Endocytic Uptake, Transport and Macromolecular Interactions of Anionic PAMAM Dendrimers within Lung Tissue

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Abstract

Purpose

Polyamidoamine (PAMAM) dendrimers are a promising class of nanocarrier with applications in both small and large molecule drug delivery. Here we report a comprehensive evaluation of the uptake and transport pathways that contribute to the lung disposition of dendrimers.

Methods

Anionic PAMAM dendrimers and control dextran probes were applied to an isolated perfused rat lung (IPRL) model and lung epithelial monolayers. Endocytosis pathways were examined in primary alveolar epithelial cultures by confocal microscopy. Molecular interactions of dendrimers with protein and lipid lung fluid components were studied using small angle neutron scattering (SANS).

Results

Dendrimers were absorbed across the intact lung via a passive, size-dependent transport pathway at rates slower than dextrans of similar molecular sizes. SANS investigations of concentration-dependent PAMAM transport in the IPRL confirmed no aggregation of PAMAMs with either albumin or dipalmitoylphosphatidylcholine lung lining fluid components. Distinct endocytic compartments were identified within primary alveolar epithelial cells and their functionality in the rapid uptake of fluorescent dendrimers and model macromolecular probes was confirmed by co-localisation studies.

Conclusions

PAMAM dendrimers display favourable lung biocompatibility but modest lung to blood absorption kinetics. These data support the investigation of dendrimer-based carriers for controlled-release drug delivery to the deep lung.

Electronic supplementary material

The online version of this article (doi:10.1007/s11095-017-2190-7) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Christopher J. Morris: Christopher.J.Morris@uea.ac.uk

Mark Gumbleton: gumbleton@cf.ac.uk

Journal

Journal ID (nlm-ta): Pharm Res

Journal ID (iso-abbrev): Pharm. Res

Title: Pharmaceutical Research

Publisher: Springer US (New York )

ISSN (Print): 0724-8741

ISSN (Electronic): 1573-904X

Publication date (Electronic): 14 June 2017

Publication date PMC-release: 14 June 2017

Publication date (Print): 2017

Volume: 34

Issue: 12

Pages: 2517-2531

Affiliations

[1 ]ISNI 0000 0001 1092 7967, GRID grid.8273.e, School of Pharmacy, , University of East Anglia, ; Norwich Research Park, NR4 7TJ UK

[2 ]Cardiff School of Pharmacy & Pharmaceutical Sciences, Redwood Building, Cardiff, CF10 3NB UK

[3 ]ISNI 0000 0001 0806 5472, GRID grid.36316.31, Department of Pharmaceutical, Chemical and Environmental Science, , University of Greenwich, ; Medway Campus, Kent, ME4 4TB UK

Article

Publisher ID: 2190

DOI: 10.1007/s11095-017-2190-7

PMC ID: 5736778

PubMed ID: 28616685

SO-VID: 44612c9a-cd34-4423-b467-b54376ecd54a

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.