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Targeted PEG-poly(glutamic acid) complexes for inhalation protein delivery to the lung

Nieto-Orellana, A.; Li, H.; Rosiere, R.; Wauthoz, N.; Williams, H.; Monteiro, C.J.; Bosquillon, C.; Childerhouse, N.; Keegan, G.; Coghlan, D.; Mantovani, G.; Stolnik, S.

Authors

A. Nieto-Orellana

H. Li

R. Rosiere

N. Wauthoz

H. Williams

C.J. Monteiro

C. Bosquillon

N. Childerhouse

G. Keegan

D. Coghlan

G. Mantovani

S. Stolnik



Abstract

Pulmonary delivery is increasingly seen as an attractive, non-invasive route for the delivery of forthcoming protein therapeutics. In this context, here we describe protein complexes with a new ‘complexing excipient’ - vitamin B12-targeted poly(ethylene glycol)-block-poly(glutamic acid) copolymers. These form complexes in sub-200 nm size with a model protein, suitable for cellular targeting and intracellular delivery. Initially we confirmed expression of vitamin B12-internalization receptor (CD320) by Calu-3 cells of the in vitro lung epithelial model used, and demonstrated enhanced B12 receptor-mediated cellular internalization of B12-targeted complexes, relative to non-targeted counterparts or protein alone. To develop an inhalation formulation, the protein complexes were spray dried adopting a standard protocol into powders with aerodynamic diameter within the suitable range for lower airway deposition. The cellular internalization of targeted complexes from dry powders applied directly to Calu-3 model was found to be 2–3 fold higher compared to non-targeted complexes. The copolymer complexes show no complement activation, and in vivo lung tolerance studies demonstrated that repeated administration of formulated dry powders over a 3 week period in healthy BALB/c mice induced no significant toxicity or indications of lung inflammation, as assessed by cell population count and quantification of IL-1β, IL-6, and TNF-α pro-inflammatory markers. Importantly, the in vivo data appear to suggest that B12-targeted polymer complexes administered as dry powder enhance lung retention of their protein payload, relative to protein alone and non-targeted counterparts. Taken together, our data illustrate the potential developability of novel B12-targeted poly(ethylene glycol)-poly(glutamic acid) copolymers as excipients suitable to be formulated into a dry powder product for the inhalation delivery of proteins, with no significant lung toxicity, and with enhanced protein retention at their in vivo target tissue.

Journal Article Type Article
Publication Date Dec 28, 2019
Journal Journal of Controlled Release
Print ISSN 0168-3659
Electronic ISSN 1873-4995
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 316
Pages 250-262
APA6 Citation Nieto-Orellana, A., Li, H., Rosiere, R., Wauthoz, N., Williams, H., Monteiro, C., …Stolnik, S. (2019). Targeted PEG-poly(glutamic acid) complexes for inhalation protein delivery to the lung. Journal of Controlled Release, 316, 250-262. https://doi.org/10.1016/j.jconrel.2019.10.012
DOI https://doi.org/10.1016/j.jconrel.2019.10.012
Keywords Polymer-protein complexes; Inhalation delivery; Spray-dried inhalation powder; Protein delivery; Targeted complexes
Publisher URL https://www.sciencedirect.com/science/article/pii/S0168365919305747
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