by Claudia S. Copeland, Ph.D.

How Fat-Soluble Molecules Gain Entry Into Their Target Cells

For bioactive molecules to exert their effects, they must first be absorbed from the outside world,which — from the body’s point of view — includes the inside of the intestinal tract. Then, they must cross another barrier, the cell membrane, to gain entry into their target cells. To do this effectively, molecules must engage in a delicate dance with several biological partners, the moves of which are largely a function of solubility.

The Watery Environment of the GI Tract

The environment inside the GI tract is aqueous, as is the environment in the blood vessels and tissues of the body. That is, the predominant liquid in which molecules must dissolve is water, a polar solvent, in which water-soluble molecules are easily dissolved but to which fat-soluble molecules are resistant. Because of this, molecules like fat- and water-soluble vitamins face quite different hurdles getting into the body. Fat-soluble molecules do not disperse well within the GI tract, and their low absorbance has been a major problem in the development of these molecules as drugs. Water-soluble molecules, in contrast, are much more easily absorbed from the intestine.

So, if you’re a molecule that wants to have a biological effect, you want to be water-soluble to be well-absorbed from the GI tract. Once you’re absorbed, though, getting into a cell is a lot easier if you’re fat-soluble.

The Cell Membrane

After being absorbed from the GI tract, where it helps to be water-soluble, molecules travel to their target cells. There, they are confronted with a completely different challenge: the cell membrane.  

The cell membrane is a structure composed of phospholipids — molecules with a polar (water-soluble) head bonded to long, nonpolar (fat-soluble) tails, arranged in double-layered sheets with the polar heads facing out (toward the inside and outside of the cell) and the nonpolar tails facing inward, toward the middle of the membrane. This matrix is called a phospholipid bilayer.
The cell membrane encases a cell, keeping the cell’s contents in and attempting to keep undesirable elements out. However, molecules can and do enter cells. The cell must let molecules in for the sake of nutrition, hydration and specialized cellular processes like neural communication. To do so, molecules (or individual atoms/ions) must cross the barrier of the cell membrane via one of several mechanisms.

Three Ways to Get Into a Cell

Although there are countless specific routes for crossing the cell membrane, the methods for getting into a cell fall into three main categories: endocytosis, active transport and diffusion.  The first, endocytosis, involves the cell engulfing the molecule. This is the method of choice for ingesting very large molecules (or viruses, or even cells — a prime mode of defense by immune cells called macrophages). In this mechanism, the membrane wraps around the target until it is surrounded in a sort of cell-membrane bubble, which is then ingested into the cell. (This is not always driven by the cell. Viruses often take advantage of this mechanism for pathogenic cell invasion.)

Second, a cell can actively transport a molecule across its membrane, using adenosine triphosphate, the body’s flexible biochemical energy source. Using this energy source, a cell can pull a molecule in even if it would not naturally tend to flow there.
Third, molecules can enter cells by diffusion — that is, by “flowing in” where they naturally “want” to go. Diffusion is the natural, passive process of dispersal of molecules from an area where they are highly concentrated to an area where they are less concentrated. It’s the same phenomenon that happens when you drop a few milliliters of purple ink in a bowl of water: the ink will start out as a small, dark purple glob, but then it will gradually disperse until the water is a uniform shade of lavender.

Two Different Types of Diffusion: Passive Transfer Versus Facilitated Diffusion

The problem for diffusion into a cell is, of course, the barrier imposed by the cell membrane, which is impermeable to many molecules. If a molecule is small and fat-soluble, though, it can slip right through the lipid bilayer of the cell membrane. Fat-soluble vitamins like vitamins A, D, E and K readily pass through the lipid core of the plasma membrane. Even if a molecule is large, if it is highly fat-soluble it can still diffuse across the lipid membrane, albeit more slowly.  Very small water-soluble molecules can also diffuse passively across the membrane, but they need to do so through pores in the membrane known as channel proteins. These pores, which function mainly to let in water, are small enough that only very small molecules can pass through them. When molecules diffuse either directly across the lipid membrane or through channel proteins, the process is known as passive transfer or passive transport

For large water-soluble molecules, and for rapid transport of large fat-soluble molecules, a little help from the cell is needed. To help these large molecules diffuse, the cell uses a process called facilitated diffusion. In facilitated diffusion, special proteins called carrier proteins bind the molecules and carry them across the membrane

Nanoemulsions, Microemulsions and Cell Entry Across the Membrane

The competitive advantage of water-soluble versus fat-soluble molecules turns upside down when faced with crossing the plasma membrane. That is to say, once the barrier of absorption from the GI tract has been overcome, fat-soluble molecules have it relatively easy. They can slip right into cells through the lipid bilayer.  If the molecules cannot overcome the challenge of absorption, though, they will never have the opportunity to do this. The problem of absorption has therefore been a primary reason for the poor bioavailability of fat-soluble drugs.

The good news is that an exciting new field — emulsion nanotechnology — is working to overcome this problem. This technology has yielded two important approaches, microemulsions and nanoemulsions, that essentially use a carrier to encapsulate fat-soluble molecules within a ~10-200 nm droplet with a water-soluble outer coat. (The two types of emulsions are similar, differing more in terms of their stability and how they are made: microemulsions are thermodynamically stable and therefore form from their ingredients spontaneously, while nanoemulsions must be created through a technique like mechanical shearing.) When these droplets fuse with the brush border of the intestinal lining, they release their fat-soluble contents, and voila! Absorption accomplished.  Ensconcing fat-soluble molecules within nanocarriers allows efficient absorption of these molecules across the intestinal lumen. (Once they have been absorbed from the intestine, they are transported to their destinations in the body’s own, natural nanoparticle carriers — protein-lipid structures called chylomicrons.) Then, once they reach their destination, it’s smooth sailing!

With their ability to diffuse across lipid membranes, fat-soluble molecules like CBD, curcumin and fat-soluble vitamins can easily enter cells, reach their targets and accomplish the biological purpose they were prepared for.


Author EmbarkNano

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