Editors' ChoiceCancer Nanotechnology

Getting Past the Bullies

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Science Translational Medicine  10 Aug 2011:
Vol. 3, Issue 95, pp. 95ec127
DOI: 10.1126/scitranslmed.3002965

Imagine two bullies stopping a child on his way to school, demanding that he hand over his lunch money. The schoolboy suddenly has two unpleasant choices: Either lose his money and go hungry, or withstand a painful beating. The anticancer drug docetaxel faces similar challenges. Intravenous administration, which is more painful and less convenient than taking the drug orally, requires a surfactant to improve solubility, but might also cause hypersensitivity. If the drug is given orally, however, two “bullies” of the intestinal barrier—the efflux transporter P-glycoprotein (P-gp) and the metabolizing enzyme CYP3A4—will drastically reduce the amount of docetaxel actually reaching the circulation. Just as the schoolboy will seek a new route to avoid the lunch-money bandits, Nassar et al. describe a novel nano-coating strategy that protects docetaxel from these two intestinal bullies, thus ensuring successful delivery.

Nassar and colleagues prepared poly(lactic-co-glycolic acid) nanocapsules containing docetaxel. These nanoparticles were then incorporated into entero-coated microparticles by means of spray-drying. When administered orally in rats, the microparticles’ enteric coating prevented early disintegration of the nanocapsules in the acidic stomach environment, protecting the drug. Fluorescence experiments demonstrated the passage of the nanocarriers across the intestinal wall into the lymphatic system, where docetaxel was released from the nanoparticles into the bloodstream. This nanoformulation significantly improved the pharmacokinetics of the drug: When a 10 mg/kg oral dose of a simple docetaxel solution was given to the rats, the maximum plasma concentration was only 19.5 ng/ml because both P-gp and CYP3A4 limited the amount of drug crossing the intestinal epithelium. Conversely, oral administration of the drug-loaded nanocapsules resulted in plasma concentrations greater than 2000 ng/ml. Further clinical translation of these nanocarriers may provide an important protective pathway for docetaxel and other drugs to avoid the intestinal bullies and reach their destinations intact.

T. Nassar et al., High plasma levels and effective lymphatic uptake of docetaxel in an orally available nanotransporter formulation. Cancer Res. 71, 3018–3028 (2011). [Abstract]

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