Degradation of biotherapeutics, such as nucleic acids and proteins, in lysozomes has been shown to be a major bottleneck in drug delivery. Existing strategies are dominated by polymer and particle based methods that are difficult to implement due to their large size, as well as complicated chemical and physical properties. In this study, we present our work on the development of small molecules that disrupt membranes in acidic environments, termed caged surfactants. The caged surfactants are based on known surfactants, such as Triton X and Tween-20, which contain a hydrophilic polyethylene glycol (PEG) chain, and a hydrophobic hydrocarbon segment, allowing for insertion and resulting disruption of membranes. However, in order to achieve pH dependent membrane disruption, the caged surfactants are modified to contain a PEG group which blocks its hydrophobic segment from entering cell membranes at neutral pH values. This blocking group is designed to hydrolyze at acidic pH values, allowing for release of active surfactants in acidic environments, causing selective membrane disruption. This was demonstrated through the disruption of red blood cells at pH 7.4 and pH 5.5, showing 50% cell lysis down to concentrations of 20μM at pH 5.5, with no detectable membrane disruption at pH 7.4 at concentrations above 1mM. The caged surfactants are synthesized in a way that allows for last-step modifications, enabling multi-functionality in a single synthetic step. This has allowed us to make a caged surfactant tailored to the binding and delivery of nucleotide-based macromolecules such as mRNA and pDNA. Taking advantage of positively charged side chains, the caged surfactant binds the negatively charged nucleic acid. Upon cell uptake of the caged surfactant-nucleic acid complex, acidification of the endosomal compartment induces release of the free surfactant. This release causes lysis of the endosomal membrane, and release of the nucleic acid into the cytosol. Using this strategy, we have shown delivery of both GFP-expressing mRNA, as well as siRNA to Hela cells. The caged surfactants are a new class of endosomal disrupting agents which can be tailored due to its flexible late-stage synthetic strategy. The caged surfactants therefore show great potential for enhancing the delivery of biomolecules such as plasmids, mRNA, siRNA and therapeutic proteins.

Caged surfactants: New class of pH dependent surfactants for the delivery of biotherapeutics

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.