Metal–Organic Frameworks as a Storage Platform
Paracetamol is a widely used painkiller and normally not harmful to cells. Certain enzymes, however, can oxidize it into a toxin. This toxic side reaction is unwanted in treatments of headache or fever, of course, but it could be useful for killing cancer cells. Hong-Cai Zhou, Texas A&M University, College Station, USA, and colleagues have developed a nanoreactor that can trigger this reaction and stop tumor growth. The nanoreactor is a composite of an oxidizing enzyme and a metal–organic framework (MOF, pictured).
MOFs are highly porous, nanosized compounds comprised of a supramolecular network of metal cations and coordinating organic ligands. These hybrid structures form channels with tunable sizes and shapes and can encapsulate gas molecules, chemicals, drugs, or even proteins. When storing proteins, the MOFs can safeguard their fragile load and protect them from unfavorable conditions such as low or high pH, heat or cold, and chemicals. Enzyme–MOF composites often outperform free enzymes in their activity and stability.
This ability to safeguard enzymes inspired the team to construct an enzyme–MOF composite that could be useful in cancer therapy. The idea was to induce an enzyme in the tumor cells in such a way that it is protected and remains active. Then, when a prodrug which is otherwise not harmful is administered, the enzyme transforms the prodrug into an active drug, which exclusively kills the infected cell. This scenario would complement common chemotherapy since no aggressive drug would travel long ways through the body. It is activated only at the place of use.
Paracetamol can become a toxin if it is oxidized by an enzyme, tyrosinase (Tyr). This reaction can take place in the liver and is a rare, but sometimes fatal side reaction of paracetamol. The oxidized benzoquinone structure will be attacked by glutathione, a cell-abundant natural tripeptide with a sulfhydryl moiety. This attack withdraws the glutathione from the cell, where it controls the level of reactive oxygen species (ROS). The raising ROS level then causes apoptosis (programmed cell death).
To achieve this effect, the tyrosinase must be kept active. The scientists constructed a MOF structure by assembling trimeric oxo clusters of aluminum and a planar triangular triazide ligand. The oxo clusters and the ligand self-assembled into a supertetrahedron, which then formed the nanoparticular porous MOF structure upon heating. With a total size of 100 nm, the MOF with the name NPCN-333 provides cages and cavities where the enzyme with its size of around 5 nm is easily accommodated.
Nanoreactors in Cancer Therapy
The enzyme–MOF composite, Tyr@NPCN-333, is active and “relatively resistant to perturbations”, as the researchers put it. Moreover, it was internalized by a tumor cell line that was resistant to several anticancer drugs. Addition of paracetamol, which on its own is innocuous, stopped the proliferation of the cells. Also, tumors grown in mice shrunk or even vanished after seven days and upon one single treatment.
Paracetamol is not really a compound known for its activity in cancer treatment. In this work, it serves as a model prodrug to demonstrate the MOF nanoreactor concept. The researchers highlight the capability of the MOFs to form composites with enzymes and their application in medicinal chemistry.
- Long-Persistent Enzyme-MOF Nanoreactor Activates Non-toxic Paracetamol for Cancer Therapy,
Xizhen Lian, Yanyan Huang, Yuanyuan Zhu, Yu Fang, Rui Zhao, Elizabeth Joseph, Jialuo Li, Jean-Phillipe Pellois, Hongcai Zhou,
Angew. Chem. Int. Ed. 2018.