Platinum(IV) anticancer
agents have demonstrated the
potential
to overcome the limitations associated with the widely used Pt(II)
chemotherapeutics, cisplatin, carboplatin, and oxaliplatin. In order
to identify therapeutic scenarios where this type of chemotherapy
can be applied, an improved understanding on the intracellular reduction
of Pt(IV) complexes is needed. Here, we report the synthesis of two
fluorescence responsive oxaliplatin(IV)(OxPt) complexes, OxaliRes
and OxaliNap. Sodium ascorbate (NaAsc) was shown to reduce each OxPt(IV)
complex resulting in increases in their respective fluorescence emission
intensities at 585 and 545 nm. The incubation of each OxPt(IV) complex
with a colorectal cancer cell line resulted in minimal changes to
the respective fluorescence emission intensities. In contrast, the
treatment of these cells with NaAsc showed a dose-dependent increase
in fluorescence emission intensity. With this knowledge in hand, we
tested the reducing potential of tumor hypoxia, where an oxygen-dependent
bioreduction was observed for each OxPt(IV) complex with <0.1%
O2providing the greatest fluorescence signal. Clonogenic
cell survival assays correlated with these observations demonstrating
significant differences in toxicity between hypoxia (<0.1% O2) and normoxia (21% O2). To the best of our knowledge,
this is the first report showing carbamate-functionalized OxPt(IV)
complexes as potential hypoxia-activated prodrugs.