title: Oral nano-delivery of anticancer ginsenoside 25-OCH3-PPD, a natural inhibitor of the MDM2 oncogene: Nanoparticle preparation, characterization, in vitro and in vivo anti-prostate cancer activity, and mechanisms of action.
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.
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Sukesh
authors.initials: S
authors.lastname: Voruganti
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Jiang-Jiang
authors.initials: JJ
authors.lastname: Qin
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Sushanta
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Subhasree
authors.initials: S
authors.lastname: Nag
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Ismail A
authors.initials: IA
authors.lastname: Walbi
authors.affiliation: Nutritional Science Program, Texas Tech University, Lubbock, TX 79409, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.|Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.|Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004337:Drug Carriers; D016503:Drug Delivery Systems; D036145:Ginsenosides / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C000628801:25-methoxylprotopanaxadiol; D000970:Antineoplastic Agents; D004337:Drug Carriers; D036145:Ginsenosides; D011091:Polyesters; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D011092:Polyethylene Glycols; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; PEG-PLGA nanoparticles; ginsenoside; molecular targeting efficiency; oral delivery