Canal, Fabiana (2008) Profarmaci polimerici di farmaci antitumorali. [Tesi di dottorato]
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Anticancer drugs are very active molecules but they present limits that often prevent their success in chemotherapy. Most common problems are low half-life, due to rapid kidney clearance and to rapid inactivation by metabolic enzymes, and low selectivity towards cancer cells that causes severe side effects. The aim of this PhD thesis is to overcome some of the limits of anticancer drugs, especially the low molecular weight ones. In particular, some polymeric conjugates were prepared by linking an anticancer drug to a polymer that acts like a carrier. Poly-(ethylene glycol) was chosen as a carrier and it was linked to two anticancer drugs: gemcitabine, an antimetabolite drug, and epirubicin, an anthracycline. The following conjugates were prepared: mPEG-gemcitabine conjugates, with different molecular weights and shapes, folate-PEG-gemcitabine conjugates, by linking the drug at one side of polymer chain and a targeting moiety at the other side. The stability at different pH values, in plasma and towards the metabolic enzyme, pharmacokinetc behaviour and cytotoxicity were studied. Some epirubicin-PEG-folate conjugates were also prepared, with different number of molecules of folic acid per polymer chain, and were compared to similar ones without folic acid. In this case the cytotoxic activity, the cellular uptake and localization were studied.
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