The influence of lipophilicity on binding of boronated DNA-intercalating compounds in human glioma spheroids

Five boronated DNA-intercalating compounds [5-ortho-carboranyl phenanthridi nium (5-o-CP), 5-para-carboranyl phenanthridinium (5-p-CP), 6-para-carboran yl phenanthridinium, water-soluble boronated phenanthridinium and water-sol uble boronated acridine (WSA1)], primarily developed for boron neutron capt ure therapy (BNCT), were analysed regarding their binding in cultured human malignant glioma spheroids. Comparisons were made with the corresponding D NA intercalators ethidium bromide and acridine orange. Octanol/phosphate bu ffered saline-water coefficients were determined for all compounds, and it was found that the most lipophilic (5-o-CP and 5-p-CP) were most toxic and accumulated high amounts of boron in monolayer cells. These compounds bound primarily in the outermost part of spheroids with poor penetration into th e inner region, even after 2 days of continuous exposure. On the other hand , the most hydrophilic compound (WSA1) showed lower toxicity and lower boro n accumulation in monolayer cells, and rapid binding in the inner region of spheroids. A reasonable explanation for this observation is that the lipop hilic compounds interact mainly with lipophilic parts of the cells, like ce llular membranes, and therefore rapidly binds to cells, preventing penetrat ion and binding to cells in the deeper region of the spheroids. The possibi lity of using these compounds for BNCT are discussed.