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Lipoamino Acid Prodrugs of Paclitaxel: Synthesis and Cytotoxicity Evaluation on Human Anaplastic Thyroid Carcinoma Cells

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Lipophilic derivatives of the anticancer drug paclitaxel (PTX) were prepared by means of its conjugation to lipoamino acid (LAA) residues, with the aim of increasing drug accumulation in tumor cells. PTX was linked to the methyl esters of norleucine (C6) or 2-aminodecanoic acid (C10). A succinic acid group was used as a spacer to link the 2'-hydroxyl group of PTX and the LAA residue, respectively by means of an ester and an amide bond. The in vitro anticancer activity of the prodrugs was tested on a human thyroid anaplastic cancer cell line (ARO). The intracellular uptake kinetics of free PTX and its prodrugs was assessed by HPLC.

PTX-LAA prodrugs showed a noticeable cytotoxic activity against ARO cells at shorter incubation time (12 h) and lower doses (0.01-0.1 μM) than PTX. Intracellular accumulation experiments indicated an improvement of drug concentration inside these cells, related to the block of the cellular expulsion by means of multi drug resistance efflux complex and improved physicochemical features that allowed the greater passive cellular membrane permeation.

The enhanced activity of PTX-LAA prodrugs, in terms of potency and onset of the effect, as well as the interesting intracellular accumulation data suggest that these compounds can be further tested as possible alternatives to PTX for the treatment of resistant cancer cells.

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Keywords: ARO cells; Lipoamino acids; cell accumulation; lipophilicity; paclitaxel; prodrugs; taxol

Document Type: Research Article

Publication date: March 1, 2009

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    As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.
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