Maleimide-functionalised platinum(IV) complexes as a synthetic platform for targeted drug delivery

Abstract

Maleimide-functionalised Pt(IV) complexes with highly selective binding properties to thiol groups were synthesised as precursors for binding of thiol-containing tumour-targeting molecules like human serum albumin.

Fig. 1

The concept of maleimide-functionalised platinum(IV) prodrugs.

Fig. 2

ORTEP plot of 3a with atom labelling scheme, the thermal ellipsoids have been drawn at the 50% probability level.

Fig. 3

Binding studies of 3b with albumin using RP-HPLC.

Fig. 4

Free SH content of HSA at various platinum complex–HSA ratios after 4 h incubation, 3a (○), 3b (▲), 4b (□) [c_HSA = 99.2 μM; pH = 7.40, 20 mM phosphate puffer + 0.10 M NaCl, 2% (m/m) DMSO].

Fig. 5

Size-exclusion chromatography (SEC)-ICP-MS determination of 3b (50 μM) in fetal calf serum after 2 h of incubation.

Fig. 6

In vivo anticancer activity. CT-26 cells were injected subcutaneously into the right flank of BALB/c mice. Mice were treated on day 5, 8, and 12 (indicated by ▼) i.v. with 18 mg kg⁻¹ 3b or 4b. Tumour volumes were calculated as described in the ESI.† Each experimental group contained four animals. Data are means ± SEM. Statistical analysis was performed by two-way ANOVA with the Bonferroni post-test (* p < 0.05; ** p < 0.01; *** p < 0.001 compared to control mice).

Scheme 1

Synthesis of novel platinum(IV) complexes ((a): N⋂N = 1,2-ethane-1,2-diamine, Y = Cl; (b): N⋂N = 1R,2R-cyclohexanediamine, Y₂ = oxalate).