International Journal of Nanomedicine (Jan 2020)
Development of Drug Dual-Carriers Delivery System with Mitochondria-Targeted and pH/Heat Responsive Capacity for Synergistic Photothermal-Chemotherapy of Ovarian Cancer
Abstract
Xiaoxia Guo, 1,* Jie Mei, 1,* Chunping Zhang 2 1Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu 610041, Sichuan, People’s Republic of China; 2The Center of Clinical Laboratory, Sichuan Great Master Diagnostics Co. Ltd, Chengdu 611731, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunping ZhangThe Center of Clinical Laboratory, Sichuan Great Master Diagnostics Co. Ltd, No. 8, Anhe the Second Road, Hi-Tech Industrial Development Zone, Chengdu 611731, Sichuan, People’s Republic of ChinaTel +86-189 8008 6040Email [email protected]: Multifunctional drug delivery systems (DDS) are emerging as a new strategy to highly treat malignant tumors. The aim of this study is to develop a drug dual-carriers delivery system (DDDS) using the natural protein ferritin (FRT) and a nanoscale graphene oxide (NGO) as dual-carriers.Methods: The FRT is a pH-sensitive hollow cage protein with disassembly and reassembly properties and the NGO has a large surface area and a photothermal effect by which it can load and release drugs under near-infrared irradiation (NIR). Due to these unique features, the NGO loaded the anticancer drug resveratrol (RSV) and the conjugated mitochondrion targeted molecule IR780 as IR780-NGO-RSV (INR), the first drug delivery platform. Next, the INR was capsulated by FRT to form the DDDS INR@FRT which was applied for synergistic photothermal-chemotherapy of ovarian cancer.Results: Through a series of characterizations, INR@FRT showed a uniform nanosphere structure and remarkable stability in physiological condition. Heat/pH 5.0 was confirmed to trigger RSV release from the INR@FRT. After taken up by cells, INR@FRT located to the lysosomes where the acidic environment triggered INR release. INR targeted the mitochondrion and released RSV to directly react with organelles, which in turn decreased the mitochondrion membrane potential and caused cell apoptosis. In-vivo experiments showed that INR@FRT combined with NIR irradiation displayed remarkable tumor suppression with a high survival rate after 60 days of treatment. Finally, the biocompatibility of INR@FRT was demonstrated in vitro and in vivo.Conclusion: These results highlight the immense potential of INR@FRT as a type of DDDS for the treatment of tumors.Keywords: resveratrol, apoptosis, drug dual-carriers delivery system, mitochondrion targeting, pH/heat-triggered tumor therapy
