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Synthesis and characterisation of novel lysine based dendrons as non-viral vectors for gene delivery

Ramaswamy, Chandrasekaran; (2005) Synthesis and characterisation of novel lysine based dendrons as non-viral vectors for gene delivery. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Efficient delivery of DNA first into the individual cells and then into the cell nucleus are crucial steps in gene delivery. Of the different vectors available for gene transfection, non-viral vectors are attractive although current non-viral vector transfection efficiency needs to be improved significantly. Dendrimers are distinguished from most other non-viral vectors by their precisely controlled topology, uniform molecular weight, and flexibility of functionalization. This thesis examines the development of some 30 new novel compounds, a new series of partial dendrimers (dendrons) as part of a search for DNA carriers. A series of dendrons based on branched lysine with or without lipidic chains were synthesised by systematically modifying the structure of the dendrons by varying the length and number of lipid chains in the core and the amino terminals created by lysine moieties. As some of the dendrons discussed here are amphiphilic, the possibility of self-assembly was studied using the surface tension measurements, NMR and asymmetric flow field-flow fractionation (aFFF). Self-assembly of both complete spherical dendrimers and partial dendrimers or dendrons have been of interest for their applications in supramolecular dendrimer chemistry. Formation of dendron - DNA complexes occurs spontaneously by the addition of cationic dendrons to DNA. These complexes we term "dendriplexes", whose biophysical properties including hydrodynamic diameter, surface charge, DNA condensing ability, DNase protection, cytotoxicity and in-vitro cell transfection ability have been studied here. Although all the dendrons condense the DNA and form compact complexes the degree of compaction increases when the lipidic chain length increases. Dendritic poly(lysine) with 8 terminal amino groups with or without three lipid chains (C10,C14,C18) in the core were studied systematically to determine the influence of lipophilicity of these dendrons on transfection properties. Of this series of dendrons those with three Cl8 carbon chains [(C18) 3(L)7(NH2)8] show higher gene transfer activity compared to their non lipidic analogues or those with shorter hydrocarbon chains, indicating that the lipophilicity of the dendrons plays a role in complex formation and thereby transfection.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Synthesis and characterisation of novel lysine based dendrons as non-viral vectors for gene delivery
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: (UMI)AAI10104748; Health and environmental sciences; Delivery; Dendrons; Lysine; Non-viral; Novel; Vectors; Viral
URI: https://discovery.ucl.ac.uk/id/eprint/10116672
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