Rapid translocation of nanoparticles from the lung airspaces to the body

Abstract

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...

Human health hazards of persistent inorganic and carbon nanoparticles

“…These include surface area of inhaled particles, surface charge, hydrophilicity and surface chemistry, including catalytic activity and solubility of substances present in the nanoparticle [1-3, 39, 65, 74-86]. For instance, as pointed out before, Choi et al [39] found that noncationic nanoparticles \34 nm were rapidly translocated from the lungs, whereas cationic nanoparticles of a similar size were not. The generation of Ag ions by silver nanoparticles [82] and the release of ionic Cd and Se from CdSe quantumdots [16,36,84,85] are determinants of nanoparticle hazard.…”

“…Translocation from the lungs may vary considerably between nanoparticles Kreyling et al [42] studied Ir nanoparticles with 15 and 80 nm diameters and found that translocation rates from the lungs to blood were in the order of 1-2%, with a relatively lower rate for the larger nanoparticles. In a study with nanoparticles containing CdSe, ZnS, silica, CdTe, and ZnS with a variety of organic coatings, Choi et al [39] found that particles with a hydrodynamic diameter \34 nm and a noncationic surface charge migrated rapidly from the lung to lymph nodes. When such nanoparticles had hydrodynamic diameter of 6 nm, they migrated rapidly from the lungs to the bloodstream [39].…”

“…In a study with nanoparticles containing CdSe, ZnS, silica, CdTe, and ZnS with a variety of organic coatings, Choi et al [39] found that particles with a hydrodynamic diameter \34 nm and a noncationic surface charge migrated rapidly from the lung to lymph nodes. When such nanoparticles had hydrodynamic diameter of 6 nm, they migrated rapidly from the lungs to the bloodstream [39].…”

“…Potential effects on the lungs include damage to membranes, cytotoxicity, genotoxicity, apoptosis (induced programmed cell death), necrosis (cell death due to toxic interference with vital cell functions), inflammation, fibrosis, and cancer [1-3, and references therein]. Inhaled nanoparticles may penetrate the alveolar-capillary barrier between the respiratory and circulatory system, and thus be translocated from the lungs [2,3,[30][31][32][33][34][35][36][37][38][39][40][41][42], and references therein]. When the nanoparticles translocate to the circulatory system, other organs may also be affected [1-3, 15, 16, 30-32, 39-42].…”

Phosphonated Near‐Infrared Fluorophores for Biomedical Imaging of Bone

“…NIR fluorescence microscopy was performed on a 4-filter Nikon Eclipse TE300 microscope system as previously described. [9,23,24] The microscope was equipped with a 100 W mercury light source (Chiu Technical Corporation, Kings Park, NY), NIR-compatible optics, and a NIR-compatible 10X Plan Fluor objective lens and a 100X Plan Apo oil immersion objective lens (Nikon, Melville, NY). Images were acquired on an Orca-AG (Hamamatsu, Bridgewater, NJ).…”