Modulation of Doxorubicin Resistance in Multidrug-resistance Cells by Targeted Liposomes Combined with Hyperthermia

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Abstract
Conventional methods that are used to overcome multidrug resistance (MDR) often involve the coadministration of chemosensitizers and anticancer drugs. However, coadministration of many chemosensitizers with anticancer drugs, such as doxorubicin (Dox) has resulted in the exacerbation of anticancer drug toxicity. Here, we hypothesized that optimization of the anticancer drug delivery using a liposomal carrier, a suitable targeting moiety, and a physical factor such as hyperthermia offer a significant advantage in the treatment of MDR cancer cells. Since, receptors for the vitamin folic acid are frequently overexpressed on epithelial cancer cells, we used folate as our targeting moiety against two types of cell lines, the human cervical carcinoma derived KB-31 (KB31) and the resistance type KB-85 (KB85). Folate-targeted thermosensitive liposomes were prepared by incorporating 1 mol% of a folate-polyethyleneglycol-distearoylphosphatidylethanolamine (folate-PEG-DSPE) construct into a lipid bilayer composed of dipalmitoylphosphatidylcholine (DPPC), hydrogenated soy phosphatidylcholine (HSPC), cholesterol (Chol) and phosphatidylethanolamine derivatized at the amino position with polyethyleneglycol (PEG-PE) at a molar ratio of 100:50:30:6. Incorporation of folate-PEG-PE in the bilayer, did not affect the thermal sensitivity of the resultant liposome vesicles. Uptake of folate-PEG-liposomal Dox by KB31 cells was 15-fold higher than that of non-targeted liposomal Dox. However, in the case of MDR type KB85, the uptake of the folate PEG liposomal Dox was 2-fold higher than the non-targeted liposomal Dox. Cytotoxicity measurements showed that folated liposomes combined with hyperthermia were found to be over 3-fold more effective (IC(50)=0.16 microM) than the free drug (IC(50)=0.543 microM) for growth inhibition of KB31. For the MDR cell type KB85, the cytotoxicity of the targeted liposomes combined with hyperthermia were found to be 4.8 times (IC(50)=0.38 microM) more effective than the free drug (IC(50)=1.81 microM). Thus, liposome associated Dox may bypass the vesicular drug transport in MDR cells, resulting in the enhancement of the drug biological activity.

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