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The purpose of this study was to prepare and characterize nanometer-sized prodrug (nanoprodrug) of camptothecin. The camptothecin prodrug was synthesized using tetraethylene glycol spacer linked via carbonate bond to camptothecin and via ester bond to alpha-lipoic acid. The nanoprodrug was prepared through the spontaneous emulsification mechanism using the mixture of camptothecin prodrug and alpha-tocopherol which served as a structural matrix. The nanoprodrug was activated readily by porcine liver esterase and, with a much slower rate, by hydrolytic degradation. Upon longterm storage, the alpha-lipoic acid moiety of the camptothecin prodrug gradually oxidized without loss of structural integrity and therapeutic efficacy. Interestingly, the hydrolytic activation was negligible before the oxidation, but was significantly accelerated after the oxidation of the alpha-lipoic acid moiety, suggesting an oxidative stimuli-responsive activation of the prodrug. The camptothecin nanoprodrug was found to possess significant inhibitory effect on the proliferation of U87-MG glioma cells with an IC(50) of 20 nM.

Several recent reports have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the growth of various malignant cells suggesting their application as anticancer agents. In this study, we prepared six nanometer-sized prodrugs (nanoprodrugs) of NSAIDs, ibuprofen, indomethacin, and naproxen through the spontaneous emulsification mechanism using monomeric and dimeric derivatives of the NSAIDs. We evaluated their effect on the proliferation of U87-MG glioma cells by cell counting, WST-1 cell proliferation reagent, and propidium iodide incorporation. The two ibuprofen nanoprodrugs inhibited the cell growth more potently than the indomethacin nanoprodrugs, whereas the naproxen nanoprodrugs did not show any significant effect. Remarkably, ibuprofen did not show any effect at an equimolar concentration. Approximately, 4.4% of the ibuprofen nanoprodrugs was found in the cell, whereas no ibuprofen could be detected suggesting that the superior effect of the nanoprodrugs can be attributed to the efficient cellular uptake of the nanoprodrugs.