Multifunctional nanocomplexes for gene transfer and gene therapy

Abstract

DNA formulated into aggregates with polycationic reagents are referred to by a variety of terms including non-viral vectors, synthetic vectors, lipoplexes, polyplexes and more recently nanoparticles. The capacity for delivery of multiple genes, genomic-sized constructs and siRNA delivery, with a diversity of possible formulations, as well as the possibilities of improved efficiency of in vivo gene deliveries, means that nanoparticles, or nanocomplexes to reflect self-assembling systems, will be investigated with increasing vigour in the coming years. This review briefly outlines the applications and challenges for nanoparticle technologies in the field of gene therapy then focuses on the development of a specific kind of formulation, receptor-targeted nanocomplex (RTN), that we have found to be particularly useful in our gene therapy research. An overriding guiding concept that has emerged in the development of synthetic nanodelivery systems is the idea to develop formulations and structures that mimic viruses, whilst retaining the safety elements of synthetic, non-viral systems. RTNs have been optimised and developed for airway epithelial transfection, leading towards gene therapy for cystic fibrosis and for vascular transfection in vein grafts used in bypass surgery. The modular design of the RTN platform further allows for the testing of specific hypotheses relating to the structure and functional role of components in the formation of stable particles and in the transfection pathway, leading to their ultimate disassembly in the nucleus.

Polymers in Small-Interfering RNA Delivery

“…The choice of polymers and the formulation should be such that the newly integrated attributes like better complexation and endosomal escape must not adversely affect the biocompatibility and stability of the delivery system. Several research groups are engaged in improving the loading efficiency and cellular uptake of the siRNA by modifying the surface of the PLGA nanoparticles with cationic coating materials, which bind negatively charged therapeutic genes through electrostatic interactions (Schiffelers et al, 2004;Hart, 2010;Xing et al, 2010). Wang et al fabricated 4 types of biodegradable NPs as the vector for siRNA delivery system .…”

From Serendipity to Mitochondria-Targeted Nanocarriers

“…Both, lipo-and polyplexes are still under intense investigation as nuclear-targeted DNA delivery systems as alternative to viral transfrection vectors (38)(39)(40)(41)(42). During the 1990s, the assembly of lipid-DNA complexes has been intensively investigated, and several models have been proposed, which are comprehensively summarized in (43).…”

Nanoparticle-delivered VEGF-silencing cassette and suicide gene expression cassettes inhibit colon carcinoma growth in vitro and in vivo

“…Importantly, systemic delivery of CPNP-shVEGF-CDTK established high efficacy in delaying tumor growth in xenograft colon carcinoma animal model. This might benefit from the properties of CPNP, such as positive surface charges, protection of the encapsulated plasmid DNA, and low toxicity [8][9][10][11]. The nanoparticles with positive surface charges are preferentially taken by the tumor cells and are retained longer than negatively charged or neutral particles [8,9].…”

“…Classic non-viral vectors, such as liposomes and cationic polymers, exhibit higher security and are easily prepared but have lower gene transferring efficiency compared with viral vectors [6,7]. Nanoparticles, on the other hand, have some prominent characteristics like small size, large superficial area, and variable surface properties [8,9], which makes them a promising delivery tool. We have developed calcium phosphate nanoparticles (CPNPs) with modified surface made of calcium chloride, which can either efficiently delivery DNA or protect DNA from degradation [10].…”