pH-Responsive Nanometric Polydiacetylenic Micelles Allow for Efficient Intracellular siRNA Delivery

Abstract

A novel generation of pH-responsive photopolymerized diacetylenic amphiphile (PDA) micelles with a diameter of 10 nm was designed and optimized for the intracellular delivery of siRNAs. Dialysis and photopolymerization of the micelles allowed a strong reduction of the cytotoxicity of the nanovector, while the hydrophilic histidine headgroup permitted enhancing the siRNA delivery potential by improving the endosomal escape via imidazole protonation. These PDA-micellar systems were fully characterized by DLS, TEM, and DOSY-NMR experiments. The resulting bioactive complexes of PDA-micelles with siRNA were shown to have an optimal size below 100 nm.

Design and evaluation of ionizable peptide amphiphiles for siRNA delivery

“…For the headgroup, we focused on 3 three amino acids, namely histidine (His), tryptophan (Trp) and tyrosine (Tyr). The first amino acid was selected based on our previous results with His-PDA-micelles [10], while Trp was chosen due to its capacity to interact with membranes. [18] Lastly, Tyr was used as it was previously reported that coupling of this amino acid onto the cationic polymer PEI results in an efficient siRNA delivery vector.…”

“…[9] With these PDA-micelles, we found that when the cationic headgroup was a histidine residue, we obtained vehicles that promote delivery of siRNA molecules into the cytoplasm of cells. [10] The good efficiency of the system is probably based on the fact that the imidazole group of His promotes release of the nucleic acid from the endosomal compartment through a proton sponge mechanism. [11][12][13] This was supported by the fact that inhibition of endosomal acidification severely reduced the silencing efficiency.…”

Co-delivery of anti-PLK-1 siRNA and camptothecin by nanometric polydiacetylenic micelles results in a synergistic cell killing

“…10,11 The last generation of PDA-micelles stabilized by UVphotopolymerization, are self-organized objects in the size range of 10 nm, containing a histidine head group (Hist-PMs, Scheme 1). The micelles allowed for a 90% silencing of a reporter gene using 10 nM siRNA concentration.…”

“…The micelles allowed for a 90% silencing of a reporter gene using 10 nM siRNA concentration. 10 In parallel, E. Doris and H. Tian's groups demonstrated the potential of polydiacetylene nanocarriers for antitumoral drug delivery.…”

Morphology‐Dependent Cell Imaging by Using a Self‐Assembled Diacetylene Peptide Amphiphile

“…[9] Fore xample, recently,p olymerized polydiacetylenes have been reported for imaging and drug delivery and they demonstrated ahigher stability and drug loading than an on-polymerized counterpart or liposomes. [10] In this work, we present an ovel diacetylene-derived peptide gemini amphiphile (DA 2 P)and investigate its supramolecular self-assembly.InDA 2 P,ahydrophilic arginine and lysine rich pentapeptide (RKARK) is attached through aCterminal glutamic acid to two hydrophobic diacetylene chains (Scheme 1). Thei dea was that the combination of ac ationic pentapeptide related to other,but normally much larger,cellpenetrating peptides with two long hydrophobic diacetylene chains should enhance the interaction of this amphiphile with the negatively charged cell membrane and might lead to more efficient cell uptake.Furthermore,the diacetylene part might undergo fluorescent changes in this process,w hich could be used for sensing or cell imaging.I nterestingly,w ef ound that DA 2 P self-assembled in ac oncentration-dependent manner first into tadpole-and bola-shaped nanostructures (low concentration) and then nanofibers (high concentration).…”