Lipophilic derivatives of the anticancer drug paclitaxel (PTX) were prepared by means of its conjugation tolipoamino acid (LAA) residues, with the aim of increasing drug accumulation in tumor cells. PTX was linked to themethyl esters of norleucine (C6) or 2-aminodecanoic acid (C10). A succinic acid group was used as a spacer to link the2’-hydroxyl group of PTX and the LAA residue, respectively by means of an ester and an amide bond. The in vitro anticanceractivity of the prodrugs was tested on a human thyroid anaplastic cancer cell line (ARO). The intracellular uptakekinetics 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 lowerdoses (0.01-0.1 M) than PTX. Intracellular accumulation experiments indicated an improvement of drug concentrationinside these cells, related to the block of the cellular expulsion by means of multi drug resistance efflux complex and improvedphysicochemical 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 intracellularaccumulation data suggest that these compounds can be further tested as possible alternatives to PTX for thetreatment of resistant cancer cells.

Lipoamino acid prodrugs of paclitaxel: synthesis and cytotoxicity evaluation on human anaplastic thyroid carcinoma cells

PIGNATELLO, Rosario;PISTARA', Venerando;PUGLISI, Giovanni;
2009-01-01

Abstract

Lipophilic derivatives of the anticancer drug paclitaxel (PTX) were prepared by means of its conjugation tolipoamino acid (LAA) residues, with the aim of increasing drug accumulation in tumor cells. PTX was linked to themethyl esters of norleucine (C6) or 2-aminodecanoic acid (C10). A succinic acid group was used as a spacer to link the2’-hydroxyl group of PTX and the LAA residue, respectively by means of an ester and an amide bond. The in vitro anticanceractivity of the prodrugs was tested on a human thyroid anaplastic cancer cell line (ARO). The intracellular uptakekinetics 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 lowerdoses (0.01-0.1 M) than PTX. Intracellular accumulation experiments indicated an improvement of drug concentrationinside these cells, related to the block of the cellular expulsion by means of multi drug resistance efflux complex and improvedphysicochemical 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 intracellularaccumulation data suggest that these compounds can be further tested as possible alternatives to PTX for thetreatment of resistant cancer cells.
Lipoamino acids; paclitaxel; taxol; prodrugs; lipophilicity; ARO cells
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/5379
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