Nanoparticles offer an intriguing possibility for treating diseases, especially neurodegenerative diseases. It has been theorized that their uses could range from simple drug delivery to full fledged microscopic machines, an inorganic version of a protein. Unfortunately, inorganic molecules are often quite lethal when allowed inside the body in considerable quantities. Nanoparticles are no different. Furthermore, their small size raises questions regarding toxicity.

New research has shown some initial data regarding toxicity and how to best clear nanoparticles from your system. Details after the jump.

Problems

The problem with nanoparticles are two-fold. First, nanoparticles are often created out of inorganic metals. You might enjoy snacking on mercury and other heavy metals but your cells do not. The second problem is size. Nanoparticles are very small (obviously). Because nanoparticles are so small, they can often diffuse in and out of cells relatively easy. Furthermore, their relative surface areas are quite large compared to their volume. This makes them quite reactive and capable of disrupting the fragile machinery existing inside a cell.

To counter the problems of inorganic metals and volatility, nanoparticles are covered in an organic coating. These coatings are often small proteins. Organic coatings increase the neighborhood friendliness value of nanoparticles but do it at a cost. They also increase the diameter of particles, nullifying the small-size benefit inherent to nanoparticles.

Quantum Dots

The research team created small nanoparticles, called quantum dots, to determine which coating was the most effective while remaining the smallest. The dots all contained a Cerium Selenide (CeSe) core covered in a Zinc Sulphate (ZnS) shell. This shell was then coated in one of several small organic proteins. It was theorized the charge of the organic protein would affect the diameter and solubility. Anionic, cationic, neutral and zwitterionic charged proteins were used as coatings.

These dots were then incubated in serum to measure absorption and solubility. Charged coatings (anionic and cationic) were associated with diameters over 15nm because they bound to many other proteins in the serum. Neutral coatings did not bind to serum proteins but were unable to be manufactered at smaller than 10nm. Shorter neutral proteins could not be used because they resulted in insoluble nanoparticles. Remarkably, zwitterioninc proteins (proteins that overall have no charge but have distribution such that minor polarity is seen) not only remained unbound to serum proteins but were also the smallest in size, ranging from 3nm to 6nm.

It would appear the charge of the organic coating makes a big difference in the solubility and size. Which is good. Nanoparticles with zwitterionic coatings remain small while being biologically friendly. The reason nanoparticles are so attractive are precisely their small size. The human vasculature system has pores on average 5nm or less. Particles larger than this, even those that are found inside the body naturally, take an inordinate amount of time to diffuse such pores. Immunoglobulin G, an antibody that naturally diffuses through the body, is about 10nm in diameter and requires over 24 hours to reach equilibrium between vascular and extracellular spaces in the body.

Clearing nanoparticles

Unfortunately, the second hurdle is getting the nanoparticles out of your system quickly and efficiently. Besides their potential to become toxic should their coating be removed, nanoparticles interfere with many diagnostic tools. Inorganic metals show up much more clearly on x-rays (conventional, CT and fluorescence), MRIs, ultrasound and even PET scans. Because they show up so clearly, and tend to conglomerate together, they make these diagnostic tools nearly useless by masking other structures in the body.

Your liver is very good at removing inorganic materials from your body. But your liver only works at sizes greater than 15nm. It seems an unfortunate catch-22. To get your liver to process nanoparticles, you must use a coating size that precludes them from diffusing through pores effectively. To diffuse through pores effectively, you allow them to diffuse straight through the liver without being picked up.

Urine to the rescue!

All is not lost though. The research team showed that renal clearance (aka peeing) is highly effective if the diameter of the nanoparticles is less than 5.5nm. Nanoparticles of varying size were followed with radioactive isotopes. Those smaller than 5.5nm were found predominantly in the bladder and then excreted in urine. Diameters larger than 5.5nm were found to conglomerate in the liver, lung and spleen more than the bladder.

This provides hope that nanoparticles, if designed small enough, are not only effective at diffusing but also clear the body quickly and safely. The team is conducting further research on how the shape of nanoparticles affect diffusion. They are also investigating different types of proteins to be used as coating. It is theorized that perhaps receptors or ligands can be attached to nanoparticles so that special tissues (say, the brain or liver) selectively “grab” nanoparticles, offering true tissue-specific targeting.

Nanoparticles offer a very interesting future. I for one welcome our new, microscopic overlords.

References

Soo Choi H, Liu W, Misra P, Tanaka E, Zimmer JP, Itty Ipe B, Bawendi MG, Frangioni JV. Renal clearance of quantum dots. Nat Biotechnol. 2007; 25(10):1165-1170. DOI:10.1038/nbt1340