Researchers have developed a new platinum-enhanced photoactivatable compound that uniquely kills cancer cells without the need for oxygen, overcoming the limitations of existing light-based cancer therapies. Their discovery paves the way for the development of the next generation of anti-cancer drugs. Photodynamic therapy involves the introduction of an agent called a photosensitizer, which is then activated by light energy of a specific wavelength (usually a laser or light-emitting diode). Reactive oxygen species (ROS) generated by light activation can destroy cancer cells and initiate the process of apoptosis or programmed cell death.
While photodynamic therapy has proven to be an effective cancer treatment, one problem with it is that it requires the presence of oxygen to produce ROS that causes cell death. Since most solid tumors have a hypoxic (low oxygen) microenvironment, the effectiveness of traditional photosensitizers is limited.
To overcome this limitation, researchers at City University of Hong Kong have developed a new platinum-enhanced photoactivator that can effectively kill cancer cells without the need for oxygen.
Platinum(II)-based chemotherapy has been used to treat cancer for many years. However, they are prone to side effects such as toxicity and drug resistance. Platinum(IV), or platinum(IV), is a raw drug, which means it has no pharmacological activity until it is metabolized after entering cancer cells, which makes it more attractive because it has higher stability and fewer side effects than platinum(II) compounds.
Previous studies have shown that adding transition metals such as platinum to photosensitizers can improve the efficiency of photosensitizers. Therefore, the researchers conjugated platinum(IV) complexes with organic photosensitive ligands and found that this resulted in an effect called "metal-enhanced photooxidation." This discovery led them to develop a new class of near-infrared activated platinum (IV) photooxidants.
They injected the new compound intravenously into mice with tumors. Four hours later, they irradiated the mice with near-infrared (NIR) light to activate the photooxidants and found that the tumor volume had shrunk by 89% and the tumor weight had decreased by 76%, indicating that platinum (IV) photooxidants have a tumor-suppressing effect. While traditional platinum-based anticancer drugs cause cancer cells to undergo apoptosis, the researchers found that their compound caused a unique form of cell death.
Guangyu Zhu, the corresponding author of the study, said: "Interestingly, we found that the 'death mode' of cancer cells induced by platinum (IV) photooxide is different from any other anti-cancer drugs. "A unique cancer cell destruction mode is initiated through the dual effects of strong intracellular oxidative stress and reduced intracellular pH."
They observed that platinum (IV) photooxide accumulated in the endoplasmic reticulum of cancer cells (a hub for protein synthesis and transport), after being activated by near-infrared light, can oxidize biological macromolecules in the cell without oxygen, producing ROSs, lipid peroxides, and protons. Oxidative quenching generated by ROS and lipid peroxides destroys important components of cancer cells, while protons reduce the intracellular pH and form an unfavorable acidic microenvironment.
In addition, the researchers observed that platinum (IV) photooxide activated the immune system of mice, recruiting and activating immune cells. Compared with the control group, the number of helper T cells increased 7-fold and the number of cytotoxic T cells increased 23-fold after light activation. Cytotoxic or killer T cells directly recognize and destroy cancer cells, while helper T cells help activate cytotoxic T cells.
"By inducing atypical necrosis, platinum (IV) photooxide can overcome the resistance of cancer cells to traditional photodynamic therapy and chemotherapy drugs, activate the immune system, and effectively eliminate cancer cells," Zhu said. "These findings serve as proof of concept and suggest that the development of photooxidants based on metal-enhanced photooxidation is a promising new direction for the development of metal-based anticancer drugs."
The researchers plan to conduct preclinical studies to fully characterize the chemical, biological and pharmaceutical properties of the new platinum(IV) photooxidants, with the goal of identifying compounds for clinical trials.
The research was published in the journal Nature Chemistry.