Think Small with Nanospheres

Solid Lipid Nanospheres for
Delivering Curcuminoids

The bioavailability of these beneficial turmeric compounds may be
improved by an offshoot of nanotechnology
By Will Block

t’s not wise to kill your son and serve him as a meal to the gods at one of their banquets—they might take offense at such boorish behavior and punish you for it. That, at least, is what happened in Greek mythology to Tantalus, a son of Zeus. He was the king of Sipylus in Asia Minor and was a good friend of the gods. They were angered, however, by his unseemly fare—and not just by that. He also shared some of their secrets with mortals, a major faux pas. Plus, they had always been irked by his craving for a lifestyle as luxurious as theirs, which made him pester them for more of everything—he could never get enough.

Eventually, Zeus had enough of his awful spawn and condemned him to Tartarus, the region below Hades, there to suffer a unique punishment for all eternity. Tantalus is immersed up to his chin (this is still going on, you know—eternity isn’t over yet) in a lovely sylvan pool, above which is an abundance of luscious, low-hanging fruit. Whenever he tries to drink, however, the water recedes from his mouth, and whenever he grabs at the fruit, the wind blows it out of reach. Thus Tantalus remains thirsty and hungry, forever tantalized by that which is so close, and yet so far.

Bioavailability—Running the Gauntlet

“Could never get enough” and “so close, and yet so far” are phrases that neatly summarize a central problem in therapeutics, whether it involves drugs or nutritional supplements. It’s the problem of bioavailability, which can be defined simply as the degree to which a drug or nutrient, unchanged by metabolic reactions, enters the systemic circulation after it’s administered. In other words, bioavailability is the proportion of an administered amount that winds up unchanged in the bloodstream and is available to fulfill its intended purpose, wherever that may be.

If a substance is injected intravenously, its bioavailability (initially, at least, before it begins to degrade) is 100%. Any other delivery route, such as intramuscular, subcutaneous, transdermal, vaginal, rectal, or oral, poses obstacles that reduce this figure, sometimes drastically.

Oral delivery, in particular, is fraught with problems, including stomach acid, digestive enzymes in the stomach and intestinal lumen (the tube’s hollow core), enzymes in the intestinal wall (through which all drugs and nutrients must pass), and enzymes in the liver, which gets first crack at them before they can enter the systemic circulation. This biochemical gauntlet is the nemesis of many such agents, which may be very poorly absorbed. Even if they’re well absorbed, however, they may still be metabolized to other substances before they ever get to first base, therapeutically speaking.

Curcuminoids Hate Water

The bioavailability problem is particularly acute with lipophilic (lipid-loving) substances—those that are soluble in lipids, such as fats, oils, and steroids. Such substances are also called hydrophobic (water-hating) because they’re not soluble in water, the basis for all of our bodily fluids. Four of the 13 human vitamins—A, D, E, and K—are lipophilic, as are many other valuable nutrients that would do us more good if our bodies could absorb them more efficiently. (As a bonus for the economy-minded: the greater the absorption efficiency for a given nutrient, the less of it one needs to take in order to obtain the benefits.)

Among the nutrients whose bioavailability is normally very poor are the curcuminoids (including the parent compound, curcumin), which are derived from the Indian spice turmeric. These are potent antioxidant, anti-inflammatory, and anticarcinogenic compounds, some of whose remarkable health benefits have been described previously, with more to come in the next issue of Life Enhancement.* As with lipophilic drugs and nutrients in general, there is a strong impetus to find efficient delivery vehicles for the curcuminoids so as to help them enter the systemic circulation despite their aversion to water.1


*For the most recent article, see “Turmeric’s Curcuminoids Help Prevent Brain Plaque” in the October 2007 issue.


Smaller Is Better with Nanospheres

Enter nanotechnology, in the form of nanoparticles. As the name implies, these particles are very small, since a nanometer is a mere one-billionth of a meter (hence one-millionth of a millimeter). A nanometer is to a meter as the diameter of a marble is to the diameter of the earth, or as a single drop of water is to a 17,000-gallon swimming pool. Although nanoparticles are tiny indeed, they’re still large compared with most molecules—everything is relative. (See the sidebar “Nanomedicine—In the Realm of the Very Large” in the September 2005 article “Gene Therapy with PEGylated Liposomes.”)

Not to scale
In the broadest sense, nanotechnology pertains to the design, production, manipulation, and use of objects in the “nano-domain,” defined as having dimensions in the range from 1 to 1000 nanometers (nm), with emphasis on the lower end of that range. Here the properties of matter can be strikingly different from those of bulk matter. Nanotechnology is a huge, multidisciplinary field of science and engineering, promising myriad new inventions that will certainly change—and probably improve and lengthen—our lives in the future.2

A small but important part of this field is that of drug- and nutrient-delivery systems based on the use of nanospheres, whose diameters are usually in the range of about 50 to several hundred nanometers. They can be fabricated from natural or synthetic polymers or from lipids, in which lipophilic compounds, such as curcuminoids, can readily dissolve. Their purpose is to improve the bioavailability of such compounds by exploiting their own special size range and unique properties.3-5 (For some perspective on this, see the sidebar, "A Nanosphere by Any Other Name . . . .")

A Nanosphere by Any Other Name . . .

Nanotechnology is hot these days, and with good reason: although still in its infancy, it represents an enormous leap toward a future of scientific and technological marvels that will make today’s high-tech world look quaintly primitive to generations yet unborn. Of course, much of what passes for “nanotechnology” today is just hype (sexy terms sell) or wild speculation—that’s inevitable.

Human nanotechnology
Most real-world applications of nanotechnology still lie far in the future, because they will require extremely sophisticated fabrication techniques that are still being developed (or have yet to be imagined) by scientists and engineers. A few simple nanotech-based products, however, have entered the market, primarily in the textile, cosmetics, food, and pharmaceutical industries. Most are based on nanospheres (or nanoparticles—not all nano-objects are spherical), which are easy to make.

What’s not easy, however, is to tailor the nanospheres’ physical and chemical properties, such as size distribution, crystal structure (in the case of solid particles), surface electric charge, chemical reactivity, long-term stability, etc. Controlling these properties precisely is difficult but vital, because the nanospheres’ behavior under any set of conditions, such as those of the human digestive tract and beyond, will depend critically on them. Being able to tailor-make nanospheres for particular purposes in this way is one thing that distinguishes modern nanotechnology from the nanotechnology of the past.

Thomas Graham
(1805–1869)
Say what? Nanotechnology has a past? It certainly does, going back at least to the ninth century, when Mesopotamian artisans developed chemical techniques that produced nanoparticles in ceramic glazes, yielding a glittering metallic sheen called luster. But nanotechnology (under a different name) didn’t become a scientific discipline until 1861, when the Scottish physical chemist Thomas Graham founded the field of colloid science, which is based almost entirely on the physical and chemical properties of particles in the (guess what?) nanometer range.*


*The term nanotechnology was first used and defined in 1974, by the distinguished Japanese engineer Norio Taniguchi.


Colloidal dispersions, or colloids, exist when clusters of gas, liquid, or solid particles in the nanometer size range are dispersed in other gases, liquids, or solids in which they’re not soluble. All but one of the nine possible types of colloid combinations are known (the exception being gas in gas, because all gases are totally miscible). The eight types are called foams (gas in liquid), solid foams (gas in solid), liquid aerosols (liquid in gas), emulsions (liquid in liquid), gels (liquid in solid), solid aerosols (solid in gas), sols (solid in liquid), and solid sols (solid in solid).

The literature on colloid science is enormous, because it’s a diverse and fascinating subject and because colloids are common in nature. Our bodies, e.g., are chock full of colloids: bodily fluids, including the cytoplasm of every cell, are not just solutions of soluble molecules but also colloidal dispersions of insoluble molecules, and of soluble molecules so large that they’re in the colloidal (nanometer) range. Much of physiology could be thought of as applied colloid chemistry.

Colloid science and nanotechnology are interesting not because the laws of physics and chemistry are different in the nano-domain—they’re not—but because the ways in which those laws are manifested there lead to unusual material properties and pose special challenges for mathematical analysis and interpretation. Nano-objects exist in a kind of no-man’s-land between bulk matter, where quantum mechanics is largely irrelevant, and atomic and molecular matter, where it’s utterly dominant. The fact that nanoscale objects, unlike bulk matter, have an enormous surface area in proportion to their volume is extremely important in their physics and chemistry.

Bovine nanotechnology
The main difference between colloid science and nanotechnology—and the line is blurry—is that in the latter, the particles are produced in more or less precise ways to have specific, desired characteristics under specific sets of circumstances, so as to exploit not only the unique physical properties associated with that size domain but also the chemical properties that are “engineered in.”

By the way, drug- or nutrient-delivery vehicles containing solid lipid nanospheres are sols. Other examples of sols are milk, paint, pigmented ink, and all your bodily fluids.

Protecting the Payload with Solid Lipid Nanospheres

Among the most promising types of nanospheres are solid lipid nanospheres (SLNs), whose development began in the early 1990s.6,7 SLNs typically consist of a central, spherical core of a natural, plant-based lipid, such as a solid triglyceride (fat). This core is typically encased by a shell consisting of a natural phospholipid, such as phosphatidylcholine, which acts as an emulsifying agent during the production process; thereafter it serves a protective function, its chemical properties playing a vital role in stabilizing the nanospheres in their aqueous environment.

The drug or nutrient “payload” (curcuminoids, e.g.) dissolves into the lipids as the nanospheres are being formed in the fabrication process (there are several different methods). Depending on various aspects of the nanospheres’ chemical composition and production method, the payload molecules may wind up being dissolved primarily in the core or in the shell.4 In the former case, and to a lesser extent in the latter, they’re protected from their environment until the nanospheres are destroyed by lipases, which are enzymes that break down fats into fatty acids and glycerol. The payload is then released.

Advantage: Nanospheres

Why nanospheres? In addition to providing much-needed solubility for lipophilic compounds, nanospheres are more readily taken up by our cells than are larger particles. Another advantage—sometimes—is that they tend to be preferentially absorbed by two types of tissues, namely, tumors and inflamed tissues, where the capillaries are more permeable (“leakier”) than normal. That allows the nanospheres to slip through tiny openings and gain access to the cells. Called passive targeting, this is a property of all ordinary nanospheres.

The ultimate goal is active targeting, in which the nanospheres are directed, via molecular recognition systems, to specific organs or tissues that need their therapeutic payload. That, however, is a difficult and expensive proposition, requiring sophisticated chemical modification of the nanospheres’ surface; it’s not feasible for low-cost products.

Meanwhile, our target is to improve the bioavailability of curcuminoids, a tantalizing prospect that may be coming to fruition with solid lipid nanospheres. Stay tuned for more on the benefits of curcuminoids next month.

References

  1. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Molec Pharmaceut 2007;4(6):807-18.
  2. For an excellent, up-to-date overview of this burgeoning field, see The Rise of Nanotech: How Control of Molecules Is Changing the World (special edition on nanotechnology), Scientific American Reports, Vol. 17, No. 3, September 2007. See also the illuminating book Nano-Hype: The Truth Behind the Nanotechnology Buzz, by David M. Berube; Prometheus Books, Amherst, NY, 2006.
  3. Kayser O, Lemke A, Hernández-Trejo N. The impact of nanobiotechnology on the development of new drug delivery systems. Curr Pharmaceut Biotech 2005;6:3-5.
  4. McClements DJ, Decker EA, Weiss J. Emulsion-based delivery systems for lipophilic bioactive components. J Food Sci 2007;72(8):R109-24.
  5. Chen H, Weiss J, Shahidi F. Nanotechnology in nutraceuticals and functional foods. Food Technology, March 2006, pp 30-6.
  6. Wissing SA, Kayser O, Müller RH. Solid lipid nanoparticles for parenteral drug delivery. Adv Drug Deliv Rev 2004;56:1257-72.
  7. Luo YF, Chen DW, Ren LX, Zhao XL, Qin J. Solid lipid nanoparticles for enhancing vinpocetine’s oral bioavailability. J Control Release 2006;114:53-9.


Will Block is the publisher and editorial director of Life Enhancement magazine.

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator