title: Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery.
abstract: One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3' kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.
authors.affiliation: Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Shrirang
authors.initials: S
authors.lastname: Karve
authors.forename: Michael E
authors.initials: ME
authors.lastname: Werner
authors.forename: Rohit
authors.initials: R
authors.lastname: Sukumar
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Cummings
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Copp
authors.forename: Edina C
authors.initials: EC
authors.lastname: Wang
authors.forename: Chenxi
authors.initials: C
authors.lastname: Li
authors.forename: Manish
authors.initials: M
authors.lastname: Sethi
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Chen
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pacold
authors.forename: Andrew Z
authors.initials: AZ
authors.lastname: Wang
mesh_terms: D000730:Androstadienes / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D059248:Chemoradiotherapy / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D019073:HT29 Cells; D006801:Humans; D007624:KB Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053758:Nanoparticles; D009369:Neoplasms / Q000628:therapy*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D000077191:Wortmannin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000730:Androstadienes; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin