Cancer drug with improved targeting and reduced toxicity

NUS researchers have found an alternative to cisplatin, a widely used chemotherapeutic agent, for improved treatment outcomes.

The discovery of cisplatin as an anti-cancer drug in 1965 was an important milestone. This has completely changed cancer treatment and significantly improved the cure rates of cancer patients worldwide. More than 50 years later, cisplatin and newer generation platinum drugs are still used in 40% of all chemotherapy treatments. However, these drugs have toxic side effects, including severe kidney dysfunction which might require some patients to undergo dialysis treatment.

Prof Giorgia PASTORIN from the Department of Pharmacy, NUS and Prof Wee Han ANG from the Department of Chemistry, NUS decided to tackle the problem of cisplatin-induced kidney toxicity and improve cancer treatment outcomes. In collaboration with Prof Dan GIBSON from the Hebrew University in Jerusalem, they have developed a platinum-based drug which could be delivered to the mitochondria in cancer cells and which induces irreversible mitochondrial damage, leading to cancer cell death.

Prof Ang said, “Cisplatin is known to kill cancer cells by damaging DNA, but cancer cells are smart and know the ways to repair this damage and become resistant to the drug treatment. As our drug is delivered directly to the mitochondria, which do not have these special repair mechanisms, the damage of mitochondrial DNA reduces the risk of drug resistance.”

The researchers found that the new drug demonstrated significant reduction of tumour size in murine models in comparison with the cisplatin-treated group. However, the NUS researchers wanted to achieve complete tumour remission.

Prof Pastorin shared that because tumours grow very rapidly, their blood vessels do not have time to develop properly and are leaky. She said, “This microenvironment enables the permeation of nanoparticles from blood vessels to the tumour microenvironment and their retention within the tumour. To exploit this phenomenon, the novel drug was encapsulated into liposomal nanovesicles and it improved the anti-cancer effects even further. When murine models were treated with the drug-loaded nanovesicles, the tumours completely disappeared!”

Dr Maria BABAK, who is part of the research team, added, “We were very excited when we did the histological analysis of the kidneys from the murine models. Our drug was not only effective in killing the cancer cells, it also demonstrated almost no signs of kidney inflammation. This shows that it could be a potential alternative to the highly toxic cisplatin!”

Figure illustrates the strategy for targeted delivery of dual-action Pt(IV) prodrugs into cancer cells through simultaneous tumour- and mitochondria-targeting, providing a unique therapeutic potential for cancer treatment. [Credit: Angewandte Chemie International Edition]

Reference:

MV Babak; Y Zhi; B Czarny; TB Toh; L Hooi; EKH Chow; WH Ang*; D Gibson*; G Pastorin*, “Dual-targeting Dual-action Platinum(IV) Platform for Enhanced Anticancer Activity and Reduced Nephrotoxicity”  ANGEWANDTE CHEMIE INTERNATIONAL EDITION DOI: 10.1002/anie.201903112 Published: 2019.