Effect of chemical linkers of curcumin conjugated hyaluronic acid on nanoparticle properties and in vitro performances in various cancer cells

Chemical linkers play an important role in determining the physicochemical properties, stability and cytotoxic activities of nanoparticles for cancer treatment. Herein, curcumin (CUR) and hyaluronic acid (HA) conjugate nanoparticles with two different chemical linkers were compared in terms of their physicochemical properties and cytotoxicity to various cancer cells. CUR (10–50 mol%) was grafted onto HA backbones using ester (non-pH-sensitive) and hydrazone (pH-sensitive) bonds. All CUR-HA conjugates were able to self-assemble in aqueous medium to form nanoparticles. The conjugates with the hydrazone bonds showed lower critical aggregation concentration (CAC) values than those with the ester bonds. Particle sizes decreased when the loading of CUR increased from 10 mol% to 30 mol% but increased from 30 mol% to 50 mol% CUR. The 30 mol% CUR-HA nanoparticles with the hydrazone bonds (30ChH) showed the smallest particle size, which was slightly smaller than those with the ester bonds (30CeH). The stability of 30ChH was better than that of 30CeH, as observed by the unchanged particle size and zeta potential over 14 days. The in vitro CUR release from 30ChH at pH 7.4 was lower than that of 30CeH, suggesting that 30ChH would remain stable in blood circulation. The in vitro cytotoxicity study demonstrated that both CUR-HA conjugates significantly induced higher cytotoxicity and inhibition of cell proliferation than CUR solution in all cell lines tested (A549, PANC-1, HCT116 and Caco-2). In summary, the chemical linkers of the CUR-HA conjugates affected the physicochemical properties of the nanoparticles. The CUR-HA conjugates with pH-sensitive linkers showed greater stability and prevented drug release at physiological pH but showed high CUR release in the acidic environment of cancer cells, which indicates the potential for cancer therapy.