by Colleen Fleiss on September 22, 2023

A significant breakthrough has been attained by a research team, led by scientists from the City University of Hong Kong (CityU), who have developed a novel category of near-infrared-activated photo-oxidants capable of efficiently eliminating cancer cells even in the absence of oxygen .

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Photodynamic therapy, an innovative cancer treatment approach, utilizes photosensitizers to generate reactive oxygen species (ROSs), which when irradiated by light, selectively kill cancer cells. However, most existing photodynamic therapies rely on the presence of oxygen, while solid cancer tumors often feature a hypoxic microenvironment with very low oxygen levels, limiting the therapeutic efficiency of this approach.

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To address this limitation, a research team led by Professor Zhu Guangyu, in the Department of Chemistry, and Professor He Mingliang, in the Department of Biomedical Sciences (BMS) at CityU, discovered an effect called "metal-enhanced photo-oxidation". By conjugating metals like platinum with organic photosensitive ligands, they significantly enhanced the photo-oxidation capability. This breakthrough led them to develop a new class of near-infrared-activated platinum(IV) photo-oxidants (Pt(IV) photo-oxidants) that can be activated by near-infrared (NIR) light to directly oxidize biomolecules and effectively kill cancer cells without the need for oxygen.

In their experiments, the team administered Pt(IV) photo-oxidants to mice with tumors through intravenous injection. Four hours later, they applied near-infrared radiation to the mice to activate the photo-oxidants to attack the cancer cells. The results demonstrated a significant reduction in tumor volume and weight of 89% and 76%, respectively, indicating the potent tumor-inhibitory effect of the Pt(IV) photo-oxidants.

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"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 Professor Zhu. "A unique mode of cancer cell destruction was initiated through the dual-action effect of strong intracellular oxidative stress and reduced intracellular pH value."

Their experimental data show that after the Pt(IV) photo-oxidants that accumulated in the endoplasmic reticulum inside the cancer cells were activated by near-infrared radiation, they vigorously oxidized crucial biomolecules inside the cancer cells without requiring oxygen, generating ROSs, lipid peroxides and protons. The ROSs and lipid peroxides then triggered intensive oxidative bursts, while the protons lowered the intracellular pH value, creating an unfavorable acidic microenvironment for the cancer cells.

Moreover, their experiments confirmed that Pt(IV) photo-oxidants effectively activate the immune system in both in vitro and in vivo settings. The Pt(IV) photo-oxidants triggered immunogenic cell death, stimulating the proliferation and activation of immune cells. The number of T helper and T killer cells, which are crucial for triggering the body's immune response, in the mice treated with photoactivated Pt(IV) photo-oxidants increased by 7- and 23-fold, respectively, compared to the control group.

"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," explained Professor Zhu.

The research team plans to conduct preclinical studies to fully characterize the chemical, biological and pharmaceutical properties of the newly invented Pt(IV) photo-oxidants. Their ultimate goal is to identify lead compounds for clinical testing.

Reference :

1. Near-infrared-activated anticancer platinum(IV) complexes directly photooxidize biomolecules in an oxygen-independent manner -(https://www.nature.com/articles/s41557-023-01242-w)