Microbubbles - Works in Progress Magazine

It’s incredibly hard to deliver drugs to the right organ, especially to reach the brain. Tiny gas-filled spheres that burst on command could change that.

One of the central problems in medicine is delivering drugs in the body, at the right time, place, and concentration. In many cases, less than one percent of an injected cancer drug dose actually reaches the tumor. The body is difficult terrain to navigate and unforgiving to outsiders. Some drugs need to evade immune cells, and many fail due to unsuccessful delivery. But the brain is even more forbidding. It has a defensive barrier that excludes nearly all large drugs, such as antibody therapies and nanoparticles, and most small molecule drugs, such as most chemotherapy drugs. This makes it much harder to treat conditions like epilepsy, Alzheimer’s and Parkinson’s than diseases in the rest of the body.<br>To overcome these problems, researchers have long experimented with vessels that could transport drugs to their destination while shielding them from the body’s defense system. These include nanoparticles, which are tiny structures made from metals, polymers or lipids that are about a thousandth of the width of a single human hair; liposomes, which are fatty spherical pouches whose walls are made from the same material as cell membranes; and nanobots, hypothetical miniature machines that could perform tasks at the molecular or cellular level.

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But all of these face challenges. The liver and spleen intercept a large fraction of nanoparticles before they ever reach the target (though they still show promise for certain breast and lung cancers, as they can more easily permeate blood vessels). Liposomes face a similar problem: macrophages in the liver recognize and engulf most of them on the journey. Working nanobots are still a distant prospect. And most are blocked from reaching the brain. These are some of the barriers that microbubbles may be able to cross.<br>Boy in the bubble<br>Microbubbles are just what they sound like: tiny gas-filled bubbles. Scientists have engineered them further, to be coated with a protective outer shell and made capable of carrying drugs or genetic material to cells in the body. They are microscopic, roughly the width of spider silk, but still hundreds or thousands of times larger than nanoparticles or liposomes. This means they’re too large to leave the bloodstream. Instead, microbubbles deliver drugs by bursting on command.<br>As they burst open, they briefly force open biological barriers that are otherwise impenetrable, such as the blood-brain barrier, allowing treatments to pass through. The force of their bursts can even be the treatment itself, as they could also be used to break apart kidney stones.

Microbubbles are far larger than liposomes or nanoparticles.

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Ambika Grover.

Microbubbles were first developed to help radiologists read scans. In the late 1960s, doctors at the University of Rochester were using ultrasound to take pictures of heart structures when they made an accidental discovery. When they injected saline into a vein near the heart, their ultrasound image lit up with a cloud of bright signals. The flashes had been created by tiny air bubbles, formed by the rush of fluid from the injection: sound waves passed through blood and tissue fairly smoothly, but once they encountered gas, the change in density reflected the waves back to the sensor.<br>That discovery became a standard technique for spotting structural defects in the heart: if bubbles crossed from one chamber to the other on the scan, it indicated a hole. But the bubbles were short-lived and inconsistent in size, so researchers began experimenting with other injectable substances, including blood and medical dyes, to produce stronger, more stable signals. These efforts to engineer reliable contrast agents for ultrasound imaging mark the beginning of what we now call medical microbubbles.<br>Over the following decades, researchers moved from experimenting with whatever was at hand to deliberately designing microbubbles from scratch, giving them thin shells of lipids, proteins, or polymers to control their size and keep them stable long enough to be clinically useful.<br>One approach to create a protective shell was to use albumin, which is familiar as the protein in egg whites but is also the most common protein in the bloodstream, where it is used to ferry molecules through the body. Since the body already produces it in large quantities, it doesn't provoke an immune response and can be used medically. It also has useful structural properties: it unfolds and hardens into a shell sturdy enough to survive circulation, but is brittle enough that it can fall apart when hit by focused sound waves. Albunex, an albumin-coated and air-filled microsphere, was approved by the FDA in the early 1990s for use in cardiac ultrasounds,...