Comparative study of dual delivery of gemcitabine and curcumin using CD44 targeting hyaluronic acid nanoparticles for cancer therapy

Abstract

Dual-delivery nanoparticles of gemcitabine (GEM) and curcumin (CUR) conjugated on hyaluronic acid (HA) were successfully developed for targeting to cancer cells. The polymer-drug conjugates (PDCs) were synthesized by grafting GEM onto CUR (hydrazone)-HA (ChH) conjugates using ester (non-pH-sensitive) and hydrazone (pH-sensitive) bonds to form two different chemical structures; random graft: GeChH and block graft: (GhC)hH, respectively. The GeChH and (GhC)hH nanoparticles were prepared by solvent diffusion evaporation. The (GhC)hH nanoparticles showed superior characteristics with smaller particle size (221 nm), narrower size distribution (PDI 0.01) and lower critical aggregation concentration (CAC 0.28 mg/mL), as compared to the GeChH nanoparticles. The release profile of GEM and CUR from both nanoparticles was specific and fast in the acidic microenvironment (pH 5.0–6.5) while retarded at physiological pH (pH 7.4), indicating pH-dependence. In particular, the GEM released from (GhC)hH nanoparticles at pH 7.4 was less than that from the GeChH nanoparticles, suggesting the suitability for anticancer drug delivery. In vitro cytotoxicity study revealed that the (GhC)hH nanoparticles had higher toxicity and synergistic effect in all cell lines (PANC-1, A549, HCT116 and Caco-2 cells) when compared to the GeChH nanoparticles and the GEM/CUR solution. The in vitro cellular uptake study supported that both nanoparticles could be internalized into the cells and deposited around the nuclei. Moreover, the %uptake of the (GhC)hHFITC nanoparticles was higher than that of the GeChHFITC nanoparticles in both A549 and HCT116 cells. After HA blockade treatment, the %uptake of the nanoparticles significantly decreased, indicating that HA targeting to CD44 receptors played an important role to enhance specificity to the cancer cells. In summary, the developed (GhC)hH nanoparticles could provide dual delivery of GEM and CUR which would be beneficial for cancer therapy.