Two-dimensional LDH nanodisks modified with hyaluronidase enable enhanced tumor penetration and augmented chemotherapy

The condensed tumor extracellular matrix (ECM) consisting of cross-linked hyaluronic acid (HA) is one of the key factors that result in the aberrant tumor microenvironment and severely impair drug delivery and tumor penetration. Herein, we report a simple design of a hyaluronidase (HAase)-modified layered double hydroxide (LDH) nanoplatform loaded with anticancer drug doxorubicin (DOX) for enhanced tumor penetration and augmented chemotherapy. In our approach, LDH nanodisks were synthesized via a co-precipitation method, modified with HAase by electrostatic attraction, and finally physically loaded with DOX. The formulated DOX/LDH-HAase complexes show a high DOX loading percentage of 34.2% with good colloidal stability, retain 86.1% of the enzyme activity, and release DOX in a pH-responsive manner having a faster release rate under slightly acidic tumor microenvironment than that under a physiological condition. With the catalytic activity of HAase to digest the HA nearby the cancer cells, the developed DOX/LDH-HAase complexes enable more significant uptake by cancer cells and penetration in 3-dimensional tumor spheroids than enzyme-free DOX/LDH complexes, thus displaying much better antitumor efficacy in vitro than the latter. The more significant tumor penetration and inhibition of the DOX/LDH-HAase complexes than that of the DOX/LDH complexes was further demonstrated by in vivo tumor imaging and therapeutic activity assessments. Our study suggests a unique nanomedicine platform combined with both anticancer drug and enzyme for improved tumor penetration and chemotherapy, which is promising for effective chemotherapy of different types of stroma-rich tumors.