Comparison of the Effects of Potential Parenteral Vehicles for Poorly Water Soluble Anticancer Drugs (Organic Cosolvents and Cyclodextrin Solutions) on Cultured Endothelial Cells (HUV-EC)

□ The effect of dilution of parenteral vehicles (organic cosolvent and 0.1M cyclodextrin solutions) on cultured endothelial cells (HUV-EC) were compared in vitro. Cell morphology was observed by phase contrast light microscopy and cell viability by measuring 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction or intracellular lactate dehydrogenase (LDH) activity and total protein. Disruption of the HUV-EC monolayer was observed at dilutions of 1 in 20 for the melphalan and PEP cosolvents, 1 in 100 for an investigational drug cosolvent, and 1 in 10 for 0.1M dimethyl-β-cyclodextrin. In comparison, 0.1M SBE7M- and HP-β-cyclodextrin caused only minor disruption at a 1 in 5 dilution. MTT reduction, intracellular LDH, and total protein were decreased following exposure to 1 in 10 dilution of the melphalan cosolvent. For other test solutions, intracellular LDH activity and total protein were measured, and reductions were observed following exposure to 1 in 10, 20, and 50 dilutions of the investigational drug cosolvent and 1 in 5 dilution of DM-β-cyclodextrin (0.1M). At a dilution of 1 in 10, no delayed toxicity was observed for cosolvents or cyclodextrin solutions. Hence, 0.1M SBE7M- or HP-β-cyclodextrin formulations may be less damaging to the venous endothelium at the site of injection than organic cosolvent formulations.