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Reversal of Chemoresistance in Ovarian Cancer by Co‐Delivery of MDR Inhibitors and Paclitaxel Using a Targeted Liposomal Platform
Author(s) -
Sriraman Shravan Kumar,
Zhang Yilin,
Lengyel Ernst,
Torchilin Vladimir
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.785.7
Subject(s) - paclitaxel , liposome , ovarian cancer , cytotoxicity , cancer research , viability assay , drug delivery , chemistry , pharmacology , cell cycle , apoptosis , cancer cell , cancer , in vitro , medicine , biochemistry , organic chemistry
The over‐expression of P‐gp drug efflux pumps has led to the emergence of multidrug resistance in a variety of tumors. With this in mind, folate‐targeted liposomes co‐loaded with paclitaxel (PCT) and P‐gp inhibitor tariquidar (XR) were developed. Aim To allow for the effective reversal of chemo‐resistance in ovarian cancer cells using targeted liposomes co‐loaded with tariquidar and paclitaxel. Methods: Folic acid was conjugated to the distal end of the PEG chain and post‐inserted onto liposomes composed of ePC, cholesterol and DOTAP. Evaluation of drug resistance of ovarian cancer lines SKOV3, HeyA8 and Tynku was carried out by quantifying MDR1 and MRP1 receptor expression followed by a rhodamine123 exclusion assay. The cytotoxicity of the formulations was evaluated using the Promega viability assay. The cellular effects of the formulations were evaluated using the iCyte imaging cytometer, M4 phase holographic imager (PHI) and fluorescence microscopy.
Results As compared to MRP1 higher expression of MDR1 was seen in the ovarian cancer cells. In vitro cytotoxicity experiments demonstrated that the XR+PCT liposomes was able to effectively overcome resistance to PCT even at low PCT doses of 50 nM. Using live cell imaging, paclitaxel‐induced arrest of cell cycle progression and onset of apoptosis following was visible from 1.5 µM to 50 nM only with the co‐loaded liposomes. The cell cycle arrest was further visualized using time‐lapse PHI. The paclitaxel‐mediated microtubule dysfunction was then visualized by the presence of polymerized microtubules around the cell nucleus by fluorescence microscopy. Conclusions The co‐loaded liposomes were able to effectively reverse chemoresistance in a variety of drug‐resistant ovarian cancers.