Dago N’Da, David2006-02-102006-02-102006-02-10http://hdl.handle.net/10539/179PhD - ScienceMethotrexate (MTX) is a highly potent drug against leukemia and other neoplasias. The drug is notorious, however, for exerting toxic side effects and inducing drug resistance in the target cells as a result of deficiencies in the active carrier-mediated membrane-crossing mechanism. The bioreversible binding to a water-soluble and biocompatible carrier polymer is an advanced technology designed to circumvent critical pharmacological hurdles the drug must clear for efficacious biological action. The present project aimed at the anchoring of MTX and other drugs to various primary amine-functionalized polymeric carriers and the evaluation of the cytotoxic performance of the resulting conjugates in cell culture tests. The polymeric carriers used were polyaspartamides, prepared by an aminolytic ring-opening process of polysuccinimide, and poly(amidoamines), on the other hand, obtained by the copolymerization of methylenebisacrylamide with mono-N- tert-butoxycarbonyl-protected primary diamine and bifunctional amines. The anchoring was achieved through formation of biofissionable amide bonds. The in vitro biological evaluation against various human cell lines revealed the polymer-MTX conjugates to be more active than the clinically used parent drug. In order to demonstrate the multidrug-binding capacity of the polyaspartamidetype carriers, and at the same time ensuring target-specific drug delivery, folic acid, a potential cell entry facilitator, was co-conjugated to selected polymeric conjugates containing MTX or ferrocene. The in vitro inhibition of cell growth by the folate-drug co-conjugates was also evaluated against the same human cell lines.1908654 bytesapplication/pdfencanceranticancerconjugatesferroceneThesis