Liposomal co-delivered oleanolic acid attenuates doxorubicin-induced multi-organ toxicity in hepatocellular carcinoma

// Muhammad Sarfraz 1, 2, * , Attia Afzal 1, 3, * , Shahid Masood Raza 1 , Sajid Bashir 2 , Asadullah Madni 4 , Muhammad Waseem Khan 1 , Xiang Ma 1 and Guangya Xiang 1 1 School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China 2 Department of Pharmacy, University of Sargodha, Sargodha, 40100, Punjab, Pakistan 3 Institute of Pharmacy, Lahore College for Women University, Lahore, 54610, Punjab, Pakistan 4 Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Bahawalpur, 63100, Punjab, Pakistan * These authors contributed equally to this work Correspondence to: Guangya Xiang, email: gyxiang1968@hotmail.com Xiang Ma, email: xiangma@hust.edu.cn Keywords: oleanolic acid, doxorubicin, cardiotoxicity, 20-HETE, HCC Received: January 17, 2017 Accepted: April 18, 2017 Published: May 02, 2017 ABSTRACT Doxorubicin in combination with other cytotoxic drugs has clinical advantages. However, doxorubicin-induced cardiotoxicity negatively impacts clinical utility and outcomes. Cardiotoxicity can result from increased oxidative stress or from a local cytochrome P450 mediated increase in 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE). Oleanolic acid (OA) is a natural pentacyclic triterpenoid with free radical scavenging, cardioprotective, and P450-mediated cyclooxygenase-upregulating properties. We investigated co-delivery of liposomal OA and doxorubicin in a HepG2 model of hepatocellular carcinoma (HCC). OA attenuated the cardiotoxicity induced by doxorubicin without compromising its anticancer activity. Apoptosis assays revealed that co-delivery of DOX and OA produced a synergistic anticancer effect. However, the drugs had antagonistic effects on cardiomyocytes. Female BALB/c nude mice treated with OA- and DOX-loaded liposomes (ODLs) exhibited reduced tumor growth, stable body weight, and stable organ indices. Reduced 20-HETE production suggested ODLs had limited cardiotoxicity. No changes in biochemical or histopathological markers were observed in mice treated with ODLs. Tailored co-delivery of OA and DOX may thus be an effective therapeutic strategy for treating HCC.