therapy; these ligands identified the receptors on the tumor cells so as to achieve a sequential targeting action. Bhattacharyya et al 20 developed a gold nanoparticle functionalized by EGF receptor and folate antibody for the treatment of ovarian cancer in which the cancer cells expressed EGF receptor and folate receptor.…”

Acceleration of gene transfection efficiency in neuroblastoma cells through polyethyleneimine/poly(methyl methacrylate) core-shell magnetic nanoparticles

“…16 Modified transfection reagents, ie, PEI-PEG and Tet1 complexes, demonstrated increased luciferase expression levels in neural progenitor cells compared with unmodified PEI-PEG complexes. 17 In this study, we investigated the use of novel synthesized magnetic nanoparticles for gene delivery in neuronal cells. Magnetic PEI/poly(methyl methacrylate) (PMMA) core-shell (mag-PEI) nanoparticles were prepared using ultrasonicationassisted emulsifier-free emulsion polymerization.…”