Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery

Shrirang Karve, Michael E. Werner, Rohit Sukumar, Natalie D. Cummings, Jonathan A. Copp, Edina C. Wang, Chenxi Li, Manish Sethi, Ronald C. Chen, Michael E. Pacold, Andrew Z. Wang

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8230-8235
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number21
DOIs
StatePublished - May 22 2012
Externally publishedYes

Keywords

  • Nanoparticle radiosensitizer
  • Nanotechnology

ASJC Scopus subject areas

  • General

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