Wedelolactone-Loaded Micelles Ameliorate Doxorubicin-Induced Oxidative Injury in Podocytes by Improving Permeability and Bioavailability

Liang Feng; Zhi-Yong Li; Long Wang; Xing-Hua Li; Ya-Ping Chen; Bing Yang; Dang Yang; Yuan-Pei Lian; Xue-Feng Hou; Jun-Hui Li; Shu-Min Ding; Xiao-Bin Jia

doi:10.3389/fbioe.2019.00333

Wedelolactone-Loaded Micelles Ameliorate Doxorubicin-Induced Oxidative Injury in Podocytes by Improving Permeability and Bioavailability

Front Bioeng Biotechnol. 2019 Nov 22:7:333. doi: 10.3389/fbioe.2019.00333. eCollection 2019.

Authors

Liang Feng¹, Zhi-Yong Li², Long Wang¹, Xing-Hua Li¹, Ya-Ping Chen¹, Bing Yang³, Dang Yang³, Yuan-Pei Lian¹, Xue-Feng Hou¹, Jun-Hui Li⁴, Shu-Min Ding⁵, Xiao-Bin Jia^{1

3}

Affiliations

¹ School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
² China Minority Traditional Medical Center, Minzu University of China, Beijing, China.
³ Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
⁴ Department of Nephrology, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China.
⁵ School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou, China.

Abstract

Wedelolactone (WED) is commonly used for the treatment of doxorubicin (DOX)-induced kidney damage, but its efficacy is limited by its poor solubility and bioavailability. In this study, we developed a novel delivery system of WED-loaded micelles (WED-M) with Solutol^® HS15 and lecithin at an optimized ratio of 7:3 to improve the poor permeability and bioavailability of WED and to enhance its efficacy. The spherically shaped WED-M (particle size: 160.5 ± 3.4 nm; zeta potential: -30.1 ± 0.9 mV; entrapment efficiency: 94.41 ± 1.64%; drug loading: 8.58 ± 0.25%; solubility: 1.89 ± 0.06 mg/ml) has continuous stability over 14 days and a sustained release profile. The permeability of WED-M in Caco-2 cells indicated a significant 1.61-fold higher Papp AP to BL ratio than WED alone. Additionally, pharmacokinetic evaluation of WED-M demonstrated that the bioavailability of WED was increased 2.78-fold. Both HE staining and transmission electron microscopy showed an obvious improvement of pathological damage in WED-M treatment. Moreover, WED-M significantly enhanced the ROS level in mice and MPC5 podocytes. We concluded that using this micelle delivery system for WED could improve its permeability and bioavailability to attenuate DOX-induced oxidative injury in podocytes. This study provided important information on the fact that the micelle delivery system, WED-M, showed a significant improvement of renal damage.

Keywords: micelles; nephrotoxicity; oxidative stress; podocytes; wedelolactone.