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Pulmonary Biodistribution and Cellular Uptake of Intranasally Administered Monodisperse Particles

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Abstract

Purpose

For the rational design of nanovaccines against respiratory pathogens, careful selection of optimal particle size and chemistry is paramount. This work investigates the impact of these properties on the deposition, biodistribution, and cellular interactions of nanoparticles within the lungs.

Method

In this work, biodegradable poly(sebacic anhydride) (poly(SA)) nanoparticles of multiple sizes were synthesized with narrow particle size distributions. The lung deposition and retention as well as the internalization by phagocytic cells of these particles were compared to that of non-degradable monodisperse polystyrene nanoparticles of similar sizes.

Results

The initial deposition of intranasally administered particles in the lungs was dependent on primary particle size, with maximal deposition occurring for the 360–470 nm particles, regardless of chemistry. Over time, both particle size and chemistry affected the frequency of particle-positive cells and the specific cell types taking up particles. The biodegradable poly(SA) particles associated more closely with phagocytic cells and the dynamics of this association impacted the clearance of these particles from the lung.

Conclusions

The findings reported herein indicate that both size and chemistry control the fate of intranasally administered particles and that the dynamics of particle association with phagocytic cells in the lungs provide important insights for the rational design of pulmonary vaccine delivery vehicles.

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Abbreviations

APC:

Antigen presenting cell

DC:

Dendritic cell

H&E:

Hematoxylin and eosin

MFI:

Mean fluorescence intensity

MΦ:

Macrophage

PMN:

Polymorphonuclear leukocyte

poly(SA):

Poly(sebacic anhydride)

PS:

Polystyrene

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Acknowledgments

The authors wish to acknowledge funding from the ONR-MURI Award (NN00014-06-1-1176), the U.S. Army Medical Research and Materiel Command (Grant no. W81XWH-09-1-0386), and HRSA (Grant no. C76HF19578). The authors would also like to thank Shawn Rigby of the Iowa State Flow Cytometry Facility for his expertise in flow cytometry. BN acknowledges the Vlasta Klima Balloun Professorship in Chemical and Biological Engineering. The authors wish to thank Dr. Paola Boggiatto for useful discussions on the analysis of the flow cytometric data.

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Authors and Affiliations

  1. Department of Chemical and Biological Engineering, Iowa State University, 2035 Sweeney Hall, Ames, Iowa, 50011, USA

    Timothy M. Brenza, Latrisha K. Petersen, Yanjie Zhang & Balaji Narasimhan

  2. Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, USA

    Lucas M. Huntimer, Amanda E. Ramer-Tait & Michael J. Wannemuehler

  3. Department of Veterinary Pathology, Iowa State University, Ames, IA, USA

    Jesse M. Hostetter

Authors
  1. Timothy M. Brenza
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  2. Latrisha K. Petersen
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  7. Michael J. Wannemuehler
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  8. Balaji Narasimhan
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Corresponding author

Correspondence to Balaji Narasimhan.

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Supplemental Figure 1

Hemotoxilyn & eosin stained lung tissues were evaluated, blindly by a board-certified veterinary pathologist using a histopathological scoring system. Scores of 0–5 were assigned to five independent parameters: inflammatory infiltration, necrosis, edema, hemorrhage, and bronchus-associated lymphoid tissue hyperplasia. A score of zero indicated the parameter was absent and a score of five indicated that the parameter was diffuse and interrupted normal tissue architecture. The data are presented as the mean ± standard error of the mean of the combined scores of all five parameters. The asterisk (*) indicates statistical significance compared to lungs from mice that were administered saline (p < 0.05) at the same time point. Each treatment group at each time point consisted of slides sectioned from a total of four mice. (GIF 34 kb)

High resolution image (TIFF 103 kb)

Supplemental Figure 2

Flow cytometry gating strategy utilized for identification of particle-positive cells. Gating sequence illustrated for mice intranasally administered either saline, 470 nm poly(SA), or 360 nm PS particles 12 h previously. After initial gating for viable cells in forward (FSC-A) and side (SSC-A) scatter plots (top plot), single cells were identified in dual forward scatter (FSC-A vs. FSC-H) plot (not shown). The viable single cells were determined as particle positive based on fluorescence intensity, demonstrated here in dot plots of particle fluorescence (y-axis) vs. forward scatter (FSC-A) (x-axis). From these dot plots, it is clear that the lungs of mice administered saline only had no particle-positive cells. In contrast, the lungs of mice administered the poly(SA) or polystyrene (PS) particles showed significant numbers of particle-positive cells which were further examined for cell type. (GIF 20 kb)

High resolution image (TIFF 2499 kb)

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Brenza, T.M., Petersen, L.K., Zhang, Y. et al. Pulmonary Biodistribution and Cellular Uptake of Intranasally Administered Monodisperse Particles. Pharm Res 32, 1368–1382 (2015). https://doi.org/10.1007/s11095-014-1540-y

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  • DOI: https://doi.org/10.1007/s11095-014-1540-y

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