Abstract
Self-assembling multifunctional peptide was designed for gene delivery systems. The multifunctional peptide (MP) consists of cellular penetrating peptide moiety (R8), matrix metalloproteinase-2 (MMP-2) specific sequence (GPLGV), pH-responsive moiety (H5), and hydrophobic moiety (palmitic acid) (CR8GPLGVH5-Pal). MP was oxidized to form multifunctional peptide dimer (MPD) by DMSO oxidation of thiols in terminal cysteine residues. MPD could condense pDNA successfully at a weight ratio of 5. MPD itself could self-assemble into submicron micelle particles via hydrophobic interaction, of which critical micelle concentration is about 0.01 mM. MPD showed concentration-dependent but low cytotoxicity in comparison with PEI25k. MPD polyplexes showed low transfection efficiency in HEK293 cells expressing low level of MMP-2 but high transfection efficiency in A549 and C2C12 cells expressing high level of MMP-2, meaning the enhanced transfection efficiency probably due to MMP-induced structural change of polyplexes. Bafilomycin A1-treated transfection results suggest that the transfection of MPD is mediated via endosomal escape by endosome buffering ability. These results show the potential of MPD for MMP-2 targeted gene delivery systems due to its multifunctionality.
Highlights
Lots of peptides have been developed and used for gene delivery systems due to their advantages [1,2,3]
multifunctional peptide (MP) consists of cellular penetrating peptide moiety (R8), matrix metalloproteinase-2 (MMP-2) specific sequence (GPLGV), C 0.5 1
Cellular penetrating moiety was introduced for condensation of pDNA by electrostatic interaction of cationic arginine residues and for enhancement of cellular uptake. pH-responsive moiety (H5) was introduced for facilitation of endosomal escape of polyplexes after cellular uptake by proton sponge effect
Summary
Lots of peptides have been developed and used for gene delivery systems due to their advantages [1,2,3]. Cellular penetrating peptides such as penetratin, Tat sequence, or oligoarginine have been extensively examined in gene delivery field because they can form nanosized complexes with nucleic acids due to their cationic property and possess high cellular uptake efficiency [5,6,7,8,9]. Besides oligopeptide forms, bioreducible cellular penetrating peptides which are linked via disulfide bonds, have been developed for gene delivery systems [10,11,12,13]. They can be degraded in reductive environment such as cytosol, showing controlled release of nucleic acids and low cytotoxicity [14]
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