[Ru(5,6-dmp/3,4,7,8-tmp)₂(diimine)]²⁺ complexes : Quantitative cellular uptake, localization and cytotoxicity of in SiHa cervical carcinoma cells

Vaiyapuri Subbarayan Periasamy¹, Mohammad Abdulkader Akbarsha*¹, Venugopal Rajendiran² , Mallayan Palaniandavar², Bangalore Suresh Srinag³, and Hanumanthappa Krishnamurthy³.

¹School of Life Sciences, ² School of Chemistry, Bharathidasan University, Tiruchirappalli – 620024, India.

³ National Centre for Biological Science, Tata Institute for Fundamental Research, Bangalore 560 065, India

ABSTRACT

During the last decade, ruthenium complexes have attracted a lot of interest owing to their immense potential of biological applications such as diagnostics, therapeutics and specific target for cells or tissues. Selective cellular uptake, intracellular localization and cytotoxicity of several ruthenium complexes could be interesting leads as therapeutic strategies such as pro-drugs (an inactive form, which is metabolized in vivo to the active species), and reach their targets with prior activation, ideally in the tumor tissue of interest, by substitution or electron transfer-induced transformations. The most prominent strategies to achieve cancer selectivity of the complexes involve selective accumulation of the drug by a suitable targeted transporter system (e.g., transferring or organic ion transporters), photo-activation (photodynamic therapy), activation by oxygen species and pH-dependent activation.

In a preliminary investigation to find the intracellular applications, a series of 14 different methyl substituted ruthenium(II) complexes ([Ru(5,6-dmp / 3,4,7,8-tmp)₂(diimine)]²⁺), were subjected to analysis in SiHa cervical carcinoma cells. It is an effort to study the role of 5,6-dmp and 3,4,7,8-tmp as the primary ligands and simple and methyl-substituted quinoxaline and phenazine as the co-ligands for cellular uptake, localization and cytotoxicity in a cancer cell adopting MTT assay, fluorescent microscopy and flow cytometry. Over all this preliminary screening reveals that ruthenium complexes are capable of penetrating the cell membranes, producing stable fluorescence in the intracellular environment and binding selectively to the nuclear and cytoplasmic entities. The time- and dose-dependency would lead to cellular modulation, like apoptosis, in cancer cells.  These selective properties can be of considerable advantage as cell death modulators, pro-drugs or redox biomarkers, which offer the potential for applications as novel nano-medicine or intracellular diagnostic tools in cancer.

Keywords: Ruthenium complexes, cellular uptake, pro-drugs, apoptosis, intracellular fluorescent

*Corresponding author contact: Full name: Dr. Mohammad Abdulkader Akbarsha, Emeritus Professor, School of Life Sciences, Bharathidasan University, Tiruchirappalli – 620024, India; Mobile No. +91 9790995854; FAX: +91 431 2407045; Email: akbarbdu@yahoo.com