Targeted PEG-Poly(glutamic acid) Polymers For The Delivery of Proteins Into The Lung Epithelium
Huitong Lucy Li1, Alejandro Nieto-Orellana1, Franco H. Falcone1, Cynthia Bosquillon1, Gemma Keegan2, Nick Childerhouse2, Giuseppe Mantovani*1 and Snow Stolnik*1
1School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
2Vectura Group plc, One Prospect West, Chippenham, SN14 6FH, UK
Pulmonary delivery via inhalation offers a potential route for non-invasive delivery of proteins and peptides. However, protein degradation, pulmonary clearance and immunogenicity issues are challenges that need to be addressed. Non-covalent polymer-protein conjugation has emerged as a potential strategy to overcome these challenges. In this work, we propose B12 targeted non-covalent polymer-protein nanocomplexes (consisting of linear PEG-polyglutamic acid polymers (PEG-poly(GA) ionically interacting with positively charged amino acid groups in proteins) in an attempt to increase the cellular internalisation.
The expression of TCN2 B12 receptor gene by lung epithelial Calu-3 cells and the receptor’s involvement in the B12 cellular internalisation was confirmed by a series of experiments. Initial studies strongly indicated that polymer-protein nanocomplexes can be formed between the polymer and lysozyme protein through electrostatic interaction. Comparisons of cellular uptake of polymer–protein nanocomplexes were assessed in vitro between B12 targeted and non-targeted nanocomplexes. The study showed B12-targeted polymer-protein nanocomplexes had enhanced cell uptake in vitro by lung Calu-3 cells, making this PEG-poly(GA) polymer a promising alternative for targeted delivery of biologicals in the lung.