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Distribution and Cellular Uptake of PEGylated Polymeric Particles in the Lung Towards Cell-Specific Targeted Delivery

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

Pulmonary drug delivery vehicles designed with a PEG surface coating can be used to delay particle uptake and promote cell-specific targeting of therapeutics.

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Abbreviations

AEM:

2-aminoethyl methacrylate

AM:

Alveolar macrophages

BALF:

Broncheoalveolar lavage fluid

COPD:

Chronic obstructive pulmonary disease

DC:

Dendritic cells

Dpi:

Dry powder inhaler

DPPC:

1,2-dipalmitoylphosphatidylcholine

ELISA:

Enzyme-linked immuno assay

HP4A:

Tetra(ethylene glycol) monoacrylate

IACUC:

Institutional animal care and use committee

IV:

Intravenous

LPPs:

Large porous particles

LPS:

Lipopolysaccharide

MΦ:

Macrophages

PEG:

Poly(ethylene glycol)

PEG700DA:

Poly(ethylene glycol)700

PRINT:

Particle Replication In Non-wetting Templates

SEM:

Scanning electron microscopy

TPO:

Diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide

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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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    Authors and Affiliations

    1. Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA

      Tammy W. Shen, J. Christopher Luft, Tojan B. Rahhal & Joseph M. DeSimone

    2. Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, 27695, USA

      Catherine A. Fromen, Marc P. Kai & Joseph M. DeSimone

    3. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA

      Gregory R. Robbins & Joseph M. DeSimone

    4. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA

      Joseph M. DeSimone

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    1. Tammy W. Shen
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    Correspondence to Joseph M. DeSimone.

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    Tammy W. Shen and Catherine A. Fromen contributed equally to this work.

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    Supplemental Figure 1

    Representative flow cytometric analysis of BALF and Lung cells. (A) Gating scheme used to define three major lung cell populations: Granulocytes CD45 + CD11c-Ly6G+, Macrophages (Mφs) CD45+CD11c+MHCIIlo, Dendritic cells (DCs) CD45+CD11c+MHCIIhi. (B) Representative gating of particle positive populations of Granulocytes, AMs and DCs. Blue curves representative data from 80 × 320 day 1 BALF. Red curves represent fluorescence minus one (FMO) controls used to set gates. Black curves represent saline controls. (JPEG 92 kb)

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    Shen, T.W., Fromen, C.A., Kai, M.P. et al. Distribution and Cellular Uptake of PEGylated Polymeric Particles in the Lung Towards Cell-Specific Targeted Delivery. Pharm Res 32, 3248–3260 (2015). https://doi.org/10.1007/s11095-015-1701-7

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    • DOI: https://doi.org/10.1007/s11095-015-1701-7

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