Polymeric organoiron compounds with carcinostatic properties (branched hydrazone linkers)

Nkazi, Bavon Diakanua
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The insufficient efficaciousness of most currently used anticancer drugs has prompted worldwide efforts to reduce toxic and resistance effects, improve overall bioavailability, and widen the therapeutic window. A particularly promising technology to this end rests on the concept of polymer-drug conjugation, in which the bioactive agent is bound to a meticulously designed macromolecular water-soluble carrier through a biofissionable link. Drug release in the cancerous cell, strongly pH dependant, proceeds hydrolytically in the acidic intracellular compartment, and this represents an advanced drug delivery method in cancer chemotherapy. The synthesis of water-soluble macromolecular anticancer drugs composed of a polymeric carrier to which the antineoplastic agents are tied via biodegradable hydrazone links were investigated in this project. Carriers were synthesized essentially by polyaddition and ring-opening methods, and polycondensation process was utilized, refined and routinely used. Polyaspartamides derived from polysuccinimide by aminolytic ring-opening was the parent carrier’s structure, allowing for: a) A non-immunogenic and non-toxic chain construction, which was amenable to biodegradation and ensured catabolic elimination of the duly fragment polymer upon drug release; b) A highly flexible backbone and the presence of intrachain-type or side group-attached solubilizing groups, which ensured conjugate solution in aqueous media required for rapid dissipation in the central circulation system, even if the conjugated drug itself does not possess water solubility; and; c) The presence of functional groups as binding sites, represented by the hydrazone entity, which ensured drug attachment and release, was introduced by treatment of polysuccinimide with hydrazine hydrate under specially developed experimental conditions, followed by treatment with selected, functionally active amines providing the aforementioned structural features. Drug systems were modified so as to contain carbonyl functionality, the crucial reaction site in this hydrazone linking process, and bioactive aldehydes, such as ferrocenylpropenal. A cinnamaldehyde was the primary drug model. In order to illustrate the multidrug-binding capacity of the polyaspartamide type carriers, and at the same time ensuring target-specific drug delivery, folic acid, a potential cell entry facilitator, was co-conjugated to selected polymeric conjugate containing ferrocenylpropenal. Cell carrier and conjugate polymers were purified, fractionated by aqueous phase dialysis in membrane tubing with 12 000 – 14 000 molecular – mass cut - off, and isolated by freeze-drying in ultimate yields of 45 – 80 % as water-soluble materials; and they were structurally characterized by spectroscopic techniques. Inherent viscosities were in the range of 8 – 36 mL g-1. The resulting cinnamaldehyde, curcumin and iron contents of the conjugates were in the range of 4 - 7 %, 10 – 14 % and 1.5 – 2.8 % respectively. In vitro experiments done under buffered solution (performed in polymer laboratory of school of chemistry of the university of the Witwatersrand) showed the released of drugs in cancer cell's pH (pH<7). The results of these tests suggest that in acidic environment PSI-hydrazine carriers drugs systems can release active drug such as ferrocenylpropenal, and on the other hand the polymers drugs systems showed higher stabilities under neutral conditions. Therefore drugs released under pH control can play an important role in future cancer therapy.