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Researchers combined cisplatin, an enhancer and a photodynamic therapy (PDT) drug into a single conjugate that had 10 times the efficacy in treating treatment resistant cancer cells. Chemists have designed a conjugate of three anti-cancer agents which can be administered as a single drug and has three modes of action in killing tumours. The aim was to create a drug that provides a simpler method for overcoming cancer resistance, by combining three of the most often combined agents – cisplatin, phenylbutyrate and a photodynamic therapy (PDT) drug. The design and pre-clinical testing of the conjugate drug, called Ru-Pt, was detailed in Angewandte Chemie. Ru-Pt combines cisplatin, the most frequently applied chemotherapy agent, phenylbutyrate, a chemical cisplatin enhancer and a PDT drug, a metal complex based on a ruthenium(II) ion. The result is a drug that can bind to DNA and distort its structure to trigger cell death and be activated by light to create a reactive oxygen species which can interfere with cell metabolism to cause death. “In clinical protocols, each drug is administered separately and may not reach the tumour at the same time or at a fixed ratio,” says Professor Gilles Gasser from the Paris Sciences et Lettres (PSL) University in Paris, France, who is one of the leading authors of the study. The idea of creating the conjugate was that it would enable the three drugs to travel through the bloodstream intact and enter their target tumour cells, which would reduce side effects and the need to adjust drug dosages. According to the team, they designed the phototherapeutic Ru(II) portion to be excited by a deep red laser light which penetrates deeply into biological tissue. The Pt, or cisplatin and phenylbutyrate component, is a pro-drug, activated by parts of the cells to limit off-target and systemic effects. The two therapeutic components are joined by a molecular spacer: “The correct spacer length was critical to ensure that both drug compounds will not interfere with each other, but the molecule remains small, water-soluble and able to travel across membranes,” Gasser said. In their experiments, the team added Ru-Pt to both normal and cancer cell lines. Ru-Pt was shown to be more effective at killing cancer cells than the single compounds Ru(II) and Pt(IV). The study’s authors reported laser irradiated samples had significantly higher tumour-killing rates, indicating the specific drug activation was possible. They concluded that Ru-Pt had a 10 times higher efficiency for drug-resistant cell lines than the single reagents, from which the researchers suggested multi-modal drugs may be the key to developing more selective and effective drugs with fewer side effects for treating cancer.