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 identified a novel ginsenoside, 25-OCH3-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 efficiency of MDM2 targeting, anticancer efficacy, 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 efficacy, providing a basis for further development of GS25 as a novel agent for cancer therapy and prevention.
Highlights
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]
Over an 8 h period, 13.8%, 18.0%, and 27.9% of the total GS25 was released from the nanoparticles at pH 7.4, pH 6.8, and pH 1.2, respectively, confirming that the majority of GS25 was successfully encapsulated into polyethylene glycol (PEG)-Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (GS25NP) is stable under these conditions (Figure 1F)
An oral formulation of GS25 is developed by employing biodegradable PEG-PLGA copolymers, leading to the steady and sustained release of GS25
Summary
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]. GS25 sensitized prostate cancer cells to chemotherapy and radiation therapy [10]
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