Sugar and Heavy Atom Effects of Glycoconjugated Chlorin Palladium Complex on Photocytotoxicity

Abstract

Palladium(II) complexes of glycoconjugated porphyrin and pyrrolidine-fused chlorin were prepared to examine sugar and heavy atom effects on in vitro photocytotoxicity. Cellular uptake into HeLa cells was enhanced by introducing sugar units regardless of other features, such as the central ion (free base or palladium(II) ion) and the ring structure (porphyrin or chlorin). The palladium(II) complex of glycoconjugated pyrrolidine-fused chlorin (PdPC2) exerted an excellent degree of photocytotoxicity not only on HeLa cells, but also on metastatic B16-BL6 cells, weakly metastatic B16F1 cells, and metastatic 4T1 cells. However, free-base glycoconjugated pyrrolidine-fused chlorin (PC2) also exerted similar or much higher photocytotoxicity rather than PdPC2. Therefore, the palladium(II) ion did not improve the in vitro photocytotoxicity of PC2. The enhanced singlet oxygen generation of palladium(II) complexes (i.e., the heavy atom effect) was confirmed at least in O(2)-saturated D(2)O. In addition, the formation of hydrogen peroxide and hydroxyl radical were also detected in O(2)-saturated phosphate buffered saline. However, the reactive oxygen species (ROS) generation efficiency, which is the product of the (relative) quantum yield of each ROS and the light absorbing ability, did not fit the trends of photocytotoxicity seen for the photosensitizers. In our glycoconjugated photosensitizers tested, the best indicator of the photocytotoxicity was found to be the light absorbing ability (namely, the oscillator strength in the wavelength region applied in the photocytotoxicity test). These results indicated that photochemical characteristics of glycoconjugated photosensitizers were notably susceptible to the microenvironment. The biological characteristics, such as the sugar effect, were a much more reliable approach to improving the photocytotoxicity of photosensitizers.

Chemical Synthesis and Medicinal Applications of Glycoporphyrins

“…The photocytotoxicity of the glycoconjugated PSs were 40 times greater than 543 where the EC 50 values decreased in the order of 543 (5.0 μM) > 93 and 91 (0.15 μM) > 543a (0.1 μM) ≈ 542a (0.09 μM). The photocytotoxicity of the chlorin derivatives 543 and 542a was ~ 1.5 times greater than the corresponding porphyrin derivatives 93 and 91 [354] . Tests of 542a and 543a were also performed with B16-BL6 melanoma cells, weakly metastatic B16F1 cells and metastatic 4T1 breast cancer cells.…”

“…[324] Human colon adenocarcinoma cells T84 [ 351] mammary carcinoma 4T1 A4-glycochlorins 542a, 543a PDT: @ 0.05 -0.1 μM, 542a > 543a. [354] Mouse colon carcinoma CT26.CL25 Cyclodextrinporphyrins:…”

“…Following from this, a comprehensive cellular uptake study of compounds 543, 543a,a', 542a, 93 and 91 was carried out showing that the glyco-conjugates had four times the uptake of 543 and with no difference in cellular uptake between the porphyrin and the chlorin macrocycles in HeLa cells [177,354] . The photocytotoxicity of the glycoconjugated PSs were 40 times greater than 543 where the EC 50 values decreased in the order of 543 (5.0 μM) > 93 and 91 (0.15 μM) > 543a (0.1 μM) ≈ 542a (0.09 μM).…”

“…While often heavy atom effects are noted in solution of in vitro studies, there is no guarantee that it is maintained in a multicellular environment [307] . It is more efficient to attempt to improve the PS efficacy through the sugar unit [177,178,354] . Benzochlorins have been of interest in PDT for a significant time [355] .…”

Metal-based glycoconjugates and their potential in targeted anticancer chemotherapy

“…Interestingly, glucose functionalization proved effective to enhance cellular uptake (up to 4-fold higher than non-glycosylated analogues). Non-acetylated derivatives showed photocytotoxicity only, whereas acetylated ones and platinum(II) counterparts did not exert any antiproliferative activity either in the dark or upon irradiation [97,98]. Nevertheless, IC 50 values were only comparable to, or even slightly higher than, non-glycosylated metal-free and metal-containing photosensitizers, so further evaluations were discontinued.…”