pH‐Responsive Polyacetal–Protein Conjugates Designed for Polymer Masked–Unmasked Protein Therapy (PUMPT)

: Polymer masked-unmasked protein therapy (PUMPT) employs polymer conjugation to protect therapeutic proteins during transit through the bloodstream and allow controlled release at a disease site via triggered degradation of the polymeric component. Most reported PUMPT systems are based on the specific enzymatic degradation of the polymeric component to release the protein and reinstate its activity. In these cases, therapeutic output is dependent on the presence of the required enzyme at the disease site at a sufficiently high concentration. The present study aims to overcome this design limitation by using pH as the protein release trigger. An acidic-pH triggered PUMPT system is described herein employing biodegradable polyacetals (PAs) and trypsin as a model protein. While this system protects trypsin activity at the neutral pH of the bloodstream, acidic pH (characteristic of disease sites, tissue damage, or lysosomal compartments) contributes to PA degradation and the "unmasking" of protein activity.