Platinum (II) complex-nuclear localization sequence peptide hybrid for overcoming platinum resistance in cancer therapy

Abstract

Platinum therapy represents first line of treatment in many malignancies but its high systemic toxicity limits the therapeutic dosage. Herein, we report the synthesis of carboplatin-like complexes with azide and alkyne functional groups and the formation of a platinum (II) - nuclear localization sequence peptide (Pt-NLS) hybrid to improve the import of platinum (II) complexes directly into the cell's nucleus. The Pt-NLS hybrid successfully enters cells and their nuclei, forming Pt-induced nuclear lesions. The in vitro efficacy of Pt-NLS is high, superior to native carboplatin at the same concentration. The methodology used is simple and cost-effective and most importantly can easily be extended to load the Pt (II) onto other supports, opening new possibilities for enhanced delivery of Pt (II) therapy.

Keywords: NLS peptides; chemoresistant; click chemistry; platinum (II) complexes.

Figure 1.

Chemical structure of Platinum (II) complexes Pt(II)-N₃ and Pt(II)-CCH. (A), and the structure of the Pt-NLS hybrid (B).

Figure 2.

Experimental and calculated IR spectra of Pt(II) complexes; Pt(II)-N₃ complex (panel A), Pt(II)-CCH complex (panel B) and Pt-NLS hybrid (panel C).

Figure 3.

Confocal images of CP70 cells incubated with NLS peptide: (A) phase contrast image, (B) fluorescence image of the same cells, (C) nuclei of the cells, (D) overlay of C and D.

Figure 4.

Viability of platinum sensitive (left) and resistant (right) cells after 72h incubation with Pt-NLS hybrid and controls. The purity of Pt-NLS hybrid was 87%. Each column represents the mean and standard deviation of N=3 and p<0.005. The concentrations are constant in each cell line, and are as follows: 24.6 μM (A2780), 52.8 μM (CP70), 56.6 μM (TOV-21G), 56.6 μM (SKOV3), 18.4 μM (ES-2), 59.0 μM (OV-90). Abbreviations: Carboplatin (Carbpt), Complex-Pt (Cplx-Pt).