SUMMARYNanoparticles (NPs) have the potential to revolutionize drug delivery, however, administering them to the human body without the need for intravenous injection remains a major challenge. In this study, a series of near-infrared (NIR) fluorescent NPs were systematically varied in chemical composition, shape, size, and surface charge, and their biodistribution and elimination were quantified in rat models after lung instillation. We demonstrate that NPs with hydrodynamic diameter (HD) less than ≈ 34 nm and a non-cationic surface charge translocate rapidly from lung to mediastinal lymph nodes. NPs of HD < 6 nm can traffic rapidly from the lungs to lymph nodes and the bloodstream, and then be subsequently cleared by the kidneys. We discuss the importance of these findings to drug delivery, air pollution, and carcinogenesis. KeywordsNanoparticles; nanomedicine; drug delivery; air pollution; lymph node uptake; biodistribution; renal clearance * Co-Senior Authors: Beth Israel Deaconess Medical Center 330 Brookline Avenue, Room SL-B05 Boston, MA 02215 Phone: 617-667-0692 Fax: 617-667-0981 jfrangio@bidmc.harvard.edu Harvard School of Public Health 665 Huntington Avenue Boston, MA 02115 Phone: 617-432-0127 Fax: 617-432-4710 atsuda@hsph.harvard.edu . AUTHOR CONTRIBUTIONS H.S.C., Y.A., J.H.L., S.H.K., A.M., N.I., and A.T. performed the experiments. H.S.C., M.G.B., M.S.B., A.T., and J.V.F. reviewed, analyzed, and interpreted the data. H.S.C., A.T., and J.V.F. wrote the paper. All authors discussed the results and commented on the manuscript. Nanoparticles (NPs) have been proposed as diagnostic, therapeutic, and theragnostic agents for a wide variety of human diseases. 1-3 Lung-based drug delivery of NPs is receiving increased attention due to the large surface area available and the minimal anatomical barriers limiting access to the body. 4 In this study, we explore whether it would be possible to administer NPs via the lung, and in so doing, attempt to define the key parameters that mediate lung to body NP translocation and subsequent elimination (i.e., clearance). COMPETING INTERESTS STATEMENTLung-administered NPs also have significant implications for air pollution. Recent toxicological studies have confirmed that nano-sized or ultrafine particles reach deep into the alveolar region of the lungs 5,6 and cause severe inflammation reactions due to their large surface areas per mass. 6 Inhalation of NPs is increasingly recognized as a major cause of adverse health effects, and has especially strong influence on the cardiovascular system and hemostasis, leading to increased cardiovascular morbidity and mortality. [6][7][8] The standard approach for studying the translocation of inhaled NPs and ultrafine air pollutants from the lungs to extrapulmonary compartments in animals is to perform postmortem analysis of tissues after inhalation of carbon-based particles, 9 radiotracers, 10 or neutron-activated metal particles. 11-13 Recently, Moller et al. reported that ultrafine NPs could pass from the lungs into bloodstream an...

Gold nanoparticles (GNP) provide many opportunities in imaging, diagnostics, and therapies of nanomedicine. Hence, their biokinetics in the body are prerequisites for specific tailoring of nanomedicinal applications and for a comprehensive risk assessment.We administered 198 Au-radio-labelled monodisperse, negatively charged GNP of five different sizes (1.4, 5, 18, 80, 200nm) and 2.8nm GNP with opposite surface charges by intravenous injection into rats. After 24 h the biodistribution of the GNP was quantitatively measured by gamma-spectrometry.The size and surface charge of GNP strongly determine the biodistribution. Most GNP accumulated in the liver increased from 50% of 1.4nm GNP to > 99% of 200nm GNP. In contrast, there was little size dependent accumulation of 18nm to 200nm GNP in most other organs. However, for GNP between 1.4nm and 5nm the accumulation increased sharply with decreasing size; i.e. a linear increase with the volumetric specific surface area. The differently charged 2.8nm GNP led to significantly different accumulations in several organs.We conclude that the alterations of accumulation in the various organs and tissues, depending on GNP size and surface charge, are mediated by dynamic protein binding and exchange. A better understanding of these mechanisms will improve drug delivery and dose estimates used in risk assessment.

1.4‐nm gold nanoparticles (NPs) are observed to cross the air/blood barrier of the lungs much more efficiently than 18‐nm gold NPs (see figure). The NP accumulation pattern in the secondary‐target organs differs strongly from those seen after direct intravenous injection. From this, it is hypothesized that NPs interact dynamically with proteins and cells, which determines their accumulation in the various organs.

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Currently, translocation of inhaled insoluble nanoparticles (NP) across membranes like the air-blood barrier into secondary target organs (STOs) is debated. Of key interest are the involved biological mechanisms and NP parameters that determine the efficiency of translocation. We performed NP inhalation studies with rats to derive quantitative biodistribution data on the translocation of NP from lungs to blood circulation and STOs. The inhaled NP were chain aggregates (and agglomerates) of either iridium or carbon, with primary particle sizes of 2-4 nm (Ir) and 5-10 nm (C) and aggregate sizes (mean mobility diameters) between 20 and 80 nm. The carbon aggregates contained a small fraction ( < 1%) of Ir primary particles. The insoluble aggregates were radiolabeled with (192)Ir. During 1 h of inhalation, rats were intubated and ventilated to avoid extrathoracic NP deposition and to optimize deep lung NP deposition. After 24 h, (192)Ir fractions in the range between 0.001 and 0.01 were found in liver, spleen, kidneys, heart, and brain, and an even higher fraction (between 0.01 and 0.05) in the remaining carcass consisting of soft tissue and bone. The fractions of (192)Ir carried with the carbon NP retained in STOs, the skeleton, and soft tissue were significantly lower than with NP made from pure Ir. Furthermore, there was significantly less translocation and accumulation with 80-nm than with 20-nm NP aggregates of Ir. These studies show that both NP characteristics--the material and the size of the chain-type aggregates--determine translocation and accumulation in STOs, skeleton, and soft tissue.