Rational design and characterisation of a linear cell penetrating peptide for non-viral gene delivery.

Autor: McErlean EM; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK., Ziminska M; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK., McCrudden CM; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK., McBride JW; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK., Loughran SP; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK., Cole G; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK., Mulholland EJ; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK., Kett V; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK., Buckley NE; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK., Robson T; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons Ireland, 111 St Stephen's Green, Dublin 2, Ireland., Dunne NJ; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; School of Mechanical and Manufacturing Engineering, Dublin City University, Dublin 9, Ireland; Centre for Medical Engineering Research, School of Mechanical and Manufacturing Engineering, Dublin City University, Dublin 9, Ireland; Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin 2, Ireland; Advanced Manufacturing Research Centre (I-Form), School of Mechanical and Manufacturing Engineering, Dublin City University, Glasnevin, Dublin 9, Ireland; Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, Ireland; Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin 2, Ireland; Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland., McCarthy HO; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; School of Chemical Sciences, Dublin City University, Dublin 9, Ireland. Electronic address: h.mccarthy@qub.ac.uk.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2021 Feb 10; Vol. 330, pp. 1288-1299. Date of Electronic Publication: 2020 Nov 21.
DOI: 10.1016/j.jconrel.2020.11.037
Abstrakt: The design of a non-viral gene delivery system that can release a functional nucleic acid at the intracellular destination site is an exciting but also challenging proposition. The ideal gene delivery vector must be non-toxic, non-immunogenic, overcome extra- and intra-cellular barriers, protect the nucleic acid cargo from degradation with stability over a range of temperatures. A new 15 amino acid linear peptide termed CHAT was designed in this study with the goal of delivering DNA with high efficiency into cells in vitro and tissues in vivo. Rational design involved incorporation of key amino acids including arginine for nucleic acid complexation and cellular uptake, tryptophan to enhance hydrophobic interaction with cell membranes, histidine to facilitate endosomal escape and cysteine for stability and controlled cargo release. Six linear peptides were synthesised with strategic sequences and amino acid substitutions. Data demonstrated that all six peptides complexed pDNA to produce cationic nanoparticles less than 200 nm in diameter, but not all peptides resulted in successful transfection; indicating the influence of peptide design for endosomal escape. Peptide 4, now termed CHAT, was non-cytotoxic, traversed the plasma membrane of breast and prostate cancer cell lines, and elicited reporter-gene expression following intra-tumoural and intravenous delivery in vivo. CHAT presents an exciting new peptide for the delivery of nucleic acid therapeutics.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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