Smart Chondroitin Sulfate Micelles for Effective Targeted Delivery of Doxorubicin Against Breast Cancer Metastasis

Abstract

Jingmou Yu,1,2 Xin Xie,2 Liangliang Wang,3 Wenbo Liu,4 Huifeng Xu,4 Xiangmei Lu,4 Xiaofan Li,4 Jin Ren,2,4 Weidong Li2,5 1Huzhou Key Laboratory of Medical and Environmental Applications Technologies, School of Life Sciences, Huzhou University, Huzhou, 313000, People’s Republic of China; 2Jiangxi Provincial Key Laboratory of System Biomedicine, Jiujiang University, Jiujiang, 332000, People’s Republic of China; 3Affiliated Hospital of Jiujiang University, Jiujiang, 332000, People’s Republic of China; 4School of Pharmacy and Life Sciences, Jiujiang University, Jiujiang, 332000, People’s Republic of China; 5Jiujiang NO.1 People’s Hospital & Water of Life Hospital, Jiujiang, 332000, People’s Republic of ChinaCorrespondence: Jin Ren; Weidong Li, Email [email protected]; [email protected]: Metastasis is a major challenge in breast cancer therapy. The successful chemotherapy of breast cancer largely depends on the ability to block the metastatic process. Herein, we designed a dual-targeting and stimuli-responsive drug delivery system for targeted drug delivery against breast cancer metastasis.Methods: AS1411 aptamer-modified chondroitin sulfate A-ss-deoxycholic acid (ACSSD) was synthesized, and the unmodified CSSD was used as the control. Chemotherapeutic drug doxorubicin (DOX)-containing ACSSD (D-ACSSD) micelles were prepared by a dialysis method. The ACSSD conjugate was confirmed by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), dynamic light scattering (DLS), and transmission electron microscopy (TEM). In vitro cellular uptake and cytotoxicity of D-ACSSD micelles were studied by confocal laser scanning microscopy (CLSM) and MTT assay in breast tumor cells. The inhibition capability of D-ACSSD micelles in cell migration and invasion was carried out in 4T1 cells. In vivo antitumor activity of DOX-containing micelles was investigated in metastatic 4T1-bearing Balb/c mice.Results: D-ACSSD and DOX-loaded CSSD (D-CSSD) micelles exhibited high drug encapsulation content and reduction-responsive characteristics. D-ACSSD micelles were spherical in shape. Compared with D-CSSD, D-ACSSD showed higher cellular uptake and more potent killing activity in 4T1 and MDA-MB-231 cells. Additionally, D-ACSSD exhibited stronger inhibitory effects on the invasion and migration of highly metastatic 4T1 cells than unmodified D-CSSD. Among the DOX-containing formulations, D-ACSSD micelles presented the most effective inhibition of tumor growth and lung metastasis in orthotopic 4T1-bearing mice in vivo. It also revealed that ACSSD micelles did not exhibit obvious systemic toxicity.Conclusion: The smart D-ACSSD micelles could be a promising delivery system for the therapy of metastatic breast cancer.Graphical Abstract: Keywords: metastasis, dual-targeting, breast cancer therapy, reduction-sensitive micelles, drug delivery

Keywords

• metastasis
• dual-targeting
• breast cancer therapy
• reduction-sensitive micelles
• drug delivery