Macromolecular derivatives of methotrexate and ferrocene as potential prodrugs in cancer chemotherapy
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Date
2010-08-03
Authors
Mufula, Ilunga
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Abstract
Cancerous diseases present a formidable health problem worldwide. While the
chemotherapy of cancer, in conjunction with other treatment modalities, has reached a
significant level of maturity, efficacious use of such agents is still restricted by numerous
pharmacological deficiencies, such as poor solubility, short serum circulation lifetimes,
and low bioavailability resulting from lack of affinity to cancer tissue and inadequate
mechanisms of cell entry. More critically still, most drugs suffer from toxic side effects
and a risk of drug resistance. In an attempt to enhance the therapeutic effectiveness of
carcinostatic drugs, the concept of anchoring bioactive agents to polymeric carriers has
proved to be a promising approach to overcome these deficiencies and was the main aim
of this project.
Water-soluble, biodegradable macromolecular carriers used were polyaspartamides,
prepared by an aminolytic ring-opening process of polysuccinimide; polyamides obtained
by ester-amine base-catalyzed polyaddition; and polyamidoamines prepared by Michaeltype
addition polymerization. The drug-anchoring potential of carrier polymers was
demonstrated by the coupling of methotrexate (MTX), ferrocene and platinum drug
models.
MTX was linked to carrier via polymer attached amine by N-acylation of linear aminefunctionalized
polyaspartamide carriers with the acid group from methotrexate. Acylation
was brought about by mediation of HBTU coupling agent. The resulting MTX content of
the conjugates was in the range of 10-19% by mass.
In the present dissertation, series of water-soluble ferrocene conjugates were synthesized
as for MTX by N-acylation of linear amine-functionalized polyaspartamide carriers with
4-ferrocenylbutanoic acid. Acylation was brought about again by mediation of HBTU
coupling agent. The resulting iron content of the conjugates was in the range of 6-13% by
mass. Polymer-attached dihydroxylato-type ligands were used to anchor the platinum drug to
the polymeric carriers. The platinum content of the conjugates was in the range of 6-8%
by mass.
A member of selected conjugates was submitted to the Department of Immunology,
University of Pretoria, and to the School of Pharmacy, University of California, Los
Angeles, CA, for biomedical activity assessment.
In order to demonstrate the multidrug-binding capacity of the polyaspartamide-type
carriers, ferrocene was co-conjugated to selected polymeric conjugates containing MTX
or folic acid. The latter was used to ensure target-specific drug delivery.