Researchers have developed a novel platinum-enhanced, light-activated compound that kills cancer cells in a unique way without requiring oxygen, overcoming a limitation with existing light-based cancer therapies. Their discovery paves the way for developing the next generation of anti-cancer drugs.
Photodynamic therapy involves the introduction of an agent called a photosensitizer that is then activated by a specific wavelength of light energy, usually a laser or LED. Light activation generates reactive oxygen species (ROSs) that damage cancer cells, kicking off the process of apoptosis or programmed cell death.
While it has proven an effective cancer treatment, a problem with photodynamic therapy is that it requires the presence of oxygen to generate the ROSs that cause cell death. Because most solid tumors possess a hypoxic (low oxygen) microenvironment, the effectiveness of conventional photosensitizers can be limited.
To overcome this limitation, researchers from City University, Hong Kong, developed a novel platinum-enhanced, light-activated agent that effectively kills cancer cells without requiring oxygen.
Platinum(II)-based chemotherapies have been used for many years to treat cancer. However, they’re prone to cause side effects such as toxicity and drug resistance. Platinum(IV), or Pt(IV), is a prodrug, meaning it is pharmacologically inactive until it’s metabolized upon entering cancer cells, making it more attractive because it has higher stability and fewer side effects than Pt(II) compounds.
Previous studies have demonstrated that adding transition metals like platinum to photosensitizers increases their efficiency. So, the researchers conjugated Pt(IV) complexes with organic photosensitive ligands and discovered that it led to an effect called ‘metal-enhanced photo-oxidation.’ Their discovery led them to develop a new class of near-infrared-activated Pt(IV) photo-oxidants.
They administered their novel compound to mice with tumors by intravenous injection. Four hours later, they applied near-infrared (NIR) light to the mice to activate the photo-oxidants and found that it led to an 89% reduction in tumor volume and a 76% reduction in tumor weight, indicating the cancer-inhibiting effect of the Pt(IV) photo-oxidants. Whereas conventional platinum-based anticancer drugs cause cancer cell apoptosis, the researchers found their compound led to a unique form of cell death.
“Intriguingly, we found that the ‘death mode’ of cancer cells induced by the Pt(IV) photo-oxidants differs from that of any other anticancer agents,” said Guangyu Zhu, corresponding author of the study. “A unique mode of cancer cell destruction was initiated through the dual-action effect of strong intracellular oxidative stress and reduced intracellular pH value.”
What they observed was that after Pt(IV) photo-oxidants that had accumulated in the cancer cells’ endoplasmic reticulum – the protein synthesis and transportation hub – were activated by NIR light, they oxidized biomolecules inside the cells without requiring oxygen, producing ROSs, lipid peroxides and protons. The ROSs and lipid peroxides produced oxidative bursts that damaged essential components of the cancer cells, while the protons lowered intracellular pH, creating an unfavorable acidic microenvironment.
In addition, the researchers observed that the Pt(IV) photo-oxidants activated the mice’s immune system, recruiting and activating immune cells. Compared to the control group, after light activation, the number of helper T cells increased seven-fold, and the number of cytotoxic T cells increased 23-fold. Cytotoxic, or killer, T cells recognize and destroy cancer cells directly, whereas helper T cells help activate cytotoxic T cells.
“By inducing nonclassical necrosis, Pt(IV) photo-oxidants can overcome the resistance of cancer cells to traditional photodynamic therapies and chemotherapy agents, activate the immune system, and effectively eliminate cancer cells,” Zhu said. “These findings serve as proof of concept and suggest that the development of photo-oxidants based on metal-enhanced photo-oxidation is a promising new direction for developing metal-based anticancer drugs.”
The researchers plan to undertake preclinical studies to comprehensively characterize the chemical, biological and pharmaceutical properties of the novel Pt(IV) photo-oxidants with the goal of identifying compounds for clinical testing.
The study was published in the journal Nature Chemistry.
Source: City University of Hong Kong
