Back in the 1970s, medical  researchers had a problem.

They were finding out the molecular  basis of a bunch of diseases, which let them design drugs that could  target those diseases at the source. Super groundbreaking stuff.

It’s still cool, it’s less groundbreak now. Unfortunately, having a drug that works on paper and a drug that works in a  human are two different things. The body is always on alert for  stuff that doesn’t belong there, so a drug has to get where it’s going without the liver or kidneys or immune system showing it the door.

One researcher had a bold idea, an idea so out there that no one believed it could possibly work. Here’s how he proved them all wrong – and probably helped you in one way or another. [Intro Music] This episode was made in  partnership with The Kavli Prize. The Kavli Prize honors  scientists for breakthroughs in astrophysics, nanoscience and neuroscience, transforming our understanding of the big, the small and the complex.

In the 1970s, Judah Folkman, a cancer researcher, was trying to solve two small problems. First, he was trying to cure cancer. No biggie there.

And second, develop a system that would let a drug be  administered slowly and evenly across a long period of time  inside a patient’s body. Compared to curing cancer, that second one might seem kind of in the weeds, but at the time there was a huge  appetite for that kind of system. that could offer long lasting treatment for conditions like chronic  diseases and allergies, things that affect a lot of people. And it could make those  treatments easier to actually use.

You could toss out your pill organizer, because a slow release  device would be long lasting. Plus it would maintain more consistent  levels of drug in your body, meaning fewer side effects. The way we take drugs now is always like spike and drop and spike and drop and that’s good for some but not good for others Cancer treatments like  chemotherapy could benefit too, replacing huge, intermittent, and toxic doses with a more consistent, targeted option.

Folkman had some ideas about how to  kill those two birds with one stone. For cancer, he knew that tumors were somehow making new blood vessels, a process called angiogenesis. So he figured a drug that  could block that process, a so-called angiogenesis inhibitor, would suffocate the tumors  and kill the cancer cells.

But those angiogenesis inhibitors needed to get into the body somehow, and that’s where he hoped a new drug delivery system could come in. It would need to release  the drug over a long period, but it would also need to be non-toxic and not alert the immune system. Folkman's idea was to use  a type of silicone rubber that was already being used in heart valves, shrink it to a centimeter and a half long capsule, and stuff it with angiogenesis inhibitors that would slowly leak out over time.

Unfortunately like many things that are attempted it failed to act as a long term device, and it didn’t work at all for drug  molecules over a certain size. Plus, he hadn’t even found an  angiogenesis inhibitor yet. And that’s around when Folkman welcomed a somewhat nontraditional  researcher to his lab.

Robert Langer was an engineering graduate, yet he was eager to tackle these problems. Langer proposed some  improvements to Folkman’s idea. Like, he thought a centimeter  and a half was way too big.

He wanted to use a nanoparticle. A centimeter is one hundredth of a meter. A nanometer is one billionth of a meter.

Basically – we’re talking really,  really, really teeny-tiny. Langer wanted to make a nanoparticle under 200 nanometers in diameter, because anything bigger than that would struggle to get through a cell’s membrane, and likely be degraded faster. Then he would stuff a drug into that nanoparticle, like a little water balloon.

At the time, the idea of using nanoparticles was a pretty wild concept. They were notorious for being  almost immediately destroyed by the body’s immune system. Plus, scientists didn’t think  there was a way for substances to get out of the nanoparticle.

Despite that though, Langer was ready to figure it out. As for finding angiogenesis inhibitors, he started where every  self-respecting scientist does: a visit to the slaughterhouse. He collected tons of cow bones,  hauled them back to the lab, then pretty much screened substances in them for anything that might inhibit angiogenesis.

He identified around one hundred  candidate compounds to test. So, next was to develop a  nanoparticle to deliver them. When it was all fleshed out a bit more, that became a polymer nanoparticle, which was essentially a ton  of small chemical subunits called monomers all linked together.

And in 3D, those links made layers with a dizzying array of nooks and crannies. Langer could then stuff drug  inside this complex polymer maze. Scientists love their mazes, and not just for putting rats inside of Over time, the drug would slowly make its way through the maze and diffuse out, allowing for long-term, slow release.

Using that method, Langer was able to steadily release drugs for over 100 days. Other improvements were made over time as well, like changing the charge of the particle to make it safer, adding a piece to the polymer to help it evade immune detection, and messing with the particle to keep it releasing the drug even as it eroded. The team ended up finding those  angiogenesis inhibitors too.

So when another researcher approached Langer hoping to use his delivery  system for brain cancer, Langer was ready. If getting drugs where they need to go elsewhere in the body is hard, getting them into the brain  is darn near impossible. The blood-brain barrier is pretty much the world’s best club bouncer, keeping a whole lot of things, including cancer treatments, out of the brain.

But maybe nanoparticles could slip through. Despite the valiant cause, Langer was facing an uphill battle trying to get this research funded. Like, the government wouldn’t fund his work because they didn’t think  the polymers could be made, so Langer and a graduate student of his synthesized it themselves.

Then concerns were raised about  how the polymer would react with the drug itself. After they solved that problem too, funders worried it couldn’t  withstand the bodily environment. Then that it would be toxic.

Then that it didn’t allow the  drug to diffuse far enough. Eventually, however, Langer’s team secured FDA  approval for their method. Langer got patents for his  slow release technology, which he did not use to create  a monopoly in the industry.

Instead he sublicensed to many companies, ensuring the technology could  help as many people as possible. He also helped found several companies, including a little Boston startup you might have heard of known as Moderna. For their COVID-19 vaccine, they used a lipid nanoparticle  to contain the mRNA, something that would not have been possible without the earlier research  into polymer nanoparticles.

So if you’ve had a COVID  shot, you can thank Langer. Indirectly, anyway. And his research doesn’t end there.

Langer and a colleague created microchips that release treatment for osteoporosis, and have been shown to work just  as well as daily injections. His company has used this kind of technology to treat everything from type 2 diabetes and alcohol use disorder to schizophrenia and pituitary dwarfism. He’s even been involved in developing treatments for Parkinson’s disease, making an inhaled alternative to the traditional oral capsules.

Langer has not only been  involved in developing effective, safe treatments for many diseases, but he has also revolutionized the way that drugs are delivered into the body. He may have been working with tiny particles, but he made such a big impact that he was awarded the 2024  Kavli Prize in Nanoscience. You can learn more about him and his research at www.kavliprize.org. [ outro ]