Editors' ChoiceNanomedicine

Abandonment Complexes

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Science Translational Medicine  23 May 2012:
Vol. 4, Issue 135, pp. 135ec89
DOI: 10.1126/scitranslmed.3004311

The highway of anticancer drug development is littered with abandoned compounds—drugs that exhibited initial promise but that have failed to be developed clinically because of pharmacological problems including toxicity, poor solubility, or poor delivery. Once molecules achieve such a status, they tend not to be revisited.

Karve and co-workers now describe the development of a nanoparticulate formulation to rescue a drug nearing abandonment (wortmannin). This drug, a kinase inhibitor, is a radiosensitizer—a compound that delays the recovery of cancer cells after radiation treatment by inhibiting DNA repair enzymes such as DNA-dependent protein kinase. However, issues including the drug’s poor solubility, chemical instability, and toxicity have prevented its clinical translation. By formulating wortmannin into nanoparticles consisting of a biodegradable polymeric core and a PEGylated lipid shell (the polyethylene glycol—PEG—prevents adsorption of serum proteins), the researchers illustrated that they can raise the maximum tolerated dose of the drug in mice between three- and fivefold. Furthermore, the toxicity of the drug toward blood cells and the liver diminished significantly. Karve et al. also show that wortmannin continues to have a similar mechanism of action in nanoparticulate form as compared with free wortmannin delivered in cremaphor, a commonly used carrier for poorly soluble drugs. Nanoparticulate wortmannin was also a more efficacious radiosensitizer of tumor xenografts in mice than the version delivered in cremaphor.

Most current research into nanoformulated anticancer drugs is focused on improving existing drugs or developing newly discovered ones, not rescuing those that have been abandoned for pharmacological reasons. Collectively, the work by Karve and co-workers indicates that wortmannin—and indeed, many formerly abandoned anticancer drugs—may represent an untapped resource that is ripe for revisiting and perhaps rescuing with nanoparticle formulations.

S. Karve et al., Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery. Proc. Natl. Acad. Sci. U.S.A., 30 April 2012 (10.1073/pnas.1120508109). [Abstract]

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