Abstract
Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a short oligonucleotide made of five floxuridine units. Specifically, we studied adding cholesterol, palmitic acid, polyethyleneglycol (PEG 1000), folic acid and triantennary N-acetylgalactosamine (GalNAc) as potential enhancers of cellular uptake. As expected, all these molecules increased the internalization efficiency with different degrees depending on the cell line. The conjugates showed antiproliferative activity due to their metabolic activation by nuclease degradation generating floxuridine monophosphate. The cytotoxicity and apoptosis assays showed an increase in the anti-cancer activity of the conjugates related to the floxuridine oligomer, but this effect did not correlate with the internalization results. Palmitic and folic acid conjugates provide the highest antiproliferative activity without having the highest internalization results. On the contrary, cholesterol oligomers that were the best-internalized oligomers had poor antiproliferative activity, even worse than the unmodified floxuridine oligomer. Especially relevant is the effect induced by palmitic and folic acid derivatives generating the most active drugs. These results are of special interest for delivering other therapeutic oligonucleotides.
Highlights
Antimetabolites are among the oldest but still the most used drugs for chemotherapy of cancer
We have investigated the effect of several small-molecule internalization enhancers in the antiproliferative and internalization properties of FdU5 oligonucleotide
FdU5 linked to cholesterol (FdU5 -Col), palmitic acid (FdU5 –Pal) and GalNAc (FdU5 –GalNAc) were synthesized straightforwardly from the corresponding commercial solid supports functionalized with the appropriate deriva
Summary
Antimetabolites are among the oldest but still the most used drugs for chemotherapy of cancer. These include various compounds such as folic acid analogs, purine and pyrimidine analogs, vinca alkaloids, and many antibiotics and other drugs that disturb nucleic acid metabolism and alter DNA synthesis [1]. Several prodrugs of FdU have been explored to improve its physicochemical and bioavailability properties to reduce toxicity [8]. These include alkyl ester, photoactivated, and amino acid ester FdU prodrugs [9,10]. The amino acid ester prodrugs of nucleoside agents have the advantage of being substrates for the
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