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 0.1 M 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 0.1 M dimethyl-beta-cyclodextrin. In comparison, 0.1 M SBE7M- and HP-beta-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-beta-cyclodextrin (0.1 M). At a dilution of 1 in 10, no delayed toxicity was observed for cosolvents or cyclodextrin solutions. Hence, 0.1 M SBE7M- or HP-beta-cyclodextrin formulations may be less damaging to the venous endothelium at the site of injection than organic cosolvent formulations.
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas 66047, USA. natalie.medlicott@stonebow.otago.ac.nz
N J
NJ
Medlicott
K A
KA
Foster
K L
KL
Audus
S
S
Gupta
V J
VJ
Stella
D000970:Antineoplastic Agents; D002478:Cells, Cultured; D002951:Citrates / Q000494:pharmacology*; D003505:Cyclodextrins / Q000494:pharmacology*; D004337:Drug Carriers / Q000494:pharmacology*; D004727:Endothelium / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology; D006801:Humans; D019946:Propylene Glycol / Q000494:pharmacology; D012997:Solvents / Q000494:pharmacology*; D014470:Umbilical Cord / Q000187:drug effects; D047392:beta-Cyclodextrins
D000970:Antineoplastic Agents; D002951:Citrates; D003505:Cyclodextrins; D004337:Drug Carriers; D012997:Solvents; D047392:beta-Cyclodextrins; D000431:Ethanol; D019946:Propylene Glycol; C031215:betadex