Although quantum dots may be bright and potentially very useful fluorescent nanoparticles in biomedical applications, there is one shadow on their otherwise brilliant future. Historically, the FDA has required that anything injected into the body be able to exit it quickly or to break down into nontoxic components. The latter is problematic with quantum dots because they contain heavy metals. As for the former, some studies have shown retention times of two or more years.These images of radioisotope-labeled quantum dots injected into a mouse show that those with a hydrodynamic diameter of 8.65 nm are retained, whereas smaller ones with a diameter of 4.36 nm are excreted easily. Both fluorescent and gamma ray images reveal that the larger quantum dots are concentrated in the liver (Li), spleen (Sp) and lungs (Lu) and not in the bladder, which is where they would be just before exiting. Reprinted from Nature Biotechnology with permission of the researchers.Now researchers from Beth Israel Deaconess Medical Center in Boston and from MIT in Cambridge have determined what characteristics quantum dots require for rapid excretion. The hydrodynamic diameter of the particles must be less than 5.5 nm, an unexpected finding given the excretion results for other biomolecules. “The threshold for renal filtration and urinary excretion of globular proteins is estimated between 6.2 and 7.1 nm,” said research team member Dr. John V. Frangioni, an associate professor of radiology and medicine at Harvard Medical School.In their study of excretion in animal models, the researchers took this information and used it in designing quantum dots with a variety of sizes and organic coatings. All of the quantum dots had a CdSe core and a ZnS shell and were encapsulated with an anionic, a cationic, a zwitterionic or a neutral coating.The size of the quantum dots designed with anionic (negatively charged) and cationic (positively charged) coatings proved difficult to control. When incubated with serum, both expanded to 15 nm or more in diameter. The researchers could not fabricate the neutrally coated nanoparticles at a size of less than 10 nm. Only with the zwitterionic coating, which is electrically neutral but contains both positive and negative charges, could they construct a quantum dot of the right size range that didn’t expand. They measured the size of the quantum dots using a Wyatt dynamic light-scattering system.The researchers labeled the quantum dots with a radioisotope so that they could obtain quantitative biodistribution data, something not possible using just the fluorescence of the quantum dots. Frangioni noted that conjugating the quantum dots with the radioisotope was a challenge because of the need to avoid a size increase while producing something stable and pure. They injected the labeled quantum dots into animal models, measuring the resulting fluorescence in real time using a prototype imaging system they developed with Marubeni Epitex LEDs and Chroma excitation and emission filters. Via the radioisotope, they tracked the clearance of the nanoparticles from the body and found that those 5.5 nm and below in hydrodynamic diameter were excreted quickly, with a half-life in the body of four or so hours.These results, noted Frangioni, are not the last word. “The ability of nanoparticles to pass the kidney filters is a function of their shape, size and surface charge,” he said.Further investigations by the group are targeting the effects of mass and charge on the biodistribution and metabolism by using various shapes of molecules. They also are researching the ability of such small quantum dots to be used therapeutically, and they say that the initial results are promising.Nature Biotechnology, October 2007, pp. 1165-1170.