Tomlinson, Ryan; (2003) Degradable polyacetals for the development of polymer therapeutics. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The synthetic polymers that are used to prepare polymer therapeutics reaching clinical use are predominantly non-biodegradable and this severely limits the molecular weight range that will give certainty of safe elimination. The aim of this thesis was to synthesize water-soluble, biocompatible, functionalised polyacetals that would display pH-dependent degradation. Such degradable polymers would not be subject to the same restrictions of molecular weight as non-degradable polymers and provide a platform for the development of improved polymer therapeutics. Several approaches were examined to produce amino-functionalised polyacetals. A terpolymerization, using the hydrolytically stable diol 9-Fluorenylmethyloxycarbonyl (Fmoc)-serinol, PEG3400 and tri(ethylene glycol) divinyl ether, produced functionalised polyacetals of MW = 20-77,000 g/mol and MW/Mn = 1.8-2.0 which displayed pH-dependent degradation. An enhanced rate of hydrolysis was seen at pH 5.5, (~40 % MW loss in 24 h), compared to pH 7.4 (10 % MW loss in 72 h). The polymers and their degradation products were non-toxic towards B16F10 cells in vitro (IC50 > 5 mg/ml) and non-haemolytic. Varying the ratios of diol monomer gave a family of polymers containing different amounts of pendent group. Preliminary biodistribution studies using 125I-labelled polyacetal (APEG) after intravenous (i.v.) administration to rats showed no preferential accumulation in the major organs, (at 1 h; liver (4.2 % dose); lung (0.7 %) and kidney (1.1 %) and the log blood clearance with time was linear over 24 h. These results prompted the synthesis and characterisation of a high MW polyacetal-DOX conjugates via a succinyl linker using standard carbodiimide coupling reagents with a range of DOX loading (4-8.5 wt% DOX). In vivo pharmacokinetic studies in B16F10 tumour bearing mice indicated that the polyacetal-DOX conjugate exhibited significantly (p < 0.05) prolonged blood circulation times and enhanced tumour accumulation compared with the HPMA copolymer-DOX conjugate (PK1) which is currently in clinical trials. These novel, degradable, polyacetals have potential for further development as polymer-drug conjugates and potentially in other areas of polymer therapeutics.

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