Selenorhodamine Photosensitizers for Photodynamic Therapy of P-Glycoprotein-Expressing Cancer Cells

Abstract

We examined a series of selenorhodamines with amide and thioamide functionality at the 5-position of a 9-(2-thienyl) substituent on the selenorhodamine core for their potential as photosensitizers for photodynamic therapy (PDT) in P-glycoprotein (P-gp) expressing cells. These compounds were examined for their photophysical properties (absorption, fluorescence, and ability to generate singlet oxygen), for their uptake into Colo-26 cells in the absence or presence of verapamil, for their dark and phototoxicity toward Colo-26 cells, for their rates of transport in monolayers of multidrug-resistant, P-gp-overexpressing MDCKII-MDR1 cells, and for their colocalization with mitochondrial specific agents in Colo-26 cells. Thioamide derivatives 16b and 18b were more effective photosensitizers than amide derivatives 15b and 17b. Selenorhodamine thioamides 16b and 18b were useful in a combination therapy to treat Colo-26 cells in vitro: a synergistic therapeutic effect was observed when Colo-26 cells were exposed to PDT and treatment with the cancer drug doxorubicin.

Selenorhodamine photosensitizers with the Texas-red core for photodynamic therapy of cancer cells

“…12 The dark toxicity of selenorhodamines 5 and 6 was evaluated in cultures of Colo-26 cells incubated for 1 h with various concentrations of 5 or 6 (1 Â 10 À8 M to 2 Â 10 À5 M). The medium was removed and fresh medium was added, and cells were incubated for 48 h prior to determination of cell viability using the sulforhodamine B assay.…”

“…2, 3 We have shown that selenorhodamines 1-4 (Chart 1) also localize in the mitochondria of Colo-26 cells. 12 The cellular localization of selenorhodamines 5 and 6 in Colo-26 cells was examined using Image Stream flow cytometry as shown in Figure 4.…”

“…11 We have recently described the utility of selenorhodamines 1-4 (Chart 1) as the first rhodamine-derived photosensitizers with values of k max >600 nm. 12 The thioamide analogues 2 and 4 were especially effective toward P-gp expressing Colo-26 cells.…”

“…Values of k max for 5 and 6 are both 626 nm, which is longer than other rhodamine photosensitizers. 1,[8][9][10]12 Both 5 and 6 not only target mitochondria and interact with P-gp in Colo-26 cells, but they are also highly phototoxic to Colo-26 cells with values of EC 50 6 4 Â 10 À8 M using 1.0 J cm À2 of laser light at 630 ± 2 nm. Values of EC 50 for 5 and 6 are an order of magnitude lower than values of EC 50 previously observed with other rhodamine photosensitizers and 1.0 J cm À2 of laser light at k max ± 2 nm.…”

“…Values of EC 50 for 5 and 6 are an order of magnitude lower than values of EC 50 previously observed with other rhodamine photosensitizers and 1.0 J cm À2 of laser light at k max ± 2 nm. 12 …”