Acid-Sensitive Surfactants Enhance the Delivery of Nucleic Acids.

The development of endosomal disruptive agents is a major challenge in the field of drug delivery and pharmaceutical chemistry. Current endosomal disruptive agents are composed of polymers, peptides, and nanoparticles and have had limited clinical impact. Alternatives to traditional endosomal disruptive agents are therefore greatly needed. In this report, we introduce a new class of low molecular weight endosomal disruptive agents, termed caged surfactants, that selectively disrupt endosomes via reversible PEGylation under acidic endosomal conditions. The caged surfactants have the potential to address several of the limitations hindering the development of current endosomal disruptive agents, such as high toxicity and low excretion, and are amenable to traditional medicinal chemistry approaches for optimization. In this report, we synthesized three generations of caged surfactants and demonstrated that they can enhance the ability of cationic lipids to deliver mRNA into primary cells. We also show that caged surfactants can deliver siRNA into cells when modified with the RNA-binding dye thiazole orange. We anticipate that the caged surfactants will have numerous applications in pharmaceutical chemistry and drug delivery given their versatility.

A self-immolative linker that releases thiols detects penicillin amidase and nitroreductase with high sensitivity via absorption spectroscopy.

This article reports the synthesis and characterization of a novel self-immolative linker, based on thiocarbonates, which releases a free thiol upon activation via enzymes. We demonstrate that thiocarbonate self-immolative linkers can be used to detect the enzymes penicillin G amidase (PGA) and nitroreductase (NTR) with high sensitivity using absorption spectroscopy. Paired with modern thiol amplification technology, the detection of PGA and NTR were achieved at concentrations of 160 nM and 52 nM respectively. In addition, the PGA probe was shown to be compatible with both biological thiols and enzymes present in cell lysates.