A moderate interaction of maltosyl-alpha-cyclodextrin with Caco-2 cells in comparison with the parent cyclodextrin.
The cytotoxicity of maltosyl-alpha-cyclodextrin (G2-alpha-CyD) and maltosyl-beta-cyclodextrin (G2-beta-CyD) toward Caco-2 cells was compared with that of natural alpha-cyclodextrin (alpha-CyD), beta-cyclodextrin (beta-CyD) and gamma-cyclodextrin (gamma-CyD). The degree of increase in cytotoxicity was dependent on the CyD's type and the concentration: the cytotoxicity of CyDs at the same concentration increased in the order of gamma-CyD<G2-beta-CyD<G2-alpha-CyD<<alpha-CyD, although beta-CyD could not be compared to other CyDs because of low solubility in water. Alpha-CyD decreased transepithelial electrical resistance (TEER) and increased the apical-to-basolateral (AP-to-BL) transport of [3H]mannitol, a paracellular transport marker, in a concentration-dependent manner, suggesting that alpha-CyD decreased the integrity of Caco-2 cell monolayers. In addition, alpha-CyD increased the AP-to-BL transport of rhodamine 123, a transcellular transport marker, under the experimental conditions being independent of P-glycoprotein. In contrast, G2-alpha-CyD, G2-betaCyD and gamma-CyD had slight effect on both TEER and the transport of mannitol and rhodamine 123 even at relatively high concentrations up to 150 mM. The inability of G2-alpha-CyD and G2-beta-CyD to effect TEER and the transport of mannitol and rhodamine 123 could be explained by the findings that these maltosylated CyDs released only a small amount of membrane constituents from Caco-2 cell monolayers and interacted only weakly with monolayers composed of L-alpha-dipalmitoylphosphatidylcholine (DPPC) formed on water. These results indicate that G2-alpha-CyD has less cytotoxicity and less disturbing ability toward Caco-2 cell monolayers than alpha-CyD, and G2-beta-CyD has, at least, comparable cytotoxicity to beta-CyD toward them. Thus, from the safety point of view, highly water-soluble G2-alpha-CyD and G2-beta-CyD may be particularly useful in various pharmaceutical formulations.
Ono
N
N
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Arima
H
H
Hirayama
F
F
Uekama
K
K
D015060:1,2-Dipalmitoylphosphatidylcholine; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003505:Cyclodextrins / Q000494:pharmacology*; D004553:Electric Conductivity; D004594:Electrophysiology; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008320:Maltose / Q000031:analogs & derivatives; D008567:Membranes, Artificial; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D013500:Surface Tension
D003505:Cyclodextrins; D008055:Lipids; D008567:Membranes, Artificial; D009363:Neoplasm Proteins; C433303:maltosyl-cyclodextrin; D015060:1,2-Dipalmitoylphosphatidylcholine; D008320:Maltose