Modeling the proton sponge hypothesis: examining proton sponge effectiveness for enhancing intracellular gene delivery through multiscale modeling

Abstract

Dendrimers have been proposed as therapeutic gene delivery platforms. Their superior transfection efficiency is attributed to their ability to buffer the acidification of the endosome and attach to the nucleic acids. For effective transfection the strategy is to synthesize novel dendrimers that optimize both of these traits, but the prediction of the buffering behavior in the endosome remains elusive. It is suggested that buffering dendrimers induce an osmotic pressure sufficient to rupture the endosome and release nucleic acids, which forms to sequestrate most internalized exogenous materials. Presented here are the results of a computational study modeling osmotically-driven endosome burst, or the “proton sponge effect.” The approach builds on previous cellular simulation efforts by linking the previous model with a sponge protonation model then observing the impact on endosomal swelling and acidification. Calibrated and validated using reported experimental data, the simulations offer insights into defining the properties of suitable dendrimers for enhancing gene delivery as a function of polymer structure.

Chitosan as a non-viral co-transfection system in a cystic fibrosis cell line

“…In the case of CS complexes, this efficiency could be attributed to the electrostatic interaction of the complexes with the negatively charged cell membrane. Endocytosed complexes are believed to release the nucleic acids based on the proton sponge effect hypothesis (Freeman et al, 2013). This hypothesis proposes that endosomes are acidified and chitosan promotes the active transport of protons due to the presence of NH2 groups at D-glucosamine residues.…”

Multilayered Nanoparticles for Gene Delivery Used to Reprogram Human Foreskin Fibroblasts to Neurospheres

“…In seeking to mediate many of the outlined inefficiencies, recent studies have demonstrated oligomeric silicate coating of bare polyplexes to effectively seal the payload during initial phases of uptake, additionally preventing destabilization by polyanions and contributing to buffering during endosomal uptake (via the proton sponge effect, a phenomenon whereby lysosomes are prematurely ruptured due to osmotic influx). 15,[47][48][49] Further layering on this anionic silicate layer presents a highly functionalized nanoparticle surface with a stable core capable of controlled nucleic acid release. Our results suggest that silicate is capable of reversibly stabilizing highly complex and otherwise readily destabilizable quaternary cores of nanoparticles, which subsequently are released into the cell and take advantage of many of the outlined benefits of histone tail peptides, cationic polymers, and anionic polymers.…”

Frontiers in Toxicity and Functionalization of Nanomaterials

“…Nanomaterials 2017, 7,79 BIBX 1382 and CL-387785. This treatment resulted in a reduced NF-κB activity in NP2 treated cells by 51.3% and 44.6%, respectively (Figure 5a), 6h after NPs exposure.…”

“…Books MDPI Nanomaterials 2017, 7,79 The best-studied nuclear target of phosphorylated ERK1/2 is the transcription factor ELK1 [20]. Stimulation with NP2 increased the binding of ELK1 to its DNA recognition site (Figure 7c) and declined 60 min after NPs treatment.…”