Purohit, Gaurang; (2004) Design and characterisation of dendritic molecules. Doctoral thesis (Ph.D.), University College London.

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Abstract

Dendritic molecules with highly versatile and synthetically controllable structures have been examined closely in the fields of drug delivery and targeting. This thesis focuses on the design and synthesis of a series of poly(lysine) dendritic molecules, and how their structural characteristics affect their physical and pharmaceutical properties. All molecules studied in this thesis were prepared using solid phase peptide synthesis. Amphipathic dendrons having three lipidic (C14) chains coupled to dendritic lysine head groups with 8, 16 or 32 free terminal amino groups were synthesised. Their interactions with charged and neutral liposomes were studied, and the interaction efficiency for all three dendrons was greater than 88%. The dendrimers produced cationic liposomes regardless of initial liposome charge and showed evidence of hydrophobic interactions with the liposome membranes. Membrane disruption of the liposomes was also seen with the highly cationic dendrons. The interaction of the series of dendrons with albumin, was studied in the presence of NaC1, using dynamic dialysis and molecular modelling. Diffusion and membrane permeability studies (using cellulose membranes) were also performed. The stoichiometry of dendron: albumin interactions was found to be 1:1.5, 1:4 and 1:5 for the dendrons with 8, 16 and 32 amino groups, respectively. Calculation of shape factors showed that the dendrons had a more spherical confirmation with each generation of growth. The synthetic approaches used to synthesise other dendrons as well as a novel didendron is detailed. Viscosity studies showed that a didendron with 128 terminal amino groups (2 x 64) had a dynamic viscosity greater than that of a single dendron with 128 terminal amino groups. A dendron with acetylated terminal groups was found to form unusual aggregates on the surfaces of glass slides.

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