Redox Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive Cancer, both Primary and Metastatic Tumors

It remains a substantial challenge to targetedly deliver drug to both primary tumors and metastatic lesions employing a single nanoparticle delivery system. Here aiming at the receptor for hyaluronic acid mediated motility (RHAMM or CD168), a specific receptor for hyaluronic acid (HA), the bioreductive responsive HA nanogels loaded doxorubicin were prepared. The targeting effects of HA nanogels in high RHAMM-expressed cancer cells, primary and metastatic tumors were investigated. It was found that HA nanogels show a strong in vitro and in vivo RHAMM-mediated cellular uptake and drug delivery. The cellular uptake of HA nanogels in high RHAMM-expressed LNCaP and H22 cells was far more than the uptake in low RHAMM-expressed NIH3T3 cells. The IC(50) value of drug-loaded HA nanogels against H22 cells was lower than that of free drug. In vivo antitumor activity examinations showed that the HA nanogels not only had significantly superior antitumor efficacy in murine H22 and human LNCaP tumor-bearing mice but also exhibited much deep tumor penetration. The drug delivery of lymph node metastasis by systemically administering HA nanogels demonstrated that the HA nanogels could sufficiently increase drug concentration in metastatic lymph node by RHAMM-HA interaction and inhibit the growth of metastatic lymph node, even completely heal malignant lymph node metastasis. Thus, RHAMM-directed drug delivery is a promising therapy route for treating both primary and metastatic tumors.