Molecular mechanism study of chemosensitization of doxorubicin-resistant human myelogenous leukemia cells induced by a composite polymer micelle.

Min Han, Yuan-Yuan Diao, Hong-Liang Jiang, Xiao-Ying Ying, Da-Wei Chen, Wen-Quan Liang, Jian-Qing Gao

Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.

International journal of pharmaceutics 2011 Nov 28

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The present study was aimed to overcome the multidrug resistance (MDR) of tumor cells which accounts for the failure of clinical chemotherapy. A novel doxorubicin (DOX)-loaded composite micelle consisting of polyethylene glycol (PEG)-polycaprolactone (PCL)/Pluronic P105 has been developed and was proved to inhibit the drug resistance of human myelogenous leukemia (K562/ADR) cells. The modulation mechanism that DOX-loaded the composite micelle inhibited MDR was for the first time investigated at cell levels. Results indicated that the cytotoxicity in K562/ADR cells treated by DOX-loaded PEG-PCL/P105 composite micelle was about 4 times higher than DOX solution at 12 μg/mL of DOX. Confocal images showed that the DOX-loaded composite micelles gradually entered into cytoplasm and nucleus, and stayed in intracellular much longer than DOX solution. All the micelles (PEG-PCL micelle, P105 micelle and PEG-PCL/P105 composite micelle) did not change Pgp expression on the surface of K562/ADR cells. However, further study revealed that micelle containing of P105 (P105 or PEG-PCL/P105 composite micelle) significantly decreased ATP level, and consequently restricted the activity of Pgp by down-regulation of mitochondrial membrane potential. On the other hand, the PEG-PCL micelle had no effect on both mitochondrial membrane potential and ATP level of the K562/ADR cells, but its access to K562/ADR cells through endocytic pathway avoided the recognition of Pgp. The PEG-PCL/P105 composite micelle was designed based on the combination of P105-mediated down regulation of mitochondrial membrane potential the malignant cells and PEG-PCL-mediated internalization effect. Therefore, the novel composite micelle is a promising drug delivery system for anticancer drug to overcome MDR. Copyright © 2011 Elsevier B.V. All rights reserved.

Citation

Min Han, Yuan-Yuan Diao, Hong-Liang Jiang, Xiao-Ying Ying, Da-Wei Chen, Wen-Quan Liang, Jian-Qing Gao. Molecular mechanism study of chemosensitization of doxorubicin-resistant human myelogenous leukemia cells induced by a composite polymer micelle. International journal of pharmaceutics. 2011 Nov 28;420(2):404-11