Distribution and Cellular Uptake of PEGylated Polymeric Particles in the Lung Towards Cell-Specific Targeted Delivery
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We evaluated the role of a poly(ethylene glycol) (PEG) surface coating to increase residence times and alter the cellular fate of nano- and microparticles delivered to the lung.
Three sizes of PRINT hydrogel particles (80 × 320 nm, 1.5 and 6 μm donuts) with and without a surface PEG coating were instilled in the airways of C57/b6 mice. At time points of 1, 7, and 28 days, BALF and whole lungs were evaluated for the inflammatory cytokine Il-6 and chemokine MIP-2, histopathology, cellular populations of macrophages, dendritic cells (DCs), and granulocytes, and particulate uptake within these cells through flow cytometry, ELISAs, and fluorescent imaging.
Particles of all sizes and surface chemistries were readily observed in the lung with minimal inflammatory response at all time points. Surface modification with PEGylation was found to significantly increase lung residence times and homogeneous lung distribution, delaying macrophage clearance of all sizes, with the largest increase in residence time observed for 80 × 320 nm particles. Additionally, it was observed that DCs were recruited to the airway following administration of unPEGylated particles and preferentially associated with these particles.
Pulmonary drug delivery vehicles designed with a PEG surface coating can be used to delay particle uptake and promote cell-specific targeting of therapeutics.
KEY WORDSMicroparticle Nanoparticle PEGylation Pulmonary drug delivery
Broncheoalveolar lavage fluid
Chronic obstructive pulmonary disease
Dry powder inhaler
Enzyme-linked immuno assay
Tetra(ethylene glycol) monoacrylate
Institutional animal care and use committee
Large porous particles
Particle Replication In Non-wetting Templates
Scanning electron microscopy
ACKNOWLEDGMENTS AND DISCLOSURES
We thank R. Roberts, K. Reuter, J. Perry, S. Tian, J. P.Y. Ting, A. Pandya, B. Udis, N. Fisher, S. Coquery, L. Wai, and, J. Weaver for useful discussions and technical assistance. We acknowledge Liquidia Technologies for providing PRINT molds, and the core facilities at UNC, including the Nucleic Acids Core Facility, CHANL imaging facility, the LCCC Histopathology Core, the Histology Facility of the Department of Cell and Molecular Physiology, the Department of Microbiology and Immunology Flow Cytometry Core Facility, and DLAM facility. This work was funded in part by the NIH Pioneer Award to J.M.D. (1DP1OD006432), DTRA award (HDTRA1-13-1-0045), and the NSF Graduate Research Fellowship, as well as NCI Center Core Support Grant CA016086. J.M.D. is a founder and maintains a financial interest in Liquidia Technologies.
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