Heavy Metal Wonder
An iridium-based photodynamic drug accumulates in cancer cell nuclei – and destroys them from within
Jonathan James | | Quick Read
After the approval of cisplatin in the late 1970s, scientists struggled to replicate the success with other heavy metal-based chemotherapeutics. But, more recently, the field has seen somewhat of a resurgence with new metal-based compounds boasting distinct modes of action (1). Now, a paper in the international edition of the German journal Angewandte Chemie highlights a new photosensitizer with iridium at its core (2).
Co-author Cinzia Imberti, a Wellcome Trust funded Research Fellow working with Peter Sadler at the University of Warwick, explains why the team focused on the heavy metal: “Iridium was particularly interesting to us for two reasons. The first was its anti-cancer properties, which are similar to platinum. The second is the fact it is phosphorescent; when you shine a light on it, it generates a trackable green color.” But a challenge remained: “Heavy metals can dissipate everywhere in the body and have unwanted effects,” says Imberti. And so, the team set out to identify a suitable molecular tether – and found one in albumin. “With the organoiridium-albumin bioconjugate, we saw delivery to the nucleus of cancer cells” – an effect that was not seen in non-cancerous tissue controls, says Imberti. Once activated by light, the complex appears to convert the oxygen within the cell to another form – singlet oxygen – which is highly toxic. “A cancer cell is very prone to oxidative stress – anything that can further modify the balance is going to be very detrimental to the cell,” she says.
Work ahead includes understanding the bioconjugate’s selectivity: “We need to understand why the albumin-iridium complex is localized to the nucleus,” says Imberti. “It’s a sort of Trojan horse in that regard.”
The ultimate goal for the international group of biologists, chemists and pharmacists has always been to translate the discovery into the clinic – and they are planning for the long road ahead. “We need to develop a better model – and identify which cell lines we would use in preclinical trials,” she says. “We will then have to work very closely with clinicians to understand therapeutic needs.”
The road ahead is not completely unknown territory; photodynamic therapy based on a palladium compound as an agent against low-risk prostate cancer has proven promising in early clinical trials (3) (4). For Imberti, the prior success offers good reason to be optimistic: “It shows there’s a real possibility our work can move forward. We just have to find the approach that would benefit patients the most.”
- U Ndagi et al., “Metal complexes in cancer therapy – an update from a drug design perspective.” Drug Des Devel Ther. 11, 599-616. (2017) PMID: 28424538.
- P Zhang et al., “Nucleus-Targeted Organoiridium-Albumin Conjugate for Photodynamic Cancer Therapy.” Angew Chem Int Ed Engl. [Epub ahead of print] (2018) PMID: 30552796.
- J Trachtenberg et al., “Vascular targeted photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent prostate cancer following definitive radiation therapy: assessment of safety and treatment response”, J Urol. 178, 1974-1979 (2007). PMID: 17869307.
- T Gheewala, T Skwor & G Munirathinam, “Photosensitizers in prostate cancer therapy”, Oncotarget. 8, 30524-30538 (2017). PMID: 28430624.