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

Abstract

Jia Zeng,1 Peng Sun,1 Xinning Fang,1 Yicheng Jiang,1 Zhenghong Wu,1 Xiaole Qi1,2 1Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Industrial Technology Innovation Platform, Zhejiang Center for Safety Study of Drug Substances, Hangzhou, People’s Republic of ChinaCorrespondence: Zhenghong Wu; Xiaole Qi, Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University, No. 639 Longmian Road, Jiangning District, Nanjing City, Jiangsu Province, 210009, People’s Republic of China, Tel [phone], Email [email protected]; [email protected]: 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 IC50 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.Graphical Abstract: Keywords: tumor microenvironment, combination chemotherapy, pH- and GSH-responsive, tumor targeting

Keywords

• tumor microenvironment
• combination chemotherapy
• ph- and gsh-responsive
• tumor targeting