Glycosylated Platinum(IV) Complexes as Substrates for Glucose Transporters (GLUTs) and Organic Cation Transporters (OCTs) Exhibited Cancer Targeting and Human Serum Albumin Binding Properties for Drug Delivery

Glycosylated
platinum­(IV) complexes were synthesized as substrates for GLUTs and
OCTs for the first time, and the cytotoxicity and detailed mechanism
were determined in vitro and in vivo. Galactoside Pt­(IV), glucoside
Pt­(IV), and mannoside Pt­(IV) were highly cytotoxic and showed specific
cancer-targeting properties in vitro and in vivo. Glycosylated platinum­(IV)
complexes 5, 6, 7, and 8 (IC50 0.24–3.97 μM) had better antitumor
activity of nearly 166-fold higher than the positive controls cisplatin
(1a), oxaliplatin (3a), and satraplatin
(5a). The presence of a hexadecanoic chain allowed binding
with human serum albumin (HSA) for drug delivery, which not only enhanced
the stability of the inert platinum­(IV) prodrugs but also decreased
their reduction by reductants present in human whole blood. Their
preferential accumulation in cancer cells compared to noncancerous
cells (293T and 3T3 cells) suggested that they were potentially safe
for clinical therapeutic use.