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Hydrophobic uncharged drugs such as docetaxel are difficult to encapsulate and retain in liposomal nanoparticles (LNP). In this work we show that a weak base derivative of docetaxel can be actively loaded into LNP using pH gradient loading techniques to achieve stable drug encapsulation and controlled release properties. Docetaxel was derivatized at the hydroxyl group in the C-2' position to form an N-methyl-piperazinyl butanoic acid ester. The free hydroxyl group in this position is essential for anticancer activity and the prodrug has, therefore, to be converted into the parent drug (docetaxel) to restore activity. Cytotoxicity testing against a panel of cancer cell lines (breast, prostate and ovarian cancer) demonstrated that the prodrug is readily converted into active drug; the derivative was found to be as active as the parent drug in vitro. The docetaxel derivative can be efficiently loaded at high drug-to-lipid ratios (up to 0.4 mg/mg) into LNP using pH loading techniques. Pharmacokinetic, tolerability and efficacy studies in mice demonstrate that the LNP-encapsulated prodrug has the long drug circulation half-life required for efficient tumor accumulation (50-100 times higher drug plasma levels compared with free derivative and Taxotere, the commercial docetaxel formulation), is active in a xenograft model of breast cancer (MDA-MB-435/LCC6), and is well tolerated at i.v. doses of 3 times higher than the maximum tolerated dose (MTD) of the parent drug. This is the first demonstration that a therapeutically active, remote-loaded, controlled-release LNP formulation of a taxane can be achieved. The approach reported here has broad applicability to other approved drugs as well as new chemical entities. more...