paper draft - A SUPRAMOLECULAR SELF-ASSEMBLY LIBRARY...

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A SUPRAMOLECULAR SELF-ASSEMBLY LIBRARY APPROACH TO NON-VIRAL GENE DELIVERY VECTOR DEVELOPMENT INTRODUCTION Gene therapy attempts to treat and even cure some of the world’s most challenging illnesses by addressing disease at the genetic level. However, nearly 20 years since the technique was first applied in a human clinical trial, its successes have been few [1]. The greatest single factor responsible for the slow progress is the lack of a safe and efficient method to deliver genetic information to patient cells. While viral vectors have been a major area of gene delivery research because of their in vivo efficiency, clinical events within the last decade have revealed that their safety is questionable [2-4]. More likely, it seems, future gene delivery will utilize synthetic vectors. While safer than viruses, these non-viral alternatives currently suffer from poor performance. As such, effort has been made to improve non-viral gene delivery efficiency through rational and semi-rational design of vectors capable of overcoming the various extra- and intracellular barriers that inhibit their performance. A variety of materials are being considered for non-viral gene delivery applications. These include a wide range of polyamines and lipids that are able to electrostatically bind and condense DNA for delivery to cells. Compared to viral gene delivery systems, these lipids and polyamines are generally safer as their genetic cargo is explicitly non-viral and is not integrated into the host genome, thereby avoiding the immunogenic and oncogenic tendencies of some viruses. They are also comparatively cheap and easy to produce [5]. The primary disadvantage of non-viral vectors, however, is poor gene delivery efficiency—typically orders of magnitude below that found in viruses. The inefficiency largely lies with extra- and intracellular barriers
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existing between the site of administration and the nucleus of target cells. Cellular association, endocytosis, vector escape from the endosomal pathway, disassociation of the non-viral carrier and the plasmid DNA, migration of the plasmid DNA to the nucleus and finally transcription all stand as obstacles to overcome [6]. Considerable effort has been put into the rational design of gene delivery vectors that are capable of effectively contending with a small, well-defined subset of the identified various extra- and intracellular barriers. For example, PEG and other steric shielding groups have been attached to polymers to promote serum stability and sustained in vivo circulation [7, 8]. Small molecules, proteins and antibodies have been incorporated into the design to permit receptor- mediated uptake by particular cells [9, 10]. Polymers and lipids with various pH-sensitive and endosomolytic moieties have been produced to facilitate escape from the endosomal pathway [11, 12]. Nuclear localization signals have also been attached to DNA in attempts to aid nuclear delivery [13]. While these strategies have been successful in tackling the various individual
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