Dual targeting curcumin loaded alendronate-hyaluronan- octadecanoic acid micelles for improving osteosarcoma therapy

Abstract

Yanhai Xi,*,1 Tingwang Jiang,*,2 Yinglan Yu,3 Jiangmin Yu,1 Mintao Xue,1 Ning Xu,1 Jiankun Wen,1 Weiheng Wang,1 Hailong He,1 Yan Shen,3 Daquan Chen,4 Xiaojian Ye,1 Thomas J Webster51Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 2Department of Immunology and Microbiology, Institution of Laboratory Medicine of Changshu, Changshu 215500, Jiangsu, People’s Republic of China; 3Department of Pharmaceutics, Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, China Pharmaceutical University, Nanjing, People’s Republic of China; 4Department of Pharmaceutics, School of Pharmacy, Yantai University, Yantai 264005, People’s Republic of China; 5Department of Chemical Engineering, Northeastern University, Boston, MA, USA*These authors contributed equally to this workIntroduction: Curcumin (CUR) is a general ingredient of traditional Chinese medicine, which has potential antitumor effects. However, its use clinically has been limited due to its low aqueous solubility and bioavailability. In order to improve the therapeutic effect of CUR on osteosarcoma (i.e., bone cancer), a multifunctional micelle was developed here by combining active bone accumulating ability with tumor CD44 targeting capacity.Methods: The CUR loaded micelles were self-assembled by using alendronate-hyaluronic acid-octadecanoic acid (ALN-HA-C18) as an amphiphilic material. The obtained micelles were characterized for size and drug loading. In addition, the in vitro release behavior of CUR was investigated under PBS (pH 5.7) medium containing 1% Tween 80 at 37℃. Furthermore, an hydroxyapatite (the major inorganic component of bone) affinity experiment was studied. In vitro antitumor activity was evaluated. Finally, the anti-tumor efficiency was studied.Results: The size and drug loading of the CUR loaded ALN-HA-C18 micelles were about 118 ± 3.6 nm and 6 ± 1.2%, respectively. CUR was released from the ALN-HA-C18 micelles in a sustained manner after 12 h. The hydroxyapatite affinity experiment indicated that CUR loaded ALN-HA-C18 micelles exhibited a high affinity to bone. CUR loaded ALN-HA-C18 micelles exhibited much higher cytotoxic activity against MG-63 cells compared to free CUR. Finally, CUR loaded ALN-HA-C18 micelles effectively delayed anti-tumor growth properties in osteosarcoma bearing mice as compared with free CUR.Conclusion: The present study suggested that ALN-HA-C18 is a novel promising micelle for osteosarcoma targeting and delivery of the hydrophobic anticancer drug CUR.Keywords: curcumin, alendronate, hyaluronic acid, osteosarcoma

Keywords

• Curcumin
• Alendronate
• Hyaluronic acid
• Osteosarcoma