Biorecognizable polymer conjugates containing 5-fluorouracil for the treatment of colon cancer

Biorecognizable polymer conjugates containing the anticancer compound, 5-fluorouracil, have the potential to increase the anticancer activity and decrease the non-specific toxicity of the parent drug. This research was conducted to evaluate the anticancer activity of biorecognizable polymer conjugates containing 5-fluorouracil based on N-(2-hydroxypropyl)methacrylamide (HPMA) toward colon cancer. The term 'biorecognizable' means that entities present either on the cell surface, such as receptors, or intracellularly, such as enzymes, can interact with the polymer conjugate to impart targetability to the conjugate or to control the intracellular release of the drug from the conjugate. The first half of the research was designed to evaluate the intracellular biorecognition of polymer conjugates containing various oligopeptide side chains terminated with a derivative of 5-fluorouracil. Polymer conjugates possessing 5-fluorouracil terminated oligopeptide side chains of varying lengths and compositions were synthesized and incubated with lysosomal enzymes to determine the effect of chain length and composition upon the enzymatically catalyzed release of 5-fluorouracil. The results of these studies revealed that longer oligopeptide side chains (hexapeptides) terminated with a derivative of 5-fluorouracil could be cleaved by the enzymes whereas the shorter oligopeptide side chains (tetrapeptides) terminated with a derivative of 5-fluorouracil could not. In addition, the compositions of the side chains directly influenced the release of 5-fluorouracil from conjugates. The more hydrophobic the residue next to the 5-fluorouracil derivative the greater the release of the free drug. The second half of the research was designed to evaluate the cell surface biorecognition of polymer glycoconjugates containing different carbohydrate moieties (galactosamine, glucosamine or fucosylamine) and to evaluate the in vitro and in vivo anticancer activity of these glycoconjugates containing 5-fluorouracil toward colon cancer cells. The glycoconjugates bound to and were endocytosed into the cancer cells. The in vitro activity of the glycoconjugates containing 5-fluorouracil was dependent on the carbohydrate moiety (galactosamine>glucosamine>fucosylamine). The in vivo anticancer studies demonstrated that the 5-fluorouracil-containing glycoconjugates indeed had anticancer activity, and the activity depended on the carbohydrate moiety, the route of administration, and the length of treatment.