pH-Independent charge-reversal strategy for enhanced tumor penetration based on hyaluronidase-responsive...

The charge-reversal strategy has been of great significance for enhancing the penetration of nanomedicines in tumors. However, conventional charge reversal has always been confined to pH variation. Herein, we proposed a pH-independent charge-reversal strategy based on hyaluronidase-responsive polycarbonate nanocarriers bearing quaternary ammonium groups. We developed multifunctional polycarbonate-based nanocarriers using tellurium/quaternary ammonium-containing carbonate copolymers. The encapsulation of cisplatin was achieved through coordination complexation with tellurium atoms. The positive charge was shielded from the circulation in vivo by the modification of hyaluronic acid and then exposed in HAase. In vitro cell experiments confirmed the selective killing effect of the drug carriers on pancreatic tumor cells and revealed a mitochondria-targeted pro-apoptotic mechanism. In vivo animal experiments verified the anti-tumor ability and significant tumor tissue penetration ability of the drug carriers. Therefore, the proposed pH-independent deep-tumor-penetration nanocarriers provide a potential nanoplatform for the stable clinical treatment of dense solid tumors.