Synthesis of water soluble polymer-bound antiproliferative agents
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Date
2006-10-31T08:13:59Z
Authors
Johnson, Mark Trevor
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Abstract
Cancer is characterised by the unconstrained growth of cancerous cells, which damages
the healthy cells and ultimately the tissue of the host. Chemotherapy forms an essential
component in the treatment of this disease, however most anti-tumour drugs suffer from
various deficiencies, e.g. increased toxicity, reduced serum half life and poor water
solubility. The focus of this project was to address some of these deficiencies by
conjugating selected drugs to a water-soluble polymeric carrier.
Selected water-soluble biodegradable carriers were synthesized. Copolyaspartamides,
polyamidoamines and polyamides were obtained by condensation polymerisation,
Michéal–type addition polymerisation and ester amine base-catalysed polymerisation.
The nascent water soluble polymers were used to conjugate platinum, ferrocene and
tetramethylmelamine derivative, respectively. The percentage drug in each polymer drug
conjugate was determined by considering the mass of the drug in the conjugate as a
percentage of the total mass of the drug-polymer conjugate.
Platinum was linked to the carrier via polymer attached amine, carboxyl and hydroxyl
ligands. Platinum content of the conjugates ranged from 7 to 11 % by mass. The
ferrocenylation agent, 4-ferrocenylbutanoic acid, and the tetramethylmelamine derivative,
3-(4,6-bis(N,N-dimethylamino)-1,3,5-triazacyclohexatrien-2-yl) propanoic acid was
polymer-bound by amidation reactions. Iron content of the ferrocence conjugated ranged
from 2 to 12 % by mass. While the drug content based on tetramethylmelamine in the
3-(4,6-bis[N,N-dimethylamino]-1,3,5-triazacyclohexatrien-2-yl) propanoic acid polymer
conjugate ranged from 8.4 to 8.6 % by mass. There was a preliminary attempt to coconjugate
both, 4-ferrocenylbutanoic acid and 3-(4,6-bis[N,N-dimethylamino]-1,3,5-
triazacyclohexatrien-2-yl) propanoic acid to the same polymer. This co-conjugate
contained 2.9 % iron and 3.4 % tetramethylmelamine by mass.
Description
Student Number : 9903022H
MSc Dissertation
School of Chemistry
Faculty of Science
Keywords
water soluble polymers, macromolecular carriers, drug conjugates