Abstract
Non-viral vector formulations comprise typically complexes of nucleic acids with cationic polymers or lipids. However, for in vivo applications cationic formulations suffer from problems of poor tissue penetration, non-specific binding to cells, interaction with serum proteins and cell adhesion molecules and can lead to inflammatory responses. Anionic formulations may provide a solution to these problems but they have not been developed to the same extent as cationic formulations due to difficulties of nucleic acid packaging and poor transfection efficiency. We have developed novel PEGylated, anionic nanocomplexes containing cationic targeting peptides that act as a bridge between PEGylated anionic liposomes and plasmid DNA. At optimized ratios, the components self-assemble into anionic nanocomplexes with a high packaging efficiency of plasmid DNA. Anionic PEGylated nanocomplexes were resistant to aggregation in serum and transfected cells with a far higher degree of receptor-targeted specificity than their homologous non-PEGylated anionic and cationic counterparts. Gadolinium-labeled, anionic nanoparticles, administered directly to the brain by convection-enhanced delivery displayed improved tissue penetration and dispersal as well as more widespread cellular transfection than cationic formulations. Anionic PEGylated nanocomplexes have widespread potential for in vivo gene therapy due to their targeted transfection efficiency and ability to penetrate tissues.
Highlights
There is great interest in developing nanocomplex formulations for gene delivery in vivo and for therapeutic applications as alternatives to viral vectors, due to their ability to package a wide range of nucleic acids, their low immunogenicity which allows repeated administration and their potential for chemical modification of vector components to optimize performance [1,2]
An alternative approach is to formulate anionic nanocomplexes that offer the advantages of better targeting specificity, lower cytotoxicity and less interaction with serum components when compared to cationic formulations [12,13,14]
Other effective approaches of preparing anionic nanocomplexes involve the use of electrostatic, anionic coating agents such as hyaluronan, polyglutamate and chondroitin sulfate applied to a cationic core nanoparticle [52,53,54,55]
Summary
There is great interest in developing nanocomplex formulations for gene delivery in vivo and for therapeutic applications as alternatives to viral vectors, due to their ability to package a wide range of nucleic acids, their low immunogenicity which allows repeated administration and their potential for chemical modification of vector components to optimize performance [1,2]. Strategies developed to overcome these challenges include using cationic agents such as Ca2+ cations [14,16,17,18,19] or protamine [20,21,22] to act as an electrostatic bridge between anionic lipids and nucleic acids, the use of anionic reagents such as polyglutamate to coat cationic nanoparticles with an anionic shell [23,24] or by formulating nanoparticles with pH-tunable lipids [25] These anionic formulations and strategies have all shown promise for in vitro and in vivo delivery of DNA and siRNA indicating their potential for non-viral genetic therapies
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