Efficient Synthesis and Photodynamic Activity of Porphyrin-Saccharide Conjugates:  Targeting and Incapacitating Cancer Cells

Abstract

Since the role of saccharides in cell recognition, metabolism, and cell labeling is well-established, the conjugation of saccharides to drugs is an active area of research. Thus, one goal in the use of saccharide-drug conjugates is to impart a greater specificity toward a given cell type or other targets. Although widely used to treat some cancers and age related macular degeneration, the drugs used in photodynamic therapy (PDT) display poor chemical selectivity toward the intended targets, and uptake by cells most likely arises from passive, diffusional processes. Instead, the specific irradiation of the target tissues, and the formation of the toxic species in situ, are the primary factors that modulate the selectivity in the present mode of PDT. We report herein a two-step method to make nonhydrolyzable saccharide-porphyrin conjugates in high yields using a tetra(pentafluorophenyl)porphyrin and the thio derivative of the sugar. As a demonstration of their properties, the selective uptake (and/or binding) of these compounds to several cancer cell types was examined, followed by an investigation of their photodynamic properties. As expected, different malignant cell types take up one type of saccharide-porphyrin conjugate preferentially over others; for example, human breast cancer cells (MDA-MB-231) absorb a tetraglucose-porphyrin conjugate over the corresponding galactose derivative. Doseametric studies reveal that these saccharide-porphyrin conjugates exhibit varying PDT responses depending on drug concentration and irradiation energy. (1) Using 20 microM conjugate and greater irradiation energy induces cell death by necrosis. (2) When 10-20 microM conjugate and less irradiation energy are used, both necrosis and apoptosis are observed. (3) Using 10 microM and the least irradiation energy, a significant reduction in cell migration is observed, which indicates a reduction in aggressiveness of the cancer cells.

One- and two-photon activated phototoxicity of conjugated porphyrin dimers with high two-photon absorption cross sections

“…40 There are many methods for measuring cell survival after PDT in vitro. Cell death may be quantified by measuring 140 enzyme activity, 41 membrane permeability 42 or redox potentials. 43 We used a purpose-built array of 657 nm LEDs (full width at half maximum = 22 nm) for the one-photon PDT experiments, as shown in Fig.…”

Chemical Synthesis and Medicinal Applications of Glycoporphyrins

“…These compounds were also investigated for their in vitro photocytotoxicity in HeLa cells [178] . In a similar way, Drain and coworkers extended from previous work on the synthesis of thioglycosylated porphyrins (95 and 91) [247] to form their 1,3-dipolar cycloadducts, i.e. chlorins (542a,a'), isobacteriochlorins (545a,a') and bacteriochlorins (546a,a') via the same procedure [274] .…”

“…S-or C-glycoside type PSs were previously synthesized in relatively low yields [171,199,218,243] . However, significantly higher yields > 85 % were observed with both the acetyl protected or the free hydroxyl sugar present with such an approach [172,247] . These strategies can also be employed for cationic water soluble systems.…”

“…In comparison to 5,10,15,20-tetrakis(4-methoxyphenyl)porphyrin they exhibited enhanced cellular binding in human breast cancer cell lines (MDA-MB-231). The glucose derivative showed higher uptake and enhanced PDT activity and induced both apoptosis and necrosis [247] . The PDT activity was dependent upon the drug dosage, length of irradiation and the degree of uptake with the glucose derivative 85 displaying the best activity.…”

“…Thus, it can be used directly in glycosylation reactions without prior activation. For example, Drain et al synthesized nonhydrolyzable tetrasubstituted glycoporphyrins (e.g., 87, 95) in high yields from TPPF 20 in a nucleophilic substitution reaction with thio-glucose and thio-galactose derivatives to decrease the acid hydrolysis of the glycosyl bond using C-or S-glycoside linkages to reduce drug dosage requirements [172,247] . S-or C-glycoside type PSs were previously synthesized in relatively low yields [171,199,218,243] .…”