Interconnected hyaluronic acid derivative-based nanoparticles for anticancer drug delivery

• Hyaluronic acid-ceramide (HACE) was cross-linked with adipic acid dihydrazide (ADH).
• Interconnected HACE nanoparticles containing doxorubicin (DOX) were fabricated.
• Drug payload and release were improved in interconnected HACE nanoparticles.
• Cellular uptake of DOX from interconnected HACE nanoparticles was also enhanced.

Doxorubicin (DOX)-loaded nanoparticles (NPs) based on interconnected hyaluronic acid-ceramide (HACE) structure were fabricated and their anti-tumor efficacy was evaluated in vitro. Interconnected HACE was synthesized by cross-linking HACE with adipic acid dihydrazide (ADH) and its synthesis was identified by 1H NMR analysis. DOX-loaded NPs with <200 nm mean diameter, negative zeta potential, and spherical shape were prepared. Interconnected HACE-based NPs increased drug-loading capacity and in vitro drug release, compared to HACE-based NPs. DOX release was dependent on the environmental pH, implying the feasibility of enhancing drug release in tumor region and endosomal compartments. Synthesized interconnected HACE did not show cytotoxic effect up to 1000 μg/ml concentration in NIH3T3 and MDA-MB-231 cells. In cellular uptake studies using confocal laser scanning microscopy (CLSM) and flow cytometry in MDA-MB-231 cells, higher uptake of DOX was observed in the interconnected HACE-based NPs than HACE NPs. In vitro anti-tumor efficacy was assessed by MTS-based assay, in which cytotoxic effect of DOX-loaded interconnected HACE NPs was higher than that of DOX-loaded HACE NPs. Thus, these results suggest the feasibility of interconnected HACE-based NPs to be used for efficient tumor-targeted delivery of anticancer drugs.

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