Controlling Nano-Sized Machines to Deliver Drugs in the Body

Title: Self-propelled supramolecular nanomotors with temperature-responsive speed regulation

Authors: Yingfenu Tu, Fei Peng, Xiaofeng Sui, Yongjun Men, Paul B. White, Jan C. M. van Hest, and Daniela A. Wilson

Journal: Nature Chemistry

Year: 2017

https://www.nature.com/articles/nchem.2674

Using tiny machines with even smaller motors in medicine has been a staple of science fiction for decades, ranging back to the 1966 film Fantastic Voyage, in which a submarine full of scientists was shrunk down to perform a microscopic operation. But small, self-propelled devices capable of moving by themselves to deliver life-saving medications are quickly becoming reality. Recently, researchers have made “nanomotors” that not only move independently, but also can stop and start by controlling temperature.

The basic chemistry used to make these motors work has been known for centuries and is based on a common household chemical: hydrogen peroxide (H2O­2). While often used as a bleach or disinfectant, hydrogen peroxide is actually naturally unstable. This means that over time, two molecules of hydrogen peroxide will break down into two molecules of water (H2O) and one molecule of oxygen gas (O2­). While this process happens slowly on its own, if it were sped up, the stream of oxygen made by the reaction could propel an object forward.

The decomposition of hydrogen peroxide into oxygen and water can be sped up in many ways, like heating or exposure to light. But luckily, a metal catalyst can also be used. When platinum nanoparticles are exposed to hydrogen peroxide in a liquid, small bubbles of oxygen gas form at the surface of the particles. If this gas can be funneled in one direction, it can push the nanoparticles forward. And if the nanoparticles are inside of some small structure, it gets pushed forward as well. Think of this a tiny rocket motor, ejecting gasses and pushing the rocket.

This is exactly what researchers were able to accomplish in a previous paper. By trapping platinum nanoparticles in a structure called a stomatocyte, which is a small hollow plastic sphere with a single opening (Figure 1D), nanomotors were made, propelled along a straight line with hydrogen peroxide as their “fuel.” The only way to control these nanomotors was to control the concentration of hydrogen peroxide in solution with them. But now, the authors have developed a way to control the motors without changing the solution: installing a “valve” on the stomatocyte’s single opening.

To understand how this valve is made, we need to become a little more familiar with stomatocytes. Figure 1 shows an outline of how these unique structures are made. We start with “polymersomes,” which are small hollow spheres with walls made of a polymer and organic solvent both inside and outside of the sphere (Figure 1A). Because of the organic solvent, these spheres are flexible, like a water balloon. But, when the solution outside the polymersome is replaced with water, the organic solvent flows out of the polymersome. This causes the polymersome to bend inside of itself, like one wall of a balloon being pulled from the inside (Figure 1B). After all of the organic solvent is pulled out of the polymersome, the polymers aren’t flexible anymore and are locked into shape, becoming a stomatocyte (Figure 1C).

Figure 1: Forming a stomatocyte from a polymersome. A. The polymersome starts with equal amounts of organic solvent (black) and water (blue) inside and outside. B. When the outside solution is replaced with just water, the walls of the polymersome pull in and change shape. C. The stomatocyte is formed with one large opening. D. Electron microscope image of a stomatocyte. (Figure from dx.doi.org/10.1021/ja104154t)

Adding a valve to the opening of the stomatocyte wasn’t easy; the researchers had to go back to the start of the polymersome synthesis. First, some of the polymers used to make the polymersome were changed so they had bromine atoms at their ends. Because of this, there were bromine atoms spotting the surface of the stomatocyte after it was made. Then, the authors used a process called surface-initiated atom-transfer radical polymerization to attach a different polymer, called poly(N-isopropylacrylamide) (PNIPAM), to the bromine on the surface.

PNIPAM is interesting because at low temperatures it is soluble in water, so the chains reach into solution and are diffuse (Figure 2A). But above 40 °C the polymer collapses into a dense layer around the stomatocyte (Figure 2B). This temperature is called the lower critical solution temperature. Because PNIPAM is hydrophobic (meaning it repels water), when it collapses no solution can flow through the opening of the stomatocyte. Thus, at high temperatures, the valve is closed and hydrogen peroxide can’t flow inside – the stomatocyte’s motor is effectively turned off. At low temperatures the valve is open, hydrogen peroxide can reach the platinum nanoparticles and decompose, producing oxygen gas and pushing the stomatocyte forward.

Figure 2: Stomatocyte “valve” opening and closing. A. At low temperatures, the polymer coating is diffuse in the fuel (hydrogen peroxide) can enter the interior. B. At high temperatures, the polymer coating is dense and the fuel cannot enter.

The authors measured this temperature effect in a few different ways. First, they looked at the velocity of the stomatocytes at different temperatures. Stomatocytes without PNIPAM didn’t slow down at higher temperatures – in fact, they moved faster due to stronger decomposition of hydrogen peroxide (Figure 3A). However, the PNIPAM coated stomatocytes stopped almost completely at 40 °C. Importantly, the motor could be restarted by lowering the temperature again to 30 °C, and then stopped again by raising the temperature (Figure 3B). The temperature could be cycled like this indefinitely, stopping and starting the nanomotor every time. The stomatocytes also moved in nearly straight lines, indicating that only one major force was pushing them forward (Figure 3C). This was measured by calculating the “directionality” (D) of the stomatocytes, where D = 1 is a perfectly straight line and D = 0 is completely random.

 

Figure 3: Measuring stomatocyte movement. A. The stomatocytes without the polymer move at both 30 °C and 40 °C, but the ones with the polymer stop moving at 40 °C. B. The “motor” can be stopped and started multiple times by cycling the temperature. C. The stomatocytes move in nearly straight lines (D = 0.761-0.865) when the “motor” is turned on.

While control of these stomatocyte nanomotors is limited – only stop/start movement, with no in-between – this method gives much more control over the motion of the stomatocytes than was possible before. The researchers have also recently published a paper with similar stomatocytes designed to deliver cancer-treating drugs and then biodegrade in the body. With these developments happening faster than ever, it seems like the science fiction vision of nano-sized drug delivery vessels may be just over the horizon.

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