Many coordination complexes of transition metals are known for their biological activity, anticancer properties in particular. Probably the best example of such compounds is cisplatin, which was first synthesized in 1845 but only as recently as in 1967 its potent antitumor activity was accidentally discovered. Since then it has become one of the mainstay anticancer drugs applied primarily in the treatment of testicular, ovarian, cervical cancer, head and neck, bladder, and lung cancer, melanoma, and lymphomas. It is estimated that the world market of cisplatin is worth about 2 billion dollars and every second oncological patient is treated with cisplatin or its derivative.
Cisplatin is administered intravenously and is bound by plasma proteins in 100% after slow infusion. It enters cells via passive diffusion through the cell membrane or is actively transferred. Inside the cell cisplatin molecules are activated and react with a genomic or mitochondrial DNA. This reaction blocks production of DNA, mRNA, and proteins, finally leading to cell necrosis or apoptosis.
These interactions are responsible for the severe adverse effects of cisplatin which include nausea, vomiting, nephrotoxicity, ototoxicity, hepatotoxicity, and neurotoxicity. Another challenge with cisplatin is the resistance to this drug. Some cancers are intrinsically resistant to cisplatin, while others develop resistance with time.
This project aims to apply a photopharmacological approach to overcome these problems. It involves the application of a photoactive molecule, which, unlike compounds used in photodynamic therapy, is a drug itself, or is attached to a drug molecule, or to a cellular structure such as ion channel. The pharmacological activity of such a system can be modified by absorption of light followed by an irreversible photochemical event affecting the molecule such as photodissociation, intramolecular group, hydrogen or electron transfer, or reversible significant change in the shape of the molecule. Molecules able to undergo reversible change of their structure upon irradiation with light of proper wavelength are called photoswitches. The change in the structure of the molecule and, consequently, its size and physicochemical properties (dipole moment, solubility, rigidity), may impart a change in its biological properties and pharmacological activity resulting in the change (enhancement or attenuation) of the therapeutic effect.
Goals of the research
The purpose of the project is to obtain and study the photochemical and biological properties in vitro of the analogs of cisplatin in which the ammonia molecules are replaced with a photoswitch of favorable photochemical properties (quantitative photoswitching, exceptional stability of both photoisomers). Photoswitchable complexes palladium, gold, and silver will also be studied.
Results
We found that photoswitching of thus modified cisplatin with near UV/visible light results in significant change in its cytotoxicity towards animal and human cancer cells (melanoma, breast and lung cancer) which may open new possibilities in light-controlled anticancer chemotherapy.