Autodegradable Polyzwitterionic Nanoplatform to Target and Suppress Solid Tumor in Mice Xenografts

Abstract Structural engineering of auto‐degradable stealth polymer nanoarchitectures to target and suppress hard‐solid tumor tissues is an unexplored territory and a challenging task in cancer research. Here, the development of a non‐toxic, non‐hemolytic, and antifouling 3D star‐shaped auto‐degradable zwitterionic nano‐delivery system is reported to achieve maximum therapeutic efficacy in pancreatic tumor‐bearing mice xenografts. Nano‐compartmentalized star‐zwitterionic system is built by layer‐by‐layer block copolymer strategy by carefully choosing lysosomal enzyme‐biodegradable neutral hydrophobic polycaprolactone (PCL), anionic carboxylic PCL (CPCL), and cationic self‐immolative poly(amino‐ester, PAE). In vitro live‐cell studies established the synergistic on‐demand auto‐degradation of the star‐zwitterion in endo‐lysosomal compartments and release of the loaded cargoes at the intracellular level. Deep‐tissue penetrable NIR biomarker‐assisted in vivo live‐animal bioimaging in tumor‐bearing mice confirmed the stability and prolonged blood circulation of star‐zwitterion for more than 72 h and its ability to penetrate and be retained via passive targeting in the tumor site. The star‐zwitterion is self‐assembled into ≈25 nm tiny nanoparticle, exhibited electroneutrality under physiological pH, high drug loading content for clinical drug doxorubicin (DOX), alongside excellent nano‐formulation serum stability. Efficacy studies validated that the DOX delivery from the star‐zwitterionic platform is remarkable in suppressing pancreatic tumor volume in mice xenografts, suggesting their long‐term usefulness in cancer treatment.