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

JOURNAL OF CONTROLLED RELEASE

卷:330

Article

McErlean, Emma M.¹  Ziminska, Monika¹  McCrudden, Cian M.¹  McBride, John W.¹  Loughran, Stephen P.¹  Cole, Grace¹  Mulholland, Eoghan J.¹  Kett, Vicky¹  Buckley, Niamh E.¹  Robson, Tracy²  Dunne, Nicholas J.^{1,3,4,5,6,7,8,9}  McCarthy, Helen O.^1,10 

[1] Queens Univ Belfast, Sch Pharm, 97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland

[2] Royal Coll Surgeons Ireland, Sch Pharm & Biomol Sci, 111 St Stephens Green, Dublin 2, Ireland

[3] Dublin City Univ, Sch Mech & Mfg Engn, Dublin 9, Ireland

[4] Dublin City Univ, Sch Mech & Mfg Engn, Ctr Med Engn Res, Dublin 9, Ireland

[5] Trinity Coll Dublin, Sch Engn, Dept Mech & Mfg Engn, Dublin 2, Ireland

[6] Dublin City Univ, Sch Mech & Mfg Engn, Adv Mfg Res Ctr I Form, Dublin 9, Ireland

[7] Royal Coll Surgeons Ireland, Adv Mat & Bioengn Res Ctr AMBER, Dublin 2, Ireland

[8] Trinity Coll Dublin, Dublin 2, Ireland

[9] Trinity Coll Dublin, Trinity Ctr Biomed Engn, Trinity Biomed Sci Inst, Dublin 2, Ireland

[10] Dublin City Univ, Sch Chem Sci, Dublin 9, Ireland

关键词: Gene delivery;    Linear peptides;    Cell penetrating;    Nucleic acids;    Non-viral;   

DOI  :  10.1016/j.jconrel.2020.11.037

来源: Elsevier

【 摘 要 】

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 noncytotoxic, 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.

【 授权许可】

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