Oncotarget 21379 www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No. 25 Oral nano-delivery of anticancer ginsenoside 25-OCH 3 -PPD, a natural inhibitor of the MDM2 oncogene: Nanoparticle preparation, characterization, in vitro and in vivo anti-prostate cancer activity, and mechanisms of action Sukesh Voruganti 1,* , Jiang-Jiang Qin 1,* , Sushanta Sarkar 1 , Subhasree Nag 1 , Ismail A. Walbi 1 , Shu Wang 3 , Yuqing Zhao 4 , Wei Wang 1,2 , Ruiwen Zhang 1,2 1 Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA 2 Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA 3 Nutritional Science Program, Texas Tech University, Lubbock, TX 79409, USA 4 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China * These authors have contributed equally to this work Correspondence to: Ruiwen Zhang, e-mail: ruiwen.zhang@ttuhsc.edu Wei Wang, e-mail: wwei.wang@ttuhsc.edu Keywords: molecular targeting effciency, MDM2, ginsenoside, PEG-PLGA nanoparticles, oral delivery Received: March 16, 2015 Accepted: May 12, 2015 Published: May 24, 2015 ABSTRACT The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identifed a novel ginsenoside, 25-OCH 3 -PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the effciency of MDM2 targeting, anticancer effcacy, pharmacokinetics, and safety were evaluated in in vitro and in vivo models of human prostate cancer. Our results indicated that, compared with the unencapsulated GS25, GS25NP demonstrated better MDM2 inhibition, improved oral bioavailability and enhanced in vitro and in vivo activities. In conclusion, the validated nano-formulation for GS25 oral delivery improves its molecular targeting, oral bioavailability and anticancer effcacy, providing a basis for further development of GS25 as a novel agent for cancer therapy and prevention. INTRODUCTION The majority of current cancer chemotherapeutic agents are natural product derivatives, and natural products represent valuable sources of bioactive compounds, with many naturally-occurring compounds and their synthetic analogs being developed for cancer therapy and prevention in both preclinical and clinical settings [1–2]. One such natural product with a long history of chemopreventive usage is ginseng, which has been used for the treatment and prevention of many diseases, including cancer [3–4]. The anticancer properties of ginseng have largely been attributed to its saponin constituents, which are termed ginsenosides [4]. We have recently identifed a novel ginsenoside, 25-OCH 3 -PPD (GS25), from Panax notoginseng, which is thought to be the most potent anticancer ginsenoside discovered thus far [5–6]. GS25 has been shown to be active against several human cancers such as lung [7], pancreatic [8], breast [9], and prostate cancers [10–11]. In various cancer