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Hypersensitizing Effect of Pluronic L61 on Cytotoxic Activity, Transport, and Subcellular Distribution of Doxorubicin in Multiple Drug-resistant Cells¹

Immunology Research Center [A. V., S. L., R. M., V. A.] and Supratek Pharma, Inc. [V. A.], Institute Armand-Frappier, University of Quebec, 531 Boulevard des Prairies, Building 18, Laval, Quebec H7N 4Z3, Canada, and Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198-6025 [A. K.]

The present study demonstrated that poly(oxypropylene) and poly(oxyethylene) block copolymer pluronic L61 (L61)-hypersensitized multidrugresistant CH^RC5 Chinese hamster ovary cells and MCF-7/ADR human breast carcinoma cells to the cytotoxic action of doxorubicin (Dox). CH^RC5 and MCF-7/ADR cells manifested 290- and 700-fold increases, respectively, in their sensitivity to Dox/L61 formulation compared with free Dox. Their sensitive counterparts Aux-B1 and MCF-7 displayed only marginal or no increase at all in their response to Dox/L61. The study of the drug transport performed by flow cytometry showed that L61 enhanced the drug uptake and reduced the P-glycoprotein-mediated drug efflux. Visualization of Dox subcellular distribution in CH^RC5 cells by fluorescent microscopy revealed that Dox was sequestered in cytoplasmic vesicles, whereas incubation of the cells with Dox/L61 altered the drug compartmentalization by releasing the drug from these vesicles and shifting it to the nucleus. These findings suggested that the hypersensitive response of multidrug-resistant cells to the action of Dox/L61 was caused by an increase in the drug accumulation and changes in its subcellular distribution.

¹ This work was supported by Industrial Research Assistance Program (IRAP) Grant 14113Q from the National Research Council of Canada.

² To whom requests for reprints should be addressed, at Supratek Pharma, Inc., c/o Institute Armand-Frappier, University of Quebec, 531 Boulevard des Prairies, Building 18, Immunology Research Center, Laval, Quebec H7N 4Z3, Canada; Phone: (514) 686-5502; Fax: (514) 686-5504; E-mail: Valery__Alakhov@IAF.UQUEBEC.CA (V. A.); or Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 600 South 42nd street, Omaha, NE 68198-6025; Phone: (402) 559-9364; Fax: (402) 559-5060; E-mail: Akabanov@UNMC.Edu. (A. K.)

Received 5/17/96. Accepted 7/ 3/96.

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