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Liposome-encapsulated Doxorubicin Targeted to CD44

A Strategy to Kill CD44-overexpressing Tumor Cells¹

Department of Biopharmaceutical Sciences and Pharmaceutical Chemistry, School of Pharmacy, University of California-San Francisco, San Francisco, California 94143-0446

Certain tumors, including many that are found in the lung, overexpress the CD44 cell-surface marker. CD44 is a receptor that binds to hyaluronan (HA), a carbohydrate consisting of ß1,3 N-acetyl glucosaminyl-ß1,4 glucuronide. We hypothesized that the incorporation of phosphatidylethanolamine lipid derivatives-containing HA oligosaccharides (HA-PE) into liposomes could target drug-containing liposomes to tumor cells that express CD44. HA-PE containing palmitoyl oleoyl phosphatidylethanolamine or dipalmitoyl phosphatidylethanolamine (HA_n-PE) were incorporated into the lipid bilayer at various mole percentages of the total lipids; and the physicochemical properties (diameter, surface charge, and stability) of the resulting liposome preparations were characterized. HA-targeted liposomes (HALs) avidly bound to the CD44-high-expressing B16F10 murine melanoma cell line but not to the CV-1 African green monkey kidney cells, which express CD44 at low levels. Binding of the HALs to the B16F10 cells was rapid, concentration dependent, and saturated at a lipid concentration of about 250 µM. HAL binding to B16F10 was inhibited by HA with high M_r and by an anti-CD44 monoclonal antibody. Binding to the B16 melanoma cells occurred at a lipid composition that contained a 0.1 mol % of the HA_n-PE lipid. The bound liposomes were internalized by a temperature-dependent process. The IC₅₀s of doxorubicin (DOX) encapsulated in either HALs or nontargeted liposomes and of nonencapsulated DOX were compared in two protocols: continuous exposure of the cells to treatment for 24 h and transient exposure in which the treatment was applied for a 3-h period, and in which non-cell-associated drug was replaced with drug-free medium for the duration of the experiment. The IC₅₀s of free DOX, DOX-loaded nontargeted liposomes, and DOX-loaded HAL (HAL-DOX) for the transient exposure were 6.4 µM, >172 µM, and 0.78 µM, respectively. For the continuous exposure protocol, the IC₅₀s were 0.60 µM, 25.0 µM, and 0.14 µM, respectively. Thus, in both protocols, HAL-delivered DOX was significantly more potent than the nonencapsulated DOX in cells expressing high levels of CD44, which suggests that HALs may be a useful targeted drug carrier to treat CD44-expressing tumors.

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