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.
Medlicott
N J
NJ
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas 66047, USA. natalie.medlicott@stonebow.otago.ac.nz
Foster
K A
KA
Audus
K L
KL
Gupta
S
S
Stella
V J
VJ
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