Conjugation of paclitaxel to C-6 hexanediamine-modified hyaluronic acid for targeted drug delivery to enhance antitumor efficacy

Polymer-based paclitaxel (PTX) conjugates have demonstrated application potentials to improve the water solubility and enhance the efficiency of drug delivery. In this study, a novel HA-based drug conjugate, HA-6-PTX, was designed and successfully synthesized by chemically grafting PTX to the C-6 position of N-acetyl-d-glucosamine (GlcNAc) of hyaluronic acid (HA) using hexanediamine as the linker. Leaving the carboxylate of HA chain unaffected, the conjugate with drug loading as high as 21.8% showed an excellent water solubility of 168 mg/mL and exhibited increased drug release in the presence of hyaluronidase. Compared to free PTX, HA-6-PTX demonstrated increased cytotoxicity and enhanced apoptosis-inducing effect against HepG2 and A549 cells due to the increased cellular uptake of drug via HA-receptor mediated endocytosis. It was concluded that the HA-6-PTX conjugate could be potentially utilized for further exploration as targeted drug delivery to enhance antitumor efficacy.