Delivery of Nucleic Acids via Disulfide‐Based Carrier Systems

Abstract

Nucleic acids are not only expected to assume a pivotal position as "drugs" in the treatment of genetic and acquired diseases, but could also act as molecular cues to control the microenvironment during tissue regeneration. Despite this promise, the efficient delivery of nucleic acids to their side of action is still the major hurdle. One among many prerequisites for a successful carrier system for nucleic acids is high stability in the extracellular environment, accompanied by an efficient release of the cargo in the intracellular compartment. A promising strategy to create such an interactive delivery system is to exploit the redox gradient between the extra- and intracellular compartments. In this review, emphasis is placed on the biological rationale for the synthesis of redox sensitive, disulfide-based carrier systems, as well as the extra- and intracellular processing of macromolecules containing disulfide bonds. Moreover, the basic synthetic approaches for introducing disulfide bonds into carrier molecules, together with examples that demonstrate the benefit of disulfides at the individual stages of nucleic acid delivery, will be presented.

Interplay of Chemical Microenvironment and Redox Environment on Thiol–Disulfide Exchange Kinetics

“…The nature of biomaterials and drug delivery systems incorporating disulfides is varied: Bauhuber et al discuss the use of disulfide-based redox linkers for the delivery of nucleic acids. [1] Meng et al report advances in the development of reduction-sensitive biodegradable polymers and conjugates, with particular focus on the up-to-date design and chemistry of various reduction-sensitive delivery systems including liposomes, polymersomes, micelles, nanoparticles, gels, etc. [2] In addition, immunoconjugates bearing disulfide linkers have been surveyed by Kratz et al [3] and Wu and Senter.…”

Photoinduced Cross‐Linking of Dynamic Poly(disulfide) Films via Thiol Oxidative Coupling

“…[ 8 ] A gradual solubilization was noted, and a slightly turbid solution was obtained after 12 d under stirring (see images in Figure S9, Supporting Information). The reaction progress was assessed using 13 C NMR. Figure 4 (down) gives the 13 C NMR spectra of 1 , P1 , and P1R the polymer after reduction.…”

“…The reaction progress was assessed using 13 C NMR. Figure 4 (down) gives the 13 C NMR spectra of 1 , P1 , and P1R the polymer after reduction. The extent of reduction is refl ected by the integral ratios of the carbon signal of the methylene group (C b ) adjacent to the thiol group at 19.7 ppm to that of a reference resonance, such as the CH 2 (C j ) in alpha position of the methyl group at 22.9 ppm.…”

Redox-responsive nanocapsules for intracellular protein delivery

“…The cytosol has a low redox potential due to the abundance of reduced glutathione (GSH) in the millimolar concentration range, whereas the extracellular glutathione concentration falls in the micromolar range 126 . To utilize this redox potential difference, a variety of gene delivery systems based on the dissociation of disulfide bonds have been reported [127][128][129][130][131] . Similarly, we reason here that protein NCs interconnected by a disulfide-containing crosslinker through interfacial polymerization can maintain the integrity of the thin polymer shell under oxidative 43 conditions outside the cell, but it should undergo rapid degradation and cargo release after entry into the cytosol.…”