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Title: Synthesis and in-vitro testing of pH-responsive biopolymers for drug delivery
Author: Chen, R.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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Abstract:
pH-responsive membrane-disruptive polymers can facilitate effective drug delivery by releasing endocytosed materials from endosomes into the cytoplasm to avoid lysosomal degradation of sensitive bio-therapeutics or non-productive lysosomal accumulation. The work presented in this thesis involved optimisation of the molecular structure and compositions of an amphiphilic polyamide poly(L-lysine iso-phthalamide) to make it sufficiently membrane-lytic under mildly acidic conditions typical of the endosomal compartment (pH 5.0-6.8), but non-lytic at physiological pH. A wide range of biopolymers were designed and synthesised by grafting poly(L-lysine iso-phthalamide) with hydrophilic chains, such as amino-PEG (PA series) and its analogue Jeffamine M-1000® (PJ series), and hydrophobic amino acids, such as L-phenylalanine (PP series), L-leucine (PL series) and L-valine (PV series). The effects of the nature of carboxyl group modification, degree of grafting, and molecular weight on the pH, concentration and kinetic properties of the polymers were evaluated. The polymers can be tailored to be non-lytic at pH 7.4, whilst extremely membrane-lytic at mildly acidic pH within the range typical of endosomes (pH 5.0-6.8). For example, PP-75 (63 mol% grafted L-phenylalamine) was 4 times (on a weight basis) more efficient at haemolysis than melittin, a highly membrane-lytic bee venom peptide. The mechanisms of the polymers to disrupt the cell membrane were elucidated. The effects of polymer concentration, incubation time, the nature of carboxyl group modification and degree of grafting on the in-vitro cytotoxicity of the grafted polymers towards various cell types at both pH 7.4 and acidic pH were examined. Furthermore the subcellular distribution of the fluorescence labelled polymers and the release of model drugs (FITC and calcein) by the polymers were investigated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.597562  DOI: Not available
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