Enhanced hepatic targeting, biodistribution and antifibrotic efficacy of tanshinone IIA loaded globin nanoparticles Zhengjie Meng a,b , Lingtong Meng a , Kaikai Wang a , Jing Li c , Xiaoli Cao a , Jinhui Wu a,⇑ , Yiqiao Hu a,⇑ a State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China b College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, PR China c School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, PR China article info Article history: Received 14 October 2014 Received in revised form 25 February 2015 Accepted 2 March 2015 Available online 10 March 2015 Keywords: Nanoparticles Antifibrotic Hepatic fibrosis Tanshinone IIA Globin abstract Tanshinone IIA (TA) has been recently used to treat liver diseases. However, the poor water solubility and fast metabolism obstruct TA in to be used for the treatment of liver diseases. To overcome this, TA was encapsulated into globin to form nanoparticles (TA-Gb-NPs) by our self-assembling method. We evalu- ated their biodistribution, pharmacokinetics, targeting ability to liver and antifibrotic effects. As a result, TA-Gb-NPs had a good hepatic targeting ability and achieved higher concentration and longer retention in liver than tanshinone IIA suspension (TA-S). Compared with TA-S, TA-Gb-NPs significantly improved serum biochemical parameters in thioacetamide (TAA) induced liver fibrosis mouse model. Furthermore, histological analysis of mouse liver slices revealed that TA-Gb-NPs could markedly reduce the fibrosis scores and attenuate the progression of the hepatic fibrosis. In conclusion, the TA-Gb-NPs may be a good candidate for the treatment of hepatic fibrosis. Ó 2015 Elsevier B.V. All rights reserved. 1. Introduction Tanshinone IIA (TA), a diterpene quinine derivative, is the major lipid-soluble compound in Salvia miltiorrhiza, which has been widely used for the treatment of various cardiovascular diseases for 30 years in China. TA has been verified to cause coronary vasodilatation, reduce myocardial infarct size (Li and Tang, 1991; Wu et al., 1993), cardiomyocyte apoptosis (Fu et al., 2007), and car- diac hypertrophy (Shang et al., 2012), as well as to inhibit platelet aggregation (Jiang et al., 1998). Recent researches indicate that TA has multiple pharmacological activities, such as anti-inflammatory (Yin et al., 2009), induction of apoptosis in hepatoma carcinoma cells and hepatic stellate cells (Chan et al., 2011; Kapoor, 2009; Li et al., 2008), reduction of kupffer cell sensitization (Xu et al., 2008), inhibition of fatty acid synthesis and stimulation its oxida- tion (Park et al., 2009). It is a potential component to treat liver dis- eases. However, the clinical use of TA is limited by its poor water solubility. To increase its water solubility, sodium tanshinone IIA sulfonate (STS) is created. After i.v. administration, STS quickly dis- tributes into many tissues, including liver, kidney, lung, heart, spleen, etc. Although STS obviously accumulates in liver after i.v. administration, there is no long-term accumulation of STS in vivo and its concentration in liver declines quickly in 30 min after drug administration (Bi et al., 2007). Such pharmacokinetic characteris- tics of STS results in limited therapeutic effects on liver diseases. Furthermore, STS aqueous solution is not stable enough since STS easily loses the sulfonic acid groups and transforms into TA again under prolonged exposure to light or vigorous shaking, which will cause pain and vasculitis at injection sites (Duan et al., 2012). Fortunately, nanotechnology provides a useful way to increase drug solubility. Tremendous progressions have been witnessed in drug delivery area due to the utilization of nanoparticles as ‘‘con- trolled release reservoirs’’ for the targeted drug delivery for fight- ing disease. However, the benefits of nanotechnology drug delivery system (DDS) are often moderated by concerning about the biodegradability, immunocompatibility, bioavailability, and biocompatibility of templates for nanoparticles, such as polymeric nanoparticles, block copolymeric nanoparticles and dendrimers. To overcome these shortages, proteins, such as albumin, Apo A-I, glia- din, ferritin, gelatin, viral capsid, and legumin (Kim et al., 2007; Kramer et al., 2004; Kratz, 2008; Maham et al., 2009) are used as carriers to deliver drugs. Hemoglobin (Hb), a globular protein (Mw = 64,500; 5.5 nm diameter), is the key oxygen binding protein in human red blood cells. It is composed of two pairs of a and b subunits (a 2 b 2 ). Each subunit is made of one protein chain (globin) and one heme group. Extracellular Hb senescence dissociates into two ab dimers, then http://dx.doi.org/10.1016/j.ejps.2015.03.002 0928-0987/Ó 2015 Elsevier B.V. All rights reserved. ⇑ Corresponding authors at: State Key Laboratory of Pharmaceutical Biotechnol- ogy, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, PR China. Tel.:/fax: +86 25 83596143. E-mail addresses: wuj@nju.edu.cn (J. Wu), huyiqiao@nju.edu.cn (Y. Hu). European Journal of Pharmaceutical Sciences 73 (2015) 35–43 Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps