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. 2018 Feb 12;4(2):463-467.
doi: 10.1021/acsbiomaterials.7b00921. Epub 2018 Jan 9.

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

Marek T Wlodarczyk  1   2 , Sylwia A Dragulska  1 , Olga Camacho-Vanegas  3 , Peter R Dottino  4 , Andrzej A Jarzęcki  1 , John A Martignetti  3   5 , Aneta J Mieszawska  1
Affiliations

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

Marek T Wlodarczyk et al. ACS Biomater Sci Eng. .

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.

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Figures

Figure 1.
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.
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.
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.
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).
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