Newswise — A critical requirement for antitumor agents is their ability to selectively eliminate cancer cells without harming healthy tissue or causing any toxic side effects. To address this challenge, a groundbreaking method utilizing "self-immolative" polyferrocenes has emerged. These copolymers disassemble into their constituent parts upon entering a tumor cell, offering a novel approach that holds promise in meeting the aforementioned criteria. Recent findings published in the journal Angewandte Chemie by a dedicated research team reveal that the drugs encapsulated within these polyferrocenes work synergistically, triggering a rapid surge in free radicals and incapacitating the defense mechanisms of tumor cells.
Xianglong Hu and Shiyong Liu, leading a team from the University of Science and Technology of China in Hefei, have successfully integrated two mutually reinforcing molecules into a copolymer structure. This innovative copolymer exhibits hydrophobic properties at one end and hydrophilic properties at the other. When introduced into an aqueous environment, the copolymer chains assemble into nanoparticles, with their hydrophobic segments orienting inward and their outer hydrophilic portions shielded by polyethylene glycol moieties. Polyethylene glycol is a harmless polymer extensively employed in cosmetics and pharmaceuticals. The presence of the polyethylene glycol layer prevents rapid disintegration of the nanoparticles in the bloodstream due to the actions of immune system components.
Within healthy tissues, the nanoparticles remain stable and inactive, exhibiting no detrimental effects. However, it is within the significantly more acidic environment of tumor cells where a remarkable phenomenon called "self-immolation" is triggered. At this critical stage, the nanoparticles undergo disintegration, causing the hydrophobic ends of the polymer chains to separate into their individual building blocks. These building blocks consist of azaquinone methide (AQM) units, which bear aminoferrocene sidechains. Aminoferrocene is a unique iron complex referred to as a "sandwich complex." In this complex, the iron atom acts as the filling, positioned between two flat, aromatic, five-membered carbon rings serving as the slices of bread.
Following the entry of the nanoparticles into tumor cells, an activation process involving glutathione takes place. Glutathione, renowned for its antioxidant properties and ability to trap free radicals, plays a crucial role in eliminating foreign substances from cells. Glutathione initiates an attack on the azaquinone methide units, binding to them and subsequently dissociating the iron sandwiches. Once liberated, this complex reacts with hydrogen peroxide (H2O2) that is naturally present within the cells, resulting in the formation of hydroxyl radicals (•OH). As part of this process, the divalent iron within the complex undergoes oxidation, converting it into trivalent iron. However, glutathione promptly reduces the trivalent iron back to FeII, thereby forming a detrimental cycle that consumes glutathione and leads to a sudden surge of hydroxyl radicals within the tumor cell. The synergistic effect of these two processes places the tumor cells under severe oxidative stress, causing substantial damage and ultimately leading to their demise.
Experiments conducted by the research team, both in vitro and in mice with tumor models, have demonstrated the remarkable efficacy of this approach in inhibiting tumor growth while exhibiting minimal side effects. These findings open up new possibilities in the field of chemodynamic therapy (CDT) for the treatment of tumors.
About the Author
Dr. Shiyong Liu is the Professor of Polymer Chemistry and Director of the School of Chemistry and Materials Science at the University of Science and Technology of China (USTC). His current research focuses on precision polymer chemistry (e.g., discrete polyethylene glycol, PEG, and derivatives, as well as sequence-defined polymers), active modulation of protein corona for delivery nanoparticles, and origin of biological homochirality (the choice of L-amino acids).
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