Catalyst makes drugs inside the body to minimize side effects

A highly active catalyst capable of synthesizing drug molecules in the body has been developed by RIKEN chemists. In mice, an anticancer drug assembled near tumors using the injected catalyst suppressed tumor growth.

The article is published in the journal Chemical science.

In conventional medications administered by injection or pill, the active drug molecule circulates throughout the body, flooding not only the target site but also healthy tissues. The resulting side effects can be so severe that they can cause permanent damage and force discontinuation of treatment.

Assembling drug molecules at target sites in the body could make them more effective while minimizing their side effects.

“Direct drug synthesis in the body would allow drugs to treat diseases without causing side effects in healthy tissues,” explains Katsunori Tanaka, chief scientist at the RIKEN Biofunctional Synthetic Chemistry Laboratory. “This is why we need a biocompatible biocatalysis system to carry out drug synthesis near target sites in the body.”

The team targeted the assembly of drugs in the body using a catalytic chemical reaction called olefin metathesis. “Olefin metathesis is one of the most efficient methods for constructing carbon-carbon double bonds for drug synthesis,” says Tanaka. “If this could be engineered in the body, it should allow us to synthesize many different types of drugs.”

Most chemical catalysts are quickly deactivated by biomolecules present in the blood. To overcome this problem, the team wrapped a ruthenium-based olefin metathesis catalyst into a protective protein called human serum albumin.

Tanaka’s team had previously shown that a ruthenium chloride complex embedded in human serum albumin, forming a catalytic assembly called an artificial metalloenzyme, was somewhat active in blood. Now they have shown that switching to a ruthenium iodide complex produces a much superior artificial metalloenzyme.

At low catalyst concentrations, the novel albumin-based ruthenium iodide (AlbRuI) catalyst catalyzed three types of olefin metathesis reactions in blood with high yield.

“AlbRuI also showed robust stability for 24 hours in blood,” says Tanaka. “This expands the biocompatibility of artificial metalloenzymes and opens the door to the development of general metal-based artificial metalloenzymes for catalytic reactions in blood.”

The team also showed that a low dose of cancer-targeting AlbRuI significantly inhibited tumor growth in mice through localized synthesis of an anti-tumor drug.

The team intends to expand the use of its catalyst. “We hope to use AlbRuI to synthesize various bioactive molecules,” says Tanaka. “We could then use it to treat not only cancer but also other diseases without side effects.”