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COMPETING FINANCIAL INTERESTSThe author declares no competing financial interests.

1. James, C. Global Status of Commercialized Biotech/GM Crops: 2009 (iSAAA 41, ithaca, New York, USA, 2009).

2. Hutchison, W. et al. Science 330, 222–225 (2010).3. Wu, K. et al. Science 321, 1676–1678 (2008).4. Tabashnik, B. et al. Nat. Biotechnol. 28, 1304–1307

(2010).5. Tabashnik, B.E. et al. J. Econ. Entomol. 102, 2011–

2025 (2009).6. Gould, F. Annu. Rev. Entomol. 43, 701–726 (1998).7. Liu, C. et al. Sci. China Life Sci. 53, 934–941

(2010).8. Bagla, P. Science 327, 1439 (2010).9. Klassen, W. & Curtis, C. in Sterile Insect Technique

(eds. Dyck, v., Hendrichs, J. & Robinson, A.) 3–36 (Springer, The Netherlands, 2005).

10. Tabashnik, B. Science 330, 189–190 (2010).11. Alphey, N., Bonsall, M.B. & Alphey, L. J. Econ. Entomol.

102, 717–732 (2009).

the same pest species10. In another approach, the US Environmental Protection Agency has approved sales of mixtures of corn seeds with and without Bt toxins that kill corn rootworms. This ensures that farmers comply with the refuge strategy. However, its use is limited to the pest species whose larvae do not migrate between plants. Finally, there are also trans-genic strategies to improve SIT efficiency by expressing dominant lethal genes, promoting refractoriness of the sterile insects to disease or facilitating strain marking, genetic sexing and molecular sterilization11. There thus seems considerable scope to further enhance the sus-tainability of Bt crops and develop new strate-gies for integrated pest management.

Wolfgang G. Kreyling, Stephanie Hirn and Carsten Schleh are at the Comprehensive Pneumology Center, Institute of Lung Biology and Disease, and Focus Network Nanoparticles and Health, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg/Munich, Germany. e-mail: kreyling@helmholtz-muenchen.de

administered nanoparticles can be rapidly excreted through the kidneys if their physi-cochemical properties are carefully chosen9,10. Efficient renal clearance represents one elegant way of keeping the accumulation and, hence, the dose to secondary organs, low9,10. The pres-ent study4 indicates how renal clearance could be achieved following deposition in the lungs.

The new work4 also defines the require-ments for targeting nanoparticles to regional lymph nodes, which may be useful for thera-pies directed to the immune system. However, further quantitative investigation is needed to differentiate between transport to the blood through lymphatic drainage and direct trans-location across the air-blood barrier to the blood. Additional challenges will arise in extra-polating from the rather simple nanoparticles used in this study to highly functionalized nanosystems bearing targeting, therapeutic and diagnostic molecules.

Finally, the results of Frangioni, Tsuda and colleagues4 may help in understanding the

The lungs represent a promising route for drug delivery because of their accessible, large surface area and because the air-blood barrier is rather thin1. After crossing the air-blood barrier, inhaled nanoparticles have been shown to reach detectable levels in the blood circulation and to enter specific cells and tissues5 (Fig. 1). Translocation and accumu-lation in tissues seem to depend on physico-chemical properties of the nanoparticle core and surface5–7. Thus far, however, few studies have described nanoparticle transport across the lungs quantitatively5,6.

Frangioni, Tsuda and colleagues4 find that noncationic nanoparticles smaller than ~34 nm in diameter that do not bind serum proteins reach the regional lymph nodes within 30 min. Nanoparticles larger than ~34 nm are consis-tently retained in the lungs. When the diameter falls below ~6 nm and the charge is zwitteri-onic, about half of the nanoparticles rapidly enter the bloodstream from the alveolar air-spaces and are mostly cleared from the body by means of renal filtration. The authors also show that nanoparticle behavior depends strongly on the surface coating, which affects binding to proteins in body fluid.

Biodegradable nanoparticles are currently considered to be the best choice for targeted drug delivery, but biopersistent nanoparticles might also be used if they are cleared from the body quickly enough to minimize exposure and retention8. As demonstrated previously by the Frangioni laboratory, intravenously

Little is known about the fate of nanoparticles that enter the lungs, either deliberately through medical treatments1 or incidentally through air pollution2,3 and occupational exposure in the workplace. As inhaled nanoparticles can cross the air-blood barrier into the cir-culation and accumulate in secondary organs and tissues, a biokinetic analysis would be the first step in a dose-response study as part of a comprehensive risk assessment (Fig. 1). In this issue, Frangioni, Tsuda and colleagues4 undertake such a biokinetic analysis in rats, using near-infrared imaging to follow the fate of intratracheally instilled nanoparticles that are varied systematically in size, surface modification and core composition. The authors study the parameters that control whether nanoparticles remain in the lung, are transported to regional lymph nodes and the bloodstream or are cleared from the body through the kidneys. Their findings should benefit several areas of research, including the design of nanoparticles for drug delivery and the evaluation of the toxicity of particu-late air pollution.

Nanoparticles in the lungwolfgang G Kreyling, stephanie Hirn & Carsten schleh

An imaging study begins to define the parameters that control the biodistribution of nanoparticles after pulmonary delivery.

Figure 1 Schematic of nanoparticle translocation from the lung epithelium to regional lymph nodes and blood circulation. Once circulating in blood, nanoparticles may accumulate in various secondary organs of the body. The study by Frangioni, Tsuda and colleagues4 highlights two important pathways of nanoparticle biodistribution: the pathway of lymphatic drainage toward regional lymph nodes and renal clearance from blood to urine. AM, alveolar macrophages.

Urine

Bronchialepithelium

Epitheliumlining fluid

AlveolarepitheliumInterstitium

Nanoparticles

AMM

Neutrophil

Circulation

Regionallymphnodes

Heart

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Liver

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membranes and of the biokinetics across the air-blood barrier, the blood-brain barrier, the placenta, etc. can be expected to allow predict-able, safe and sustained application of nanopar-ticles in biomedicine.

COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.

1. Mansour, H.M., Rhee, Y.S. & Wu, X. Int. J. Nanomedicine 4, 299–319 (2009).

2. Oberdörster, G., Oberdörster, E. & Oberdörster, J. Environ. Health Perspect. 113, 823–839 (2005).

3. Maynard, A.D. et al. Nature 444, 267–269 (2006).4. Choi, H.S. et al. Nat. Biotechnol. 28, 1300–1303

(2010).5. Semmler-Behnke, M. et al. Small 4, 2108–2111

(2008).6. Geiser, M. & Kreyling, W. Part. Fibre Toxicol. 7,

2 (2010).7. Oberdorster, G. J. Intern. Med. 267, 89–105

(2010).8. Kostarelos, K. Nanomed. 5, 341–342 (2010).9. Choi, H.S. et al. Nat. Nanotechnol. 5, 42–47 (2010).10. Choi, H.S. et al. Nat. Biotechnol. 25, 1165–1170

(2007).

aerosol concentration of 1012 m–3 (beyond that, coagulation changes the concentration rapidly within one minute under ambient air condi-tions), and the daily volume of air inhaled by an adult is ~15 m3. Assuming a nanoparticle deposition probability of 0.3, the daily depo-sition amounts to ~5 × 1012 nanoparticles. Frangioni, Tsuda and colleagues4 used doses of ~1015 nanoparticles per animal, which exceed human daily doses to the lungs. Their results must therefore be interpreted with caution when attempting to extrapolate to the effects of particulate air pollutants in humans.

In the context of a field that lacks elemen-tary knowledge about the short- and long-term transport of nanoparticles delivered to the lungs, the present study4 represents an important advance. Ultimately, a comprehen-sive mechanistic understanding of the inter-actions of nanoparticles with biomolecules and proteins in body fluids or with cellular

health effects of air pollution as the nanoparticles studied may share common properties with the nano-fraction of particulate air pollutants. Most previous work in this field has used inhalation of nanoparticle aerosols as the ‘gold standard’ method of exposure because the particles will deposit throughout the entire bronchiolar and alveolar epithelium in a physiological manner. However, such studies are rather elaborate and expensive, and the deposited nanoparticle dose is usually difficult to determine. Intratracheal instillation of small nanoparticle suspension volumes, as used in the present study4, is widely accepted as an alternative method of delivery to the lungs. Although the dose administered by this method is well controlled, lung deposi-tion is less uniform and far from physiological7. Moreover, the dose is frequently high in order to observe adverse short-term effects.

The daily dose of inhaled nanoparticles in humans is limited to a maximal nanoparticle

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