Self-immolative polyferrocene for tumor treatment
Antitumor agents must kill off cancer cells while protecting healthy
tissue and having no toxic side-effects. A novel approach based on
“self-immolative” polyferrocenes—copolymers that split apart into their
components as soon as they enter a tumor cell—could meet these demands.
The drugs they hold then synergistically cause an abrupt increase in
free radicals and incapacitate the defenses of tumor cells, as reported
by a research team in the journal Angewandte Chemie.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
A team led by Xianglong Hu and Shiyong Liu at the University of
Science and Technology of China (Hefei, China) incorporated two
synergistically cooperative molecules together into a copolymer. The
copolymer chains are hydrophobic at one end and hydrophilic at the
other. In aqueous environments, they aggregate into nanoparticles in
which the hydrophobic ends are all pointed toward the inside and the
outer, hydrophilic portions, are shielded by polyethylene glycol
moieties. Polyethylene glycol is a nontoxic polymer that is widely used
in cosmetics and pharmaceuticals. The polyethylene glycol layer prevents
the nanoparticles from being rapidly broken up in the blood by
components of the immune system.
In healthy tissues, the nanoparticles remain intact and inactive.
Only the significantly more acidic environment of tumor cells triggers
the process of “self-immolation”. The particles fall apart and the
hydrophobic ends of the polymer chains split apart into their individual
building blocks. These are made from azaquinone methide (AQM) units
carrying aminoferrocene sidechains. Aminoferrocene is a special iron
complex, a so-called sandwich complex: the iron atom is the “filling”
between two flat, aromatic, five-membered carbon rings as the “slices of
bread”.
Within the tumor cells, glutathione is subsequently activated.
Glutathione is a free radical trap and antioxidant that helps to remove
foreign substances from cells. Glutathione attacks the azaquinone
methide units, binds to them, and splits off the iron sandwiches. Once
released, this complex reacts with hydrogen peroxide (H2O2)
present in the cells to form hydroxyl radicals (•OH). In this process
the divalent iron in the complex is oxidized to trivalent iron, which
the glutathione reduces back to FeII—a fatal cycle that consumes the
glutathione and abruptly produces a high concentration of hydroxyl
radicals in the cell. The synergy of these two processes puts the tumor
cells under severe oxidative stress, which damages and kills them.
Experiments performed by the team both in vitro and in mice with
tumors demonstrated that this efficiently inhibited tumor growth with
negligible side-effects. This approach could allow for new possibilities
in the chemodynamic therapy (CDT) of tumors.
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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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