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Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved April 12, 2012 (received for review December 13, 2011)
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.
Footnotes
↵1S.K. and M.E.W. contributed equally to this work.
- ↵2To whom correspondence should be addressed. E-mail: zawang{at}med.unc.edu.
Author contributions: S.K., M.E.W., R.C.C., M.E.P., and A.Z.W. designed research; S.K., M.E.W., R.S., N.D.C., J.A.C., and E.C.W. performed research; C.L. contributed new reagents/analytic tools; S.K., M.E.W., R.S., N.D.C., J.A.C., C.L., R.C.C., and A.Z.W. analyzed data; and S.K., M.E.W., M.S., M.E.P., and A.Z.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1120508109/-/DCSupplemental.
Nanoparticle wortmannin as a radiosensitizer
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