Swimming Particles - Future Drug Delivery Vehicles?

For my Ph.D. dissertation, I studied tiny metallic rods that propel themselves ("swim") through hydrogen peroxide.  You can read more about them in my previous post here.  When I tell people about these rods, the most common question I get is, "that's neat and all, but what can you use them for?"  It's a fair question.

My work was mostly focused on figuring out how the rods swim in the first place, which was fun in itself.  But there's some rather tasty icing on the cake: in addition to being interesting, it turns out that "nanomotors," the general term for microscopic swimmers such as the platinum-gold rods, may indeed have some important useful applications.

A rod-shaped "nanomotor" swims toward a piece of inert cargo (green), tugs it along for a short period (red), and releases it at a predetermined location before swimming away (green).

Above, we see that the rods can "tow" a piece of "cargo" (e.g. a tiny polystyrene sphere) from one pre-defined point to another (for more, see this previous post). Today we'll discuss one of the possibilities this raises, related to improving cancer treatment.

A Brief Introduction to Chemotherapy 

Chemotherapy (or "chemo") generally refers to the use of drugs to treat cancer.  Most chemo drugs are administered intravenously, entering the patient's bloodstream and attacking cells all over the body (including, but not limited to, the cancer cells - see note 1).  Thus, even when successful, chemotherapy often kills healthy cells, causing many of the serious side effects of chemo that you're probably familiar with (and may have experienced yourself).  It's kind of like setting off an atomic bomb inside the body; it destroys more than just the intended target.

Can we do better?

Targeted chemotherapy

There's a new type of cancer treatment known as targeted cancer therapy.  The idea is to make "smarter" drugs that target the attributes of cancer cells that make them cancerous in the first place.  As their name suggests, targeted cancer drugs need to be delivered to a specific location: directly to the tumor, rather than the whole body.  But drugs can't find cancer cells on their own.  To make targeted chemotherapy work, you typically need something to carry a drug directly to a cancer cell to kill it, but not harm the surrounding healthy cells in any way.  Instead of an atomic bomb, these drugs act like a sniper, only targeting the bad guys.

But how do you get the drug to the cancer cell?

Could Nanomotors Deliver Drugs?  

Enter Professor Joseph Wang, at the University of California, San Diego, and his research team (a one-time collaborator of ours).  They recently developed a different kind of swimmer from the ones I studied: they manufactured tiny, cylindrical tubes made of a bio-compatible (i.e., non-toxic) material coated with zinc.  They're about 20 micrometers long, about 1/5th as long as a human hair is wide.  Most importantly, these swimmers are powered not by peroxide (which is toxic to humans), but by acid: the zinc reacts with the hydrogen ions in the acid and turns them into hydrogen gas bubbles.  The bubbles are ejected from the tube, which acts kind of like a rocket: the recoil from the bubble release propels the swimmer forward, as illustrated below.

Schematic of zinc-powered nanomotors that use stomach acid as a fuel.  The chemical equation illustrates that solid zinc (on the motor surface) reacts with protons in the acid (H+), creating hydrogen bubbles (H2) which propel the swimmer forward.  Meanwhile, the zinc dissolves harmlessly into the acid (forming zinc ions, with a 2+ charge).

So, why would an acid-propelled swimmer be useful? Isn't acid harmful?

Well, the stomachs of many mammals, including ours, are highly acidic.  Acid, as you may recall, contains plentiful amounts of hydrogen ions, which are basically protons floating around in the solution.  So our stomachs are full of nanomotor fuel.

Professor Wang's research team built these swimmers and coated them with gold nanoparticles (tiny spheres of gold much smaller than the swimmers), which serve as a model "drug."  They administered the gold-laden nanomotors orally to live mice.  After 2 hours, the mice were, as we researchers politely put it, "sacrificed" (for science!) and their stomachs were examined.  Compared to mice that had received an oral dose of nanoparticles alone, the mice that received the nanoparticle-laden swimmers showed over three times as much retention of the gold in their stomach lining.

In other words, the nanomotors acted like delivery trucks, delivering the gold "drugs" into the mice's stomach linings!

The useful thing about these swimmers is that, like the platinum/gold rods I studied, they can carry payloads.  However, unlike the platinum-gold rods, they don't need hydrogen peroxide to move.  They just move based on the stomach acid that's already present!  Even better, the motors slowly dissolve in the stomach acid, leaving nothing toxic behind!

This is a step forward for the field of man-made micro-swimmers.  There are certainly still roadblocks to overcome, of course: for one thing, we need to show that this is viable in humans, and not just for delivering drugs into the stomach lining.  Remember, for targeted cancer treatment, we need to be able to guide these swimmers to a specific location - the swimmers here indiscriminately swam until they collided with the stomach lining.  We do have ways of guiding self-propelling particles, but guiding them to a tumor is still a ways away.

Still, this work shows that the idea of using nanomotors to deliver drugs is not simply a pie-in-the-sky idea, as some people believe.

NOTES!

1. If you're wondering, traditional chemotherapy drugs typically target cells that divide quickly.  Cancer cells divide quickly, which is why chemo drugs often work against them.  The problem is that there are many other cells in the body that also divide quickly but are completely healthy.  These cells are vulnerable to the chemo drugs.

Why Is It So Hard To Solve The World's Energy Crisis?

I'm teaching a class at MIT this semester called "Thermal-Fluids Engineering II."  The class is largely concerned with energy, and how it is generated using machines like internal combustion engines and power plants.  This post will provide some background on the current state of affairs regarding energy.

Recently, former NASA astronaut and current NASA climate scientist Piers Sellers was diagnosed with stage 4 pancreatic cancer.  Two weeks ago he wrote an op-ed in the New York Times where, rather than feel sorry for himself or wax sentimental about his life, he described (in broad terms) what humanity needs to do to avoid the potentially catastrophic consequences of runaway global warming, since it is now likely that he won't be around to see what happens.  After describing the initial challenges associated with making effective energy and environmental policy (which are substantial), he writes (emphasis mine),

Ultimately, though, it will be up to the engineers and industrialists of the world to save us. They must come up with the new technologies and the means of implementing them. The technical and organizational challenges of solving the problems of clean energy generation, storage and distribution are enormous, and they must be solved within a few decades with minimum disruption to the global economy.

Here we'll address the question that is probably on many people's minds: why are the technical challenges associated with generating cleaner energy so enormous?  Let's start by looking at the current ways in which we extract energy.

Consider a conventional gasoline-powered car like the Toyota Camry, one of the most common cars on American roads.  The gas mileage on such a car is, accounting for highway and city driving, about 30 miles per gallon.  Since there are 16 cups in one gallon, this means you get about 2 miles per cup, or one mile out of about this much gas:

Pictured: a one-mile drive in a Toyota Camry...from an engineer's perspective at least.
(SEE NOTE 1)

Let's say you put that much gasoline in the tank of a Toyota Camry and drive a mile.  Then, the car breaks down, and the nearest service station is a mile away.  Now imagine the amount of energy you would have to expend to push the car (which typically weighs about 3,240 pounds) for the entire mile to get there.  There's a LOT of energy in that half-cup of gasoline (which, at today's prices, would currently set you back a whopping 5 cents)!

As it turns out, gasoline has a very high energy density compared with many other substances.  Here's a comparison with a few other notable substances (SEE NOTE 2).

	Food calories per pound	Compared to TNT
TNT	295	1
Chocolate chip cookies	2,269	7.7
Coal	2,723	9.2
Butter	3,176	11
Gasoline	4,538	15
Natural gas	5,899	20
Uranium-235	9,000,000,000	32,000,000

(Yes, 1 pound of chocolate chip cookies has the energy of 7.7 pounds of TNT!)

Now let's compare gasoline with other sources from which we draw energy, like a AA battery.  How much energy is stored in it?

Batteries deliver energy in the form of electricity, which at the most basic level means moving electrons.  Batteries are typically characterized by the amount of current (essentially, number of electrons per second) they can deliver, and the voltage (essentially, the amount of energy each electron carries) at which they can deliver it.  Different applications require different amounts of each.  A typical alkaline AA battery can deliver around 2500 milliamp-hours at 1.5 V.  A milliamp is a unit of current, so in other words, it can deliver 2500 milliamps of current for 1 hour at 1.5 V.  Carrying out the calculations,

Power = Energy per Time = Current x Voltage (see this article for an explanation)

Energy = Current x Voltage x Time

Energy = 3750 Watt-hours, or 13,500 Joules.

Here I'm using the metric unit for energy, called the Joule (after James P. Joule, a pioneer in the area of thermodynamics).

So......is 13,500 Joules a lot of energy?  Let's compare this to the amount of energy in food.

What we call 1 food calorie is actually 1,000 "actual" calories, or 1 kilocalorie (long story - see this article), and 1 kilocalorie turns out to equal 4,184 Joules.  So a AA battery contains a little over 3 calories' worth of energy.  Compare that to a granola bar, which has around 200 calories in it.  So, a granola bar is equivalent to 62 AA batteries in terms of energy stored!

What about the equivalent amount of gasoline?  A granola bar weighs about 56 g.  From the table above and some simple arithmetic, 56 g of gasoline has about 567 food calories, or the equivalent of about 186 AA batteries!

But, you say, there's plenty of energy in the Sun!  We just need to harvest and store it, right?

The rate at which we receive energy (in the form of electromagnetic radiation) from the Sun turns out to be about 1000 Joules per square meter per second.  On a perfect sunny day, a patch of ground with an area of 1 square meter receives about 1000 Joules every second.  Sounds like a lot of energy, right?  Well, setting aside the fact that this is only true in direct sunlight (and so by definition only during daytime), the issue is that most solar cells are only about 10% efficient.  This means we can only extract about 100 Joules per second for every square meter of (generally expensive) solar cells that we build.   

So, let's say we buy a 1-square-meter solar cell and collect sunlight for 1 hr.  In the best case scenario, this will give us about 86 food calories' worth of energy.  This is equivalent to half a granola bar, or about 3/4 of a Tablespoon of gasoline!

Conclusion:

Burning stuff like gasoline or coal releases a LOT of energy, and it's going to be hard to find other energy sources that are as cheap and energy-rich.

But that won't stop us from trying.  In future posts, I will address the steps we are taking at MIT to try to come up with new ways to generate clean energy, and just as crucially, how to store and distribute it.

NOTES!
1. Some of you may be surprised that that much gasoline is actually required.  (I was.)  But the thing to keep in mind is that cars are actually quite inefficient when it comes to extracting energy from gasoline: for a typical auto engine, the average efficiency (amount of useful mechanical energy actually extracted divided by the total extractable amount) is around 18-20%.  In fact, thermodynamics shows us that the best we can ever hope for with this kind of engine is around 37%.  So, the "large" amount of gasoline required to drive one mile is not due to a limited amount of energy in gasoline, but due to the limitations on our capability to extract useful energy from it.

2. Source: Muller, R.A., Energy for Future Presidents.  New York: W.W. Norton, 2012.

Electro-osmosis: Moving Water With Electricity

If you ever find yourself with a glass of water, two drinking straws of different diameters, and a little free time, you might notice that if you drink out of the smaller drinking straw, you don't get as much water as you do with the larger one. In other words, if you want to drink water at the same rate through each straw, you need to exert more effort when drinking out of the smaller straw. In general, the smaller the straw, the more effort (i.e., pressure) it takes to drive fluid at a given rate through it. This principle makes good intuitive sense, and is predicted by the mathematical equations that govern fluid flows. Perhaps a little interesting, but nothing special. Why does it matter?

It matters if you work in microfluidics, which, true to its name, involves fluids flowing through extremely small passageways. These passageways are usually hundreds of times smaller than a drinking straw - usually about as big around as a human hair. So, from what you now know about the exciting world of drinking straw physics, you would suppose that we'd need a lot more pressure to make the water flow through a microchannel than a straw, if we wanted to push water at the same flow rate through the straw and the microchannel. And you would be right. The pressure demands for driving fluid through microchannels are significant (see note 1).

If you want to drink water out of a drinking straw, there is pretty much only one way you're going to get the water to go against gravity and creep upward through the straw toward your lips: exert pressure by creating suction with your mouth. How else could you do it, right? But if you want to drive water through a tiny microchannel, it turns out there is an alternative to using pressure that you don’t have when drinking out of a straw. On small size scales, there is a completely different way to make water flow.

What if I told you that if you put two metal electrodes on opposite ends of a microchannel filled with water and applied some electricity, the water would instantaneously begin to flow from one electrode to the other? This is indeed what happens. It is possible to make water flow from one place to another in a microchannel using two pieces of metal and some electricity. That's all you need. No pumps or any other moving parts are necessary. This technique is very common and people in microfluidics use it every day.

What is going on here?

More than H2O molecules

Let’s take a closer look at that glass of water. A much closer look. If you magnified a glass of water a few million times, you would discover a lot more than just H2O molecules swimming around. Among other things, in a typical glass of water there are also a vast amount of protons (the same protons that make up the nuclei of atoms) "swimming" freely about as well. How many protons? A 1-liter bottle of water contains about 60 million billion (6 times 10 to the 16th power) free protons (although there are many, many more H2O molecules than that - see note 2). Recall also that protons have a positive electric charge. This will be important in a moment.

Now that we know there are charged particles swimming around your glass of water along with the H2O molecules, let's look at what goes on at the interface between the glass and the water.

When glass is exposed to air, the silanol (SiOH) groups stay composed and mind their own business.  However, whenever water is brought into contact with the glass, the SiOH molecules deprotonate (give up their protons), rendering the glass surface negatively charged.  Protons from the bulk water solution flock to the surface to "shield" the charged surface, so that the region between the 2 red lines is electrically neutral.  This layer of protons, along with the charges on the glass surface, constitute the electrical double layer.

Glass is primarily composed of silicon dioxide (SiO2), but the outer surface of the glass, the part that "sees" the water, is made of a chemical compound called silanol. The formula for silanol is SiOH: one silicon atom, one oxygen atom, and one hydrogen atom bound together. A single grouping of these atoms is called a silanol group. The reason I bring this up is that whenever SiOH groups are brought into contact with a fluid that has a pH higher than about 3, they cannot hold on to their hydrogens anymore. Or, more specifically, they cannot hold on to the protons from the hydrogens (remember that a hydrogen atom consists of one proton and one electron), and the protons escape from the glass surface into the water, like a top hat blown off of an old man's head in the wind. This loss of protons does happen for a reason, but it is not really that important to the present discussion. The important thing is that this process happens whenever water and glass are brought into contact, and it is called deprotonation.

Positive Band-Aids

Deprotonation has some interesting consequences in a drinking glass-water system. Once the glass loses protons, its surface becomes negatively charged (see note 3). Nature would rather this didn't happen. It's a little like an open wound exposed to open air. Nature would like to apply a positively charged “band-aid” to the surface so that it becomes electrically neutral, which is the preferred configuration.

Now, remember the quadrillions of positively charged protons swimming around in the water? Recall that protons are positively charged, and as discussed above they are readily available. So it only makes sense that the protons act as the "band-aid" to the charged surface. And this is precisely what happens: some (not all) of the freely floating protons gather very (very) near the glass surface, "shielding" the negatively charged glass (see figure above). So the negatively charged "wound" is now covered with the positively charged "band-aid," and this band-aid is known as the Electric Double Layer (EDL). If all this sounds time-consuming, it's not. The whole process takes less than a millionth of a second. Something to think about the next time you pour yourself a glass of water.

Now consider that microfluidic channels are often made from glass. So whenever we fill a microfluidic channel with water, the glass deprotonates, becomes charged, and attracts protons to its surface. By the way, the electrical double layer is extremely thin. If a microchannel the size of a human hair were magnified to the size of an average-size classroom, the EDL would be as thick as the paint on the walls.

Putting it all together

Now for the reason why I've been rambling about protons in glasses of water all this time. Now let’s say you fill a glass microcapillary (basically a tiny hollow glass tube, about as big around as a human hair) with water. As always, there will be layers of protons shielding the glass walls. Now, take your metal electrodes and place them on either end of the channel and apply a voltage between them, i.e., make one electrode negatively charged with respect to the other. Remember that, as always, opposites attract. The protons in the EDL sense a positive and negative electrode in their midst. The protons, being protons, would much rather head towards the negative electrode, and that's what they do. The transport of protons (and indeed, any ions in an aqueous solution) in response to electricity is called electromigration.

Now, you might think that since protons are so tiny, they don’t exert any influence on the surrounding water when they move. Not so. When a proton moves in a fluid through electromigration, it “drags” the surrounding fluid along with it. Now, since protons are indeed incredibly small, one proton drags a minuscule amount of fluid. But remember that there are billions upon billions of these protons coating the walls of the microchannel. There are enough that you can think of the protons as a “sheath” that “coats” the microchannel edges. This proton sheath is substantial enough to drag the rest of the water in the microchannel along with it. The "micro-paint-thin" layer of protons drags the rest of the water in the "micro-room." Again, this process is extremely quick to get started, fast enough so that when you flip the switch, the flow has effectively reached full speed instantaneously.

Schematic of electro-osmotic flow.  The arrows indicate the direction of the proton migration, and ultimately of the fluid flow.

Thus, it is possible to move water through a microchannel by the simple application of electricity. This type of flow is generally known as ­electro-osmotic flow, or EOF, and it is used every day in microfluidics research and industry. It provides an alternative to using pressure to drive flow. It is a key component of capillary electrophoresis, an extremely useful technique used in analytical chemistry to separate different compounds out of a single sample. It is the basis for electro-osmotic pumps, which use EOF to “pump” water, generating sufficient pressures to do useful work using no moving parts.  At MIT, we discover new uses for EOF almost daily, and the technique will likely continue to be useful for many years to come.

Notes
1) Despite this, pressure-driven flow is still used in microfluidics when the required flow rate is not too high.

2) It is very important to note, though, that even though there are charged particles swimming around in your glass of water, there are (roughly) just enough that they cancel each other out. In a standard glass of water, there are about as many hydroxide (OH-) ions as there are protons (also known as H+ ions), so that you can think of any given droplet of water as being electrically neutral. There are about 60 million billion hydroxide ions in your 1-liter bottle of water as well. They are completely harmless and are present in every glass of water you drink.

3) Incidentally, surfaces other than glass can and do become electrically charged when brought into contact with water as well. It turns out there are many different mechanisms for surfaces to become charged in the presence of liquids.