Hyaluronic acid–nimesulide conjugates as anticancer drugs against CD44-overexpressing HT-29 colorectal cancer in vitro and in vivo

摘要: Carrier-mediated drug delivery systems are promising therapeutics for targeted and improved efficacy safety of potent cytotoxic drugs. Nimesulide is a multifactorial cyclooxygenase 2 nonsteroidal anti-inflammatory with analgesic, antipyretic anticancer properties; however, the low solubility nimesulide limits its applications. Drugs conjugated hyaluronic acid (HA) innovative carrier-mediated characterized by CD44-mediated endocytosis HA intracellular release. In this study, hydrophobic was to two different molecular weights (360 kDa as high weight [HAH] 43kDa [HAL]) improve tumor-targeting ability hydrophilicity. Our results showed that hydrogenated (N-[4-amino-2-phenoxyphenyl]methanesulfonamide) successfully both types carbodiimide coupling degree substitution 1%, which 1H nuclear magnetic resonance 400 MHz total correlation spectroscopy. Both Alexa Fluor® 647 labeled HAH HAL could selectively accumulate in CD44-overexpressing HT-29 colorectal tumor area vivo, observed vivo imaging system. vitro test, HA-nimesulide conjugate displayed >46% cell killing at concentration µM cells, whereas exiguous effects were on HCT-15 indicating causes death cells. Regarding antitumor HAL-nimesulide HAH-nimesulide caused rapid shrinkage within 3 days inhibited growth, reached 82.3% 76.4% day 24 through apoptotic mechanism xenografted mice, without noticeable morphologic differences liver or kidney, respectively. These indicated selectivity HA/CD44 receptor interactions has potential enhance therapeutic cancer treatment.