Examples of water-soluble prodrugs. a Orally administered therapeutics that possess a water-soluble promoiety (e.g. phosphate or phosphonooxymethyl group). b Intravenously administered commercial drugs possessing various water-soluble promoieties. Created in BioRender. Smith, M. (2024) BioRender.com/l22c048. Credit: Nature Communications (2024). DOI: 10.1038/s41467-024-52793-6

For many people with cancer, intravenous (IV) infusions of chemotherapy are their best chance at a cure. But these infusions can be inconvenient or inaccessible to patients, and some complications arise not from the active drug itself, but the infusion. Turning these drugs into pills could be transformative.

In a study published in Nature Communications, a team of researchers led by Mark Smith, the director of medicinal chemistry at Sarafan ChEM-H at Stanford University, has designed a small molecular tag that—when appended to almost any drug molecule—can make drugs normally administered through an IV effective as oral pills.

It also makes pills more effective at lower doses. Through early trials in mice, the team showed that their version of oral paclitaxel, one of the most prescribed chemotherapy drugs for many common cancers, performed better than the typical IV dose.

“This is an embarrassingly simple solution to an old problem,” said Smith. “With this strategy, we can accelerate a huge variety of new drugs through the clinic.”

“The impact of a nontoxic and effective oral paclitaxel could be enormous,” said James Dickerson, a Stanford oncologist who specializes in breast cancer care and health equity. Dickerson is not affiliated with the study. “It could lead to a better patient experience and, globally, it would increase access to care for patients with the most common cancers.”

Oil and water

The journey of a pill from mouth to bloodstream has a few important stages. After a person swallows a tablet, it dissolves in the stomach, releasing the drug molecules packaged inside. These molecules then get absorbed into the walls of the stomach or the intestines and make their way into the bloodstream.

Once they get into the bloodstream, the drug molecules can travel to the organs where they are needed. There, they cross cell membranes and get inside the cells, where they finally have the chance to do the job they were designed to do. Oftentimes, drugs work by lodging themselves into very specific pockets in particular proteins and blocking the proteins from performing a task.

To quantify how well a drug navigates the journey through the body, drug developers use the term “bioavailability,” which refers to the percentage of the total amount of drug you swallow that ends up in your bloodstream. It’s normal for this number to be pretty low, around 20%, but the reason may be surprising. It’s because oil and water do not mix.

To complete the final steps of their journey—crossing cell membranes and slotting into their protein pocket—a lot of drugs need to be lipophilic, or soluble in oil. But to complete the first steps of the journey—formulating into a pill and dissolving in the stomach—the drug needs to be soluble in water. This is the central paradox of bioavailability: The drug needs to be both water and oil soluble.

Sometimes, a patient only needs a small amount of a particular medicine in their blood to have an effect, so low water solubility is OK. But sometimes, patients need to meet a higher threshold of medicine. In these cases, they may need to take many pills several times a day, or they need to take the medicine via IV infusion just to get enough in their blood.

A tough pill to swallow

Most drug developers take one of two strategies to make oil-soluble drugs more water soluble. In one strategy, they formulate the drug in a cocktail of other molecules. But scientists have to customize the “cocktail” for each new drug.

In a second strategy, they create a “prodrug,” which involves adding a small chemical tag onto their drug molecule. The challenge is that the tag needs to stay attached for just the right amount of time. If it falls off too early, the drug will not be soluble in the stomach and it will never be absorbed by the intestines. If the tag never falls off, the drug will not be able to slot into its protein pocket.

These two strategies are complicated, time-consuming, and expensive, which means that scientists may have a molecule that could be transformative as a medicine, but they will spend years of research trying to turn it into something that a patient can swallow.

Smith first came across the problem when two clinicians reached out to him in the same week, frustrated that they could not dissolve two FDA-approved drugs in any liquid, which was a necessary step in their research. They needed Smith’s help.

Smith, who developed drugs at Roche before being recruited to lead the medicinal chemistry group at Sarafan ChEM-H in 2013, saw the potential to solve both the laboratory annoyance and the chronic clinical problem of low drug solubility. He thought that he could develop a simple prodrug tag that would make any drug that it is attached to soluble in water and then fall off at exactly the right moment.

To do that, he designed the tag to have the same chemical properties that allow soaps to cut through grease, and he engineered the tag such that it would only be cleaved off by enzymes that sit atop the cells that line the stomach and intestines. Just as the prodrug is absorbed, the soap-like tag is ejected, and the water-soluble prodrug transforms into the oil-soluble drug.

He called this new tag “sol-moiety,” and he hoped that by dangling it off the side of insoluble drugs, he could make them effective as pills.

Passing the test

One of the first drugs the team tackled was vemurafenib, a melanoma therapeutic that is extremely insoluble in water. That insolubility means that patients need to take huge doses—four large pills twice a day—and only a small amount ever gets absorbed in the body. The solubility of the drug is so low that some patients do not respond at all to the therapy.

The results were dramatic. Adding sol-moiety to the vemurafenib skyrocketed the bioavailability from nearly zero to 100%. This means that adding the small chemical tag could make the melanoma drug more effective for more patients at a significantly lower dose.

“At the outset of the project, we were merely hoping to make drugs soluble in water,” said Smith. “With this example, we went way beyond our expectations.”

The team then became more ambitious. Paclitaxel, often sold under the brand name Taxol, is one of the most widely prescribed chemotherapy drugs and is used to treat a variety of cancers, including breast, ovarian, and lung. Over one million patients have been treated with the drug over the last 30 years.

The drug is also nearly completely insoluble in water and is only soluble in a mixture that contains castor oil, which means that the drug can only be given as an IV infusion. But many patients have adverse reactions to castor oil, so they often have to be treated with an IV infusion of steroids before the hours-long chemotherapy infusion. The need for IV infusion also means patients have to go to a medical center to be treated, limiting global access to this medicine.

An oral paclitaxel was the team’s ultimate test of their sol-moiety tag. In a mouse model of pancreatic cancer, the modified oral paclitaxel, which was now water soluble, performed better than a typical IV dose.

This is the first report ever of an effective oral paclitaxel prodrug. Importantly, the researchers have so far not seen any toxicity associated with their sol-moiety tag.

“This could transform the way millions of patients around the world receive chemotherapy,” said Smith. “They’ll have the convenience of staying home to receive care, and they won’t have to do long infusions or receive steroids.”

These results are still early and have only been tested in mice. Given the results so far, the team has high hopes that this could also improve the effectiveness of the drug in humans, while also lowering treatment costs.