Use synthetic chemistry to plan the route of drugs into the body

Researchers at the RIKEN Cluster for Pioneering Research (CPR) have developed a technique that allows the body to change the recognized identity of proteins.

The innovation, published October 2 in Nature Communications, allows researchers to target tumors in mice with a protein and transport the protein out of the body. This means that cancer-killing drugs can be delivered directly to tumors and excreted from the body after dropping their payload.

This technology also has the potential to enable multipurpose drugs that can travel from organ to organ and exert distinct effects in each location.

Proteins in the blood travel throughout the body, making them ideal carriers for targeted treatments for diseases such as cancer. To avoid damage to non-target tissues, drugs must bind to and damage the correct cells, and this requires a complex molecular ID card.

The new study, led by RIKEN CPR’s Katsunori Tanaka, was able to alter the tissues in the mouse body to which albumin can attach by altering the identification marker on the surface of albumin, the most abundant protein in the blood. focused.

In previous research, Tanaka’s team investigated the cancer-targeting ability of various identifying marking molecules (called glycans) that bind to albumin. They found that identification pattern “A” not only binds to human colon cancer, but can also be transported to the bladder and excreted in the urine, whereas identification pattern “B” transports albumin to the liver. It is taken up, sent to the intestines, and excreted from there.

The main innovation of the new research was to figure out how to change albumin’s molecular ID card after it reaches its destination in the body. To accomplish this, the researchers used a chemical click-to-release method.

First, albumin-1 was created by adding the identification pattern “A” to albumin. So they devised a switching carrier and its partner. The switcher had the identification pattern “B” and its partner was bound to albumin-1.

When albumin-1’s partner encountered the switcher in the dish, a click-to-release reaction occurred, clicking on the “B” identifier and releasing many “A” identifiers. The new albumin was called albumin-2 and was a mixture of identification patterns “A” and “B”.

In an initial proof-of-concept experiment in mice, they labeled albumin-1 with a fluorescent protein and injected albumin-1 into the bloodstream of mice with or without a switcher. As expected, when using the switcher to inject albumin-1, the researchers observed fluorescence in the intestine similar to that observed after injecting albumin-2. Without the switcher, fluorescence was only seen in blood, bladder, and urine.

Having shown that they can indeed change the surface properties of albumin in the body, the researchers next tested whether albumin-1 could be delivered to tumors and removed through the intestine, mimicking drug delivery and clearance. Tested.

They injected albumin-1 into mouse colon tumors with and without a switcher after a short 10-minute delay. In both cases, albumin was observed to be attached to tumor cells. After injecting Switcher, the properties of the albumin changed, and much of it moved from the tumor to the intestine within 5 hours. Without the switcher, albumin-1 would not have reached the intestine.

The biocompatible reactions used in the new technique make it particularly attractive, and this new technology has the potential to revolutionize the treatment of multiple conditions.

“Our strategy could be used as a drug delivery system to enhance the excretion of drugs or medical radionuclides from tumors after treatment,” explains Professor Tanaka. It could potentially be used to treat multiple diseases at the same time, like the technology depicted in the movie Fantastic Voyage. ”