Rapid translocation of nanoparticles from the lung airspaces to the body

Journal name:
Nature Biotechnology
Volume:
28,
Pages:
1300–1303
Year published:
DOI:
doi:10.1038/nbt.1696
Received
Accepted
Published online

Nano-size particles show promise for pulmonary drug delivery, yet their behavior after deposition in the lung remains poorly understood. In this study, a series of near-infrared (NIR) fluorescent nanoparticles 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 nanoparticles with hydrodynamic diameter (HD) less than 34 nm and a noncationic surface charge translocate rapidly from the lung to mediastinal lymph nodes. Nanoparticles 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 for drug delivery, air pollution and carcinogenesis.

At a glance

Figures

  1. Schematic structures of inorganic/organic hybrid nanoparticles (INPs, 800 nm emission) and organic nanoparticles (ONPs, 700 nm emission) and their size- and charge-dependent translocation.
    Figure 1: Schematic structures of inorganic/organic hybrid nanoparticles (INPs, 800 nm emission) and organic nanoparticles (ONPs, 700 nm emission) and their size- and charge-dependent translocation.

    (a) INPs comprised 800 nm NIR quantum dots composed of various core(shell) configurations and coatings (INP1–INP5, 5–40 nm HD) and silica nanospheres with incorporation of small-molecule NIR fluorophores (INP6–INP9, 50–300 nm HD) into the coating. ONPs comprised human serum albumin (HSA) conjugated with a 700 nm NIR fluorophore (ONP1, 7 nm HD), a 700 nm NIR dye-conjugated mPEG (ONP2, 9 nm HD) and spherical organic nanoparticles consisting of polystyrene core and chemically cross-linked polyacrylate chains with 700 nm fluorophore conjugation (ONP3–ONP7, 20–300 nm HD). Different charged organic ligands were used for coating the core(shell) of INPs. (b) Size-dependent translocation of INPs from lungs to lymph nodes. Four INPs were administered into lungs and their translocation was observed at 30 min after administration. Shown are representative (n = 3) images of color video (left), NIR fluorescence (middle) and a pseudo-colored merge of the two (right). Ga, gauze; Lu, lung; Mu, muscle; Tr, trachea. Arrows and red dotted circles indicate lymph node. Scale bar, 500 μm. λExc = 667 ± 11 nm and λEm = 700 ± 17.5 nm for ONPs. λExc = 760 ± 20 nm and λEm = 795 nm longpass for INPs. All NIR fluorescence images have identical exposure times and normalizations. (c) Charge-dependent translocation of nanoparticles from lungs to lymph nodes. ONP1 (zwitterionic), ONP2 (polar), INP3 (anionic) and INP4 (cationic) were administered into lungs and their translocation was observed at 30 min after administration. See b for abbreviations and experimental details.

  2. Biodistribution, clearance and histological analysis of INPs in Sprague-Dawley rats.
    Figure 2: Biodistribution, clearance and histological analysis of INPs in Sprague-Dawley rats.

    (a) Translocation into lymph node, blood and urinary excretion of INP1 (left) and INP3 (right) using real-time NIR fluorescence imaging. Each point represents the mean ± s.d. of n = 3 animals. SBR, signal-to-background ratio. (b) Frozen sections obtained from resected organs of INP1-administered Sprague-Dawley rats at 1 h after instillation. From top to bottom are representative images of lung, lymph node, kidney (arrow: cortex; arrowhead: calyces), and liver. Mu, muscle; LN+, posterior mediastinal lymph node; LN−, negative para-aortic lymph node. Scale bars, 5 mm. Shown are color video and NIR fluorescence of intact specimens (left two panels, respectively) along with representative histological images from the same organ/tissue (H&E, NIR, right two panels, respectively). Green dotted circle, bronchiole; blue dotted circle, glomerular basement membrane; red dotted circle, portal area (portal vein, hepatic artery and bile duct). Scale bars, 200 μm. All NIR fluorescence images (λExc = 760 ± 20 nm and λEm = 795 nm longpass) have identical exposure times and normalizations. (c) Quantitative biodistribution and clearance using 99mTc-conjugated INPs administered intratracheally into Sprague-Dawley rats. The small molecule TcO4 was used as a control. Translocation from lung to blood over time (top). Translocation from lung to regional lymph nodes (bottom left) 1 h after injection. Recovery of injected dose in urine, lung, body (without lungs) and total (bottom right). Each data point represents the mean ± s.d. of n = 3 animals. All values in blood curves are statistically different (ANOVA) from each other at 1 h.

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Author information

  1. These authors contributed equally to this work.

    • John V Frangioni &
    • Akira Tsuda

Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

    • Hak Soo Choi,
    • Yoshitomo Ashitate,
    • Jeong Heon Lee,
    • Soon Hee Kim,
    • Aya Matsui &
    • John V Frangioni
  2. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Numpon Insin &
    • Moungi G Bawendi
  3. Institute of Lung Biology and Disease, Helmholtz Center München—German Research Center for Environmental Health, Neuherberg/Munich, Germany.

    • Manuela Semmler-Behnke
  4. Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

    • John V Frangioni
  5. Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Akira Tsuda

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.

Competing financial interests

All FLARE technology is owned by Beth Israel Deaconess Medical Center, a teaching hospital of Harvard Medical School. As inventor, Dr. Frangioni may someday receive royalties if products are commercialized. Dr. Frangioni is the founder and unpaid director of The FLARE Foundation, a non-profit organization focused on promoting the dissemination of medical imaging technology for research and clinical use.

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Supplementary information

PDF files

  1. Supplementary Text and Figures (1 MB)

    Supplementary Figs. 1–6

Zip files

  1. Supplementary Video 1 (1.3 MB)

    Real-Time Translocation of NPs from the Lung to a Mediastinal Lymph Node

  2. Supplementary Video 2 (3.5 MB)

    Real-Time Clearance of NPs from Kidneys to Bladder

Additional data