A thesis submitted to the Faculty of Science, University of the
Witwatersrand, Johannesburg, in fulfillment of the requirements for the
degree of Doctor of Philosophy of Science.
Johannesburg, 2013 / Chemotherapy, while representing a vital component of cancer treatment
modalities, has so far not fulfilled basic expectations with unsatisfactory cure
rates and frequent relapse due to limited effectiveness of the therapeutic
drugs, severe side effects and resistance problems. The platinumcontaining
drugs used in present clinical practice are no exception to this
generalized finding. While highly effective against a small number of
malignancies, they generally share in the deficiencies of other anticancer
agents. To address this issue, intense research is being undertaken to
develop novel platinum-compounds offering enhanced therapeutic
effectiveness. To accomplish this, several new avenues of development are
being pursued world-wide, and one of these involving the binding of
monomeric anticancer drug systems to water-soluble, biocompatible and
biodegradable polymeric carriers, was utilized in the current research. As
part of the ongoing research, this dissertation demonstrates the preparation
of several water-soluble polymeric carriers bearing pre-synthesized
monomers aimed to anchor the platinum drug. The monomers of interest
were aspartic acid, p-aminobenzoic acid and p-aminosalicylic acid
derivatives; while the water-soluble carriers were polyaspartamides,
prepared by an aminolytic ring-opening process of polysuccinimide. The
platination agents were conjugated to the polymer backbone both via amine
and via leaving-group ligands, such as dihydroxylato, dicarboxylato and
carboxylatohydroxylato. In order to demonstrate the multidrug-binding
capacity of the carriers, platinum complexes were co-conjugated to
polymeric conjugates containing ferrocene. The in vitro studies against a
human breast cancer (MCF-7) cell line showed IC50 values ranging from
48.92 μg.mL-1 to 281.37 μg.mL-1 for the platinum conjugates, 13.18 μg.mL-1
to 149.67 μg.mL-1 for ferrocene conjugates and 6.22 μg.mL-1 to 83.86
μg.mL-1 for platinum/ferrocene co-conjugates; and these values were on
average 4 fold more active than the parent drug. The results of these
preliminary tests provide proof of the principle that polymer-drug conjugates
can play a role in future cancer therapy.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/13357 |
| Date | 07 January 2014 |
| Creators | Mukaya, Hembe Elie |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf, application/pdf |
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