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

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.