Zwitterionic Strategy to Stabilize Self‐Immolative Polymer Nanoarchitecture under Physiological pH for Drug Delivery In Vitro and In Vivo

The major bottleneck in using polymer nanovectors for biomedical application, particularly those based on self-immolative poly(amino ester) (PAE), lies in their uncontrolled autodegradation at physiological pH before they can reach the intended target. Here, an elegant triblock-copolymer strategy is designed to stabilize the unstable PAE chains via zwitterionic interactions under physiological pH (pH 7.4) and precisely program their enzyme-responsive biodegradation specifically within the intracellular compartments, ensuring targeted delivery of the cargoes. To achieve this goal, biodegradable polycaprolactone (PCL) platform is chosen, and structure-engineered several di- and triblock architectures to arrive the precise macromolecular geometry. The hydrophobic-PCL core and hydrophilic anionic-PCL block at the periphery shield PAEs against autodegradation, thereby ensuring stability under physiological pH in PBS, FBS, cell culture medium and bloodstream. The clinical anticancer drug doxorubicin and deep-tissue penetrable near-infrared IR-780 biomarker is encapsulated to study their biological actions by in vitro live cancer cells and in vivo bioimaging in live animals. These zwitterions are biocompatible, nonhemolytic, and real-time in vitro live-cell confocal studies have confirmed their internalization and enzymatic biodegradation in the endo-lysosomal compartments to deliver the payload. In vivo bioimaging establishes their prolonged blood circulation for over 72 h, and the biodistribution analysis reveals the accumulation of nanoparticles predominantly in the excretory organs.