Floxuridine Oligomers Activated under Hypoxic Environment

Abstract

Floxuridine oligomers are anticancer oligonucleotide drugs composed of a number of floxuridine residues. They show enhanced cytotoxicity per floxuridine monomer because the nuclease degradation of floxuridine oligomers directly releases highly active floxuridine monophosphate in cells. However, their clinical use is limited by the low selectivity against cancer cells. To address this limitation, we herein report floxuridine oligomer prodrugs that are active under hypoxia conditions, which is one of the distinguishing features of the microenvironment of all solid tumors. We designed and synthesized two types of floxuridine oligomer prodrugs that possess hypoxia-responsive moieties on nucleobases. The floxuridine oligomer prodrugs showed lower cytotoxicity under normoxia conditions (O 2 = 20%), while the parent floxuridine oligomer showed similar anticancer effects under hypoxia conditions (O 2 = 1%). The floxuridine oligomer prodrug enabled tumor growth suppression in live mice. This would be the first example demonstrating the conditional control of the medicinal efficacy of oligomerized nucleoside anticancer drugs.

Noncanonical Amino Acids for Hypoxia-Responsive Peptide Self-Assembly and Fluorescence

“…The intimate relationship between the structural features of peptide nanostructures and amino acid sequences has been thoroughly elucidated over the past few decades. − This has inspired establishment of various controllable self-assembling peptide systems based on stimuli-responsive reactions of natural or noncanonical amino acids, including redox-, − pH-, − photo-, and enzyme-responsive reactions, − and among others, , for creation of functional materials with great potential in disease diagnosis and treatment. − Among the internal or external stimuli, nitroreductase (NTR) is a flavin-containing enzyme conventionally overexpressed in the hypoxic region of solid tumors and enables one to reduce the nitro groups to (hydroxy)­amino groups using NAD­(P)H as the electron source . Thus far, a considerable number of NTR-responsive hydrogels, , imaging probes, − drug delivery vehicles, − or activatable prodrugs − have been developed and exhibit broad biomedical applications. For instance, the 1,6-elimination reaction of the 4-nitrophenyl group induced by NTR reduction has been utilized to create smart supramolecular hydrogels or the target release of hydrogen sulfide as demonstrated by the Hamachi or Matson laboratory, respectively. , Despite the remarkable progress achieved in stimulus-responsive self-assembly of peptides, reliable strategies for manipulating the self-assembly of peptides through NTR-reduction of amino acids remain scarce, thus limiting the development of NTR-responsive peptide-based biomaterials.…”

Characterization of 2‐Fluoro‐2’‐deoxyadenosine in Duplex, G‐Quadruplex and i‐Motif

“…Not only fluorinesubstituted nucleoside analogues, fluorine-substituted oligonucleotides have potential as therapeutic reagents. [29][30][31][32][33] Furthermore, nucleic acids have been regarded as an attractive platform to develop functional nanodevices. Incorporation of 2FA has a potential to modulate properties of oligonucleotides such as thermal stability, pH responsiveness, and topology of non-canonical structures.…”

“…On the other hands, characteristic of DNA containing 2FA has not been investigated in detail. Not only fluorine‐substituted nucleoside analogues, fluorine‐substituted oligonucleotides have potential as therapeutic reagents [29–33] . Furthermore, nucleic acids have been regarded as an attractive platform to develop functional nanodevices.…”

DNA‐Damage‐Response‐Targeting Mitochondria‐Activated Multifunctional Prodrug Strategy for Self‐Defensive Tumor Therapy

“…The active form of FUDR, 5‐fluorouracil (5‐FU), which can be formed through FUDR catabolism, interferes with RNA and DNA synthesis [14] . FUDR exerts cytotoxic effects by disrupting DNA replication and inducing DNA damage or thymineless cell death through thymidylate synthetase inhibition [15] . Although FUDR and other fluoropyrimidine drugs are used clinically to manage various tumor types, DNA repair proteins, including uracil N ‐glycosylase 2 (UNG2), X‐ray repair cross‐complementing 2 (XRCC2), RAD51, flap endonuclease 1 (FEN1), cyclin D1 (CCND1), and poly(ADP‐ribose) polymerase (PARP), have limited their use for therapeutic purposes [16–19] .…”

“…[14] FUDR exerts cytotoxic effects by disrupting DNA replication and inducing DNA damage or thymineless cell death through thymidylate synthetase inhibition. [15] Although FUDR and other fluoropyrimidine drugs are used clinically to manage various tumor types, DNA repair proteins, including uracil N-glycosylase 2 (UNG2), X-ray repair cross-complementing 2 (XRCC2), RAD51, flap endonuclease 1 (FEN1), cyclin D1 (CCND1), and poly(ADP-ribose) polymerase (PARP), have limited their use for therapeutic purposes. [16][17][18][19] These proteins promote cancer cell survival by repairing damaged DNA lesions initiated by the base excision repair (BER) pathway.…”