“Shell-Core” Bilayer Nanoparticle as Chemotherapeutic Drug Co-Delivery Platforms Render Synchronized Microenvironment Respond and Enhanced Antitumor Effects

BACKGROUND: Synergistic chemotherapy has been proved as an effective antitumor means in clinical practice. However, most co-administration treatment often lacks simultaneous control over the release of different chemotherapeutic agents. MATERIALS AND METHODS: β-cyclodextrin modified hyaluronic acid was the “shell”, and the oxidized ferrocene-stearyl alcohol micelles served as the “core”, where doxorubicin (DOX) and curcumin (CUR) were loaded in shell and core of the bilayer nanoparticles (BNs), respectively. The pH- and glutathione (GSH)-responsive synchronized release behavior was evaluated in different mediums, and the in vitro and in vivo synergistic antitumor effect and CD44-mediated tumor targeting efficiency were further investigated. RESULTS: These BNs had a spherical structure with the particle size of 299 ± 15.17 nm, while the synchronized release behaviour of those two drugs was proved in the medium with the pH value of 5.5 and 20 mM GSH. The co-delivery of DOX and CUR reduced the IC(50) value by 21% compared to DOX alone, with a further 54% reduction after these BNs delivery measurements. In tumor-bearing mouse models, these drug-loaded BNs showed significant tumor targeting, enhanced antitumor activity and reduced systemic toxicity. CONCLUSION: The designed bilayer nanoparticle could be considered as potential chemotherapeutic co-delivery platform for efficient synchronized microenvironment respond and drug release. Furthermore, the simultaneous and synergistic drug release guaranteed the enhanced antitumor effects during the co-administration treatment.