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X-Rays Help Deliver Drugs With Pinpoint Accuracy

X-Rays Help Deliver Drugs With Pinpoint Accuracy

Microscopic drug-filled "balloons" can be ruptured precisely where needed.

target cancer-top.jpg

Researchers are developing a new way to deliver targeted chemotherapy. They send tiny medicine-filled balloons into the body and use X-rays to pop them near the tumors.

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Mopic via Shutterstock

Monday, April 11, 2016 - 16:30

Dave Zobel, Contributor

(Inside Science) -- A submicroscopic, remote-controlled, organic "medicine bottle," capable of traveling throughout the body and releasing its contents only where needed, could pave the way to more effective disease treatments.

At the February meeting of the Biophysical Society in Los Angeles, biophysicist Daniel Fologea, of Boise State University in Idaho, briefly outlined recent work in this field, portions of which are undergoing patent review.

In the technology, sometimes referred to as "biocompatible nanocarriers for drug delivery," microdroplets of therapeutic agents are stored inside liposomes, tiny artificial bubbles made of fat molecules. Once inserted into the body, the liposomes travel harmlessly throughout the body, the medication safely bottled up inside them like paint inside water balloons, until a burst of X-rays ruptures them at the desired location and moment.

One potential application for the new technology is cancer therapy, which has historically represented "a delicate tradeoff between killing the disease and killing the patient," said Tatyana Gurvich, a geriatric clinical pharmacologist at the University of Southern California School of Pharmacy and the University of California, Irvine Medical Center who wasn't involved in the research.

Chemotherapeutic agents specifically target fast-growing cells, such as those found in tumors, she said. But when they're allowed to flood the entire body, other fast-growing tissues, including the gut lining and the red and white cells of the blood, are also at risk.

"Chemotherapy's effectiveness is limited by patients' inability to tolerate its side effects, which go far beyond hair loss," said Gurvich. "They include anemia, immunosuppression, and crippling nausea. If the patient loses the ability to fight infection, or if persistent nausea is causing extreme weight loss, effective dosing may become impossible."

The skin of a liposome, by contrast, acts as an insulating layer, protecting the body's healthy cells from its contents. Its membrane, like that of a living cell, consists of a double layer of fat molecules. To help the tiny bubble adhere to specific tissues, the membrane may also incorporate a coating of proteins or other organic compounds. Liposomes tend to concentrate where they are most needed as their small size allows them to seep out of damaged blood vessels often found near tumor sites. These "medicine bottles," which can be manufactured to be smaller than viruses, can last for a couple of weeks, leaking only slightly, before the body naturally breaks them down.

Bursting them open with X-rays, however, takes a bit more work.  That's because the X-radiation used is too weak to tear a hole in the fatty membrane, so a small quantity of a fat-digesting enzyme is prepackaged inside the liposome in an inactive state. Something to activate the enzyme, such as calcium ions, is also added, sequestered in special molecular "cages" to prevent premature interaction. Also included in the package are nano-scintillators, tiny particles that release ultraviolet light when excited by X-rays.

The entire chain of events takes less than two minutes and proceeds as follows: Criss-crossing X-rays intersecting in a region of the body illuminate any liposomes at that location, causing their nano-scintillators to glow. The resulting ultraviolet light bends the atomic bonds that act as the "bars" of the molecular cages, distorting the cages and freeing the calcium ions trapped inside. The freed ions activate the fat-digesting enzyme, which proceeds to break down the liposome's fatty membrane, causing the therapeutic agent to spill out into the surrounding tissue.

Accomplishing this seemingly simple task by such a complicated sequence of steps calls to mind many of cartoonist Rube Goldberg's fanciful "do-it-the-hard-way" contraptions. Wouldn't a one-step process -- perhaps one in which the radiation somehow opens the liposome's shell directly -- be more desirable?

"I would love to have a single-step process," acknowledged Fologea. To that end, he's been working on creating a liposome membrane that's sensitive to pH level, meaning relative acidity or alkalinity. Instead of enzymes, ions, and molecular cages, the bubble contains water and a chemical called an organic halogen. X-rays cause the two to interact, which lowers the liposome's internal pH and makes its membrane permeable.

However, it takes days for this process to release an effective amount of a drug. For maximum efficiency, most drugs should be released in one quick burst. Fologea is currently exploring methods of increasing the liposome's pH sensitivity by completely replacing the lipid bilayer with a polymer-based membrane.

Elsewhere, researchers have developed liposome shells triggered by light instead of X-rays. University of Buffalo scientists recently reported that exposure to certain wavelengths of red light ruptures the chemical skin of a "porphyrin-phospholipid liposome" (or “nanoballoon”). One advantage of this technique is that removing the light causes the hollow shell to seal itself again, allowing any material that may have leaked in to be analyzed later.

Still, the Boise team, and their colleagues at the University of Arkansas, prefer to stick with X-rays, which penetrate much farther into the body than light, while spreading out less. And, noted Fologea, "Since we're using X-rays anyway, some patients might be able to undergo chemotherapy and radiation therapy at the same time."

Dave Zobel is a Los Angeles-based freelance science writer whose credits include the radio shows The Loh Down on Science, StarDate, Day to Day, and “Says You!” His latest book is The Science of TV’s The Big Bang Theory.

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