TY - JOUR
T1 - Oxali(IV)Fluors
T2 - Fluorescence Responsive Oxaliplatin(IV) Complexes Identify a Hypoxia-Dependent Reduction in Cancer Cells
AU - Boulet, Marie H. C.
AU - Bolland, Hannah R.
AU - Hammond, Ester M.
AU - Sedgwick, Adam
N1 - Funding Information:
A.C.S. would like to thank the Glasstone Research fellowship (University of Oxford) and Jesus College, Oxford for financial support as a Junior Research Fellow. A.C.S. would also like to acknowledge Professor Stephen Faulkner (University of Oxford) for mentorship and guidance. We would like to thank Aaron J. King and Eric S. Yang for helping with the cyclic voltammetry experiments.
Funding Information:
H.R.B. and E.M.H. thank the EPSRC for the support of program grant EP/S019901/1.
Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023/6/21
Y1 - 2023/6/21
N2 - 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% O2 providing 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.
AB - 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% O2 providing 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.
UR - http://www.scopus.com/inward/record.url?scp=85163383618&partnerID=8YFLogxK
U2 - 10.1021/jacs.3c03320
DO - 10.1021/jacs.3c03320
M3 - Article
SN - 0002-7863
VL - 145
SP - 12998
EP - 13002
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 24
ER -
