Design and synthesis of polymeric anticancer agents
Date
2009-03-31T12:30:34Z
Authors
Jacques, Kayembe Diainabo
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Abstract
Presently used anticancer drugs deficiency prompted studies of their possible
binding to polymeric structures called carriers which serve as vehicles for
transportation of the drug to the target cell. Availability of natural polymers, firstly
used, was limited by intrinsic characteristics required by anticancer agents.
Synthetic polymers are advantageous as they may be tailored to meet specific
structural requirements. They should thus possess desirable biomedical
properties such as water-solubility, biodegradability and biocompatibility. They
should also bear functional groups for drug binding.
In the present dissertation project, known and novel water-soluble carriers were
synthesized and some of them were used for bioreversible binding (anchoring) of
antineoplastic agents, such as methotrexate and ferrocene, to provide conjugates
for biomedical application.
Polyaspartamide carriers equipped with hydrosolubilizing and amine-terminated
side chains suitable for drug attachment were prepared from poly-D, Lsuccinimide
by a previously developed technique involving successive aminolytic
ring-opening steps mediated by amines. Chosen amines include
diethylenetriamine (DET), 2, 2’-(ethylenedioxy)diethylamine (EDDA), hydrazine (HY), 1,3-propylenediamine (PDA) and 3-(N,N-dimethylamino)propylamine
(DMP).
Other aliphatic polyamide carriers were prepared by polycondensation methods
involving 2-hydroxypyridine as a catalyst, diethyl L-tartrate (TART) and diamines
ethylenediamine (EDA), EDDA and 4, 7, 10-trioxa-1,13-tridecanediamine (TRIA).
The use of diethyl L-tartrate leads to polyamides bearing hydroxyl groups for drug
iv
attachment, while the three diamine monomers enhance polymer solubility and
provide intra-chain drug anchoring sites.
Polyamidoamine carriers, possessing intra-chain functional amino and hydroxyl
groups for drug binding, were synthesized by a Michael polyaddition reaction of
methylene bisacrylamide (MBA) with comonomer 3-amino-1, 2-propanediol
(APD) and 3-(N,N-dimethylamino)propylamine (DMP).
All polymeric carriers prepared were fractionated by aqueous-phase dialysis in
12000-14000 molecular-mass cut-off membrane tubing (25000 cut-off for
selected polymers) and isolated by freeze-drying. Yields ranged from 10 to 69%
and inherent viscosities, ηinh, from 6 to 29 mL/g. They were then characterized
spectroscopically. All polymers dissolved completely in aqueous media, thus
fulfilling the requirements of water solubility.
Methotrexate is one of the highly potent anticancer drugs. The literature reveals
high folic acid antagonistic properties and high antiproliferative activity against all
kinds of cells.
In the present dissertation, a series of water-soluble methotrexate conjugates
was synthesized by N-acylation of linear appropriately amine-functionalized
polyaspartamide carriers with methotrexate. Acylation was brought about by
mediation of O-benzotriazol-1-yl-tetramethyluronium salt (HBTU) as coupling
agent.
The anticancer The anticancer activity of metal compounds has been of major interest in drug
research for two decades. The literature shows certain ferrocene-bound
conjugates to possess the same high antineoplastic activity against HeLa cells as
observed with analogous platinum conjugates.
In the present dissertation, a series of water-soluble ferrocene conjugates was
synthesized by using the same method as for methotrexate: N-acylation of linear
amine-functionalized polyaspartamide carriers with 4-ferrocenylbutanoic acid. Acylation was here again brought about by mediation of O-benzotriazol-1-yltetramethyluronium
salt (HBTU) as coupling agent.
All conjugates synthesized were purified by aqueous-phase dialysis and collected
by freeze-drying as water-soluble solids. Resulting water-soluble polymer-drug
conjugates displayed inherent viscosities, ηinh, of 5 to 24mL/g, and contained 18-
23 % of drug by weight.
In conformance with the project’s objective, methotrexate conjugates were
contributed to a major pool of experimental polymeric antineoplastic agents, to be
submitted to the department of Pharmacology, University of Pretoria, for
extended cell culture testing to asses their antiproliferative activity.