Multifunctional receptor-targeted nanocomplexes for magnetic resonance imaging and transfection of tumours

Abstract

The efficient targeted delivery of nucleic acids in vivo provides some of the greatest challenges to the development of genetic therapies. We aim to develop nanocomplex formulations that achieve targeted transfection of neuroblastoma tumours that can be monitored simultaneously by MRI. Here, we have compared nanocomplexes comprising self-assembling mixtures of liposomes, plasmid DNA and one of three different peptide ligands derived from ApoE, neurotensin and tetanus toxin for targeted transfection in vitro and in vivo. Neurotensin-targeted nanocomplexes produced the highest levels of transfection and showed a 4.7-fold increase in transfected luciferase expression over non-targeted nanocomplexes in Neuro-2A cells. Transfection of subcutaneous Neuro-2A tumours in vivo with neurotensin-targeted nanocomplexes produced a 9.3-fold increase in gene expression over non-targeted controls. Confocal microscopy analysis elucidated the time course of DNA delivery with fluorescently labelled nanocomplex formulations in cells. It was confirmed that addition of a gadolinium lipid conjugate contrast agent allowed real time in vivo monitoring of nanocomplex localisation in tumours by MRI, which was maintained for at least 24 h. The peptide-targeted nanocomplexes developed here allow for the specific enhancement of targeted gene therapy both in vitro and in vivo, whilst allowing real time monitoring of delivery with MRI.

Peptide and nucleic acid-directed self-assembly of cationic nanovehicles through giant unilamellar vesicle modification: Targetable nanocomplexes for in vivo nucleic acid delivery

“…Previously, we described the use of liposome-peptide receptor-targeted nanoparticles (RTNs) for both in vitro [7][8][9][10][11] and in vivo [12][13][14][15][16][17][18] nucleic acid delivery to various sites and targets in the body. These lipopolyplexes are capable of inducing nucleic acid compaction and their protection against premature degradation in biological fluids.…”

Lipid Nanoparticles for Gene Delivery

“…Jiang et al used C14–200 lipidoids and DSPC to coat iron oxide nanoparticles in N-methyl-2- pyrrolidone solvent and showed efficient DNA and siRNA delivery upon the application of an external magnetic field, with performance exceeding that of Lipofectamine 2000 (Jiang et al, 2013). Kenny et al developed an MRI-visible gene delivery nanocomplex system comprised of self-assembling mixtures of liposomes, plasmid DNA, and targeting ligands, which specifically enhanced transfection efficiency and allowed real-time in vivo monitoring of the specific tumor tissue (Kenny et al, 2012). In another study, Writer et al prepared lipid peptide nanocomplexes with Gadolinium-chelated lipid, DNA-binding peptide, and plasmid DNA (Writer et al, 2012).…”

Development of Magnetic Nanoparticles for Cancer Gene Therapy: A Comprehensive Review

“…In the development of a gene-carrier platform, some strategies for polymers feasible for gene therapy require modification with targeting moieties. Moieties such as antibody [113][114][115], peptides [116][117][118], aptamers, and ligands [119] endow nanosystems with tumor specificity. Apart from the EPR phenomenon and magnetic field application in the case of magnetic nanocarriers, modification with targeting moieties consequently increases nanocarrier concentration in tumor tissue and thus the in vivo efficiency of gene therapy.…”