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A Versatile Prodrug Approach for Liposomal Core-Loading of Water-Insoluble Camptothecin Anticancer Drugs
Authors
Arun B.
Denny W. A.
+10 more
For
Kawato Y.
Maurer-Spurej E.
Ratain M. J.
Reviews
Sadzuka Y.
Tardi P.
Vishnuvajjala B. R.
Wadkins R. M.
Wall M. E.
Publication date
3 July 2002
Publisher
'American Chemical Society (ACS)'
Doi
Cite
Abstract
We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble camptothecins. The procedure involves conversion of an active camptothecin analogue to a 20-OR ω-aminoalkanoanic ester prodrug in which R = CO[CH2]nNH2 and n = 1-3. The basic amino group of the prodrug serves three roles. First, at pH ranges of 3-5, the amine enhances aqueous solubility. Second, it enhances responsiveness to a transmembrane ammonium sulfate gradient across the liposomal bilayer, thereby facilitating active loading of the agent into the liposomal aqueous core. Third, at a physiological pH of 7 or above (the pH to be encountered following drug release at the tumor site), the nucleophilicity of the amine manifests itself and cyclization to the C-21 carbonyl carbon occurs. This cyclization triggers a rapid and convenient nonenzymatic decomposition process that releases active camptothecin. Accordingly, this novel liposomal approach offers a potential system for tumor-targeting prodrugs of many water-insoluble camptothecins, including the highly lipophilic and clinically attractive analogues SN-38, 9-nitrocamptothecin and DB-67. The rate of formation of the active agent at the tumor site can be controlled through the selection of n (the length of the alkyl spacer group). Copyright © 2002 American Chemical Society
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