Acid-Cleavable Poly(Oxazoline) Surfactants

The low pH of the cancer tumor microenvironment and the late endosome is a tantilizing target for stimuli-responsive nanotherapeutics due to the accessibilility of these particular chemical differences to nanomaterials. Acid-cleavable surfactants are well-established for the formulation of stimuli-responsive nanoparticles and much work has been done to tune the sensitivity of these motifs to match their intended application. Acid-labile hydrazone-linked surfactants, specifically display increased stability over the more common imine linkage to prevent premature release outside of the cell, but remain labile enough for effective payload release once endocytosed. Furthermore, their cationic byproducts are known to facilitate enhanced endosomal escape through membrane disruption. Herein, we report the synthesis of a hydrazone-linked poly(oxazoline)-based diblock copolymer surfactant. This surfactant cleaves in a pH-dependent manner both in solution, and at the perfluorocarbon-water interface. We then demonstrate the ability of nanoemulsion encapsulated payloads to partition into cell membrane mimics only after cleavage of the surfactant. In all, this work demonstrates a viable route to create POx-based nanomaterials with controlled release capabilities in biologically relevant conditions and is a promising platform for advancing the endosomal escape and cancer targeting of nanomaterials.