Enhanced cellular uptake of platinum by a tetracationic Pt(II) nanocapsule and its implications to cancer treatment

Abstract

Despite the known limitations of cisplatin chemotherapy, the treatment of cancer by platinum-based drugs remains the method of choice for many oncologists. The advancement in drug delivery formulations and protocols of combined treatments provided effective tools to ameliorate the side effects of platinum-based therapies. Another approach to improve the pharmacological profiles of anticancer platinum drugs is to properly modify their structure and composition, which has produced numerous platinum complexes with improved therapeutic effect. Recently, we have demonstrated the strong anticancer potency of supramolecular nanocapsules that form by self-assembly of four bis-anthracene ligands with two metal ions, either Pt(II) or Pd(II). Herein, we focus our study on the Pt(II) nanocapsule and its uptake by two types of cancer cells, suspension cultures of HL-60 cells and the adherent cancer cells HT-29. Comparison of the platinum uptake by cancer cells treated with the nanocapsule and with cisplatin evidenced superior uptake of platinum caused by the nanocapsule, which in HT-29 and HL-60 cells prevails by 21 and 31 times, respectively. Morphological changes in the HL-60 cells induced by the Pt(II) nanocapsule were studied by transmission electron microscopy (TEM) which provided plausible explanation of the uptake results. These data corroborate also with the known nanocapsule's very high cytotoxicity, better selectivity, and lack of cross-resistance with cisplatin. Additionally, our estimations of the drug-drug interactions in combined treatments established the propensity of the nanocapsule to exert supra-additive cytotoxicity in combination with cisplatin against the bladder cancer T-24 cells. All these findings define the scope for more detailed pharmacological characterization of the presented Pt(II) nanocapsule.