This invention describes a novel
polysaccharide prodrug of 5-
fluorouracil (5-FU) with enhanced target specificity for
colorectal cancer treatment, and its preparation methods. The
prodrug is synthesized by chemically linking anti-
cancer drug 5-
fluorouracil (5-FU) with a specially selected
polysaccharide with molecular weight of 105˜107 Da containing
galactose residues. Its distinctive characteristics are that it is a
prodrug synthesized by chemically linking polysaccharides with 5-FU through different bridge links for the targeted treatment of
colorectal cancer; that the polysaccharides in the
chemical compound contain
galactose residues; and that these polysaccharides are prepared from natural gums or
plant materials. Due to these unique characteristics, as an oral preparation, the
polysaccharide component of this novel prodrug can protect the
active agent 5-FU from absorption (or
metabolism) in the
upper gastrointestinal tract and deliver a
high concentration of the 5-FU to the colorectal area. Upon reaching the colorectal area, the 5-FU-
galactose portion of the prodrug will bind to
galectin-3, a-
galactoside-
binding protein implicated in
tumor progression by interactions with its ligands, such as TF (Thomsen-Friedenreich, Galb3GalNAc), Tn (GalNAcaThr / Ser), and Sialy-Tn with galactose residues, which are highly expressed among
colorectal cancer cells. Finally, the active 5-FU component will be released locally from the polysaccharide via
enzymatic hydrolysis from the local bacterial
flora, allowing it to actively kill the colorectal
cancer cells. In summary, this novel target-specific prodrug can enhance the selectivity of 5-FU and increase its therapeutic effects in the treatment of colorectal
cancer. In addition, with this enhanced target specificity, it is possible to maximize the 5-FU
efficacy in cancer patients by having either less
toxicity with the same or higher therapeutic
dose, and / or administer a lower dosage (if so desired) to achieve the same therapeutic effects, but with much less
toxicity. Multiple examples of various approaches to synthesize this novel prodrug are enclosed herein along with several
animal model experiments to substantiate the claims as stated above.