Structure-Photodynamic Effect Relationships of 24 Glycoconjugated Photosensitizers in HeLa Cells

Abstract

Photodynamic therapy (PDT) with a photosensitizing dye and light irradiation is used to treat cancer; the photosensitizer accumulated in malignant cells photochemically generates highly cytotoxic reactive oxygen species (ROS), such as singlet oxygen ( 1 O 2 ) and hydroxyl radical (OH · ). 1-6) These ROSs damage the microorganella, such as mitochondria, lysosomes, plasma membrane, Golgi apparatus and endoplasmic reticulum, leading to necrotic and/or apoptotic cell death. Because the efficacy of PDT treatment crucially depends on the photosensitizer used, development of an efficient photosensitizer is very important. Porphyrin derivatives, including reduced porphyrins such as chlorins and bacteriochlorins, are the most studied photosensitizing dyes in PDT applications owing to their large molar absorption coefficient in the longer wavelength region, sufficient photochemical stability, and inherent "enhanced permeability and retention (EPR) effect" in tumor tissue. However, the tetrapyrrolic macrocycle of porphyrin derivatives is quite hydrophobic, and so chemical modification is usually required for physiological application. Modification with saccharide is a wellknown approach for improving the water-solubility of a compound. Since the discovery of the glycoconjugated porphyrin derivatives by Fülling et al.,7) many glycoconjugates have been reported. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][27][28][29][30][31][32]34) Momenteau and Mailard et al. synthesized a number of O-glycosylated tetraphenylporphyrins (TPPs) and chlorins (TPCs) having various substituents (phenyl, alkyl and so on) and examined 1 O 2 generation, partition coefficients and photocytotoxicity in KB cells. 17) They reported that the photocytotoxicity varies with the sugar unit attached, and concluded that planar structure and amphiphilic character were the keys to a potent photocytotoxic effect on KB cells. Sol and Krausz et al. reported many O-glycosylated TPPs having unique structures, such as strapped porphyrin, 18) charged porphyrin, 19,20) peptide-conjugated porphyrin 21,22) and porphyrin dimer.23) The photocytotoxicity of these O-glycosylated TPP derivatives can usually be interpreted in terms of the hydrophilicity and the molecular asymmetry. Saccharide also plays an important role in cellular recognition. Aoyama et al. reported that hydrophobicity masking is important for saccharide-directed cell recognition of glycoconjugated porphyrin derivatives by rat hepatoma cells (RLC-16).24) Focusing on PDT application, Pandey et al. synthesized of benzochlorins bearing galactosamine, glucosamine and lactosamine, and examined their photocytotoxicity in radiation-induced fibrosarcoma (RIF). 25) They found that preincubation with lactose inhibited the photocytotoxicity of benzochlorins bearing galactosamine and lactosamine, suggesting an interaction with galectin-mediated photocytotoxicity. Zheng et al. prepared pyropheophorbide bearing 2-deoxyglucosamine and showed that these compounds are taken up via the glucose tr...

Improvement of Tumor Localization of Photosensitizers for Photodynamic Therapy and Its Application for Tumor Diagnosis

“…This approach was utilized in developing 2-[ 18 F]fluoro-2-deoxy-D-glucose for tumor diagnostics using positron emission tomography (PET) as cancer cells tend to show enhanced D-glucose uptake. Yano et al systematically synthesized forty 5, 10, 15, 20-tetraphenylporphyrin (TPP) and chlorine (TPC) derivatives having O-glycoside [34][35][36][37][38]. O-glycosylated TPPs and TPCs have numerous advantages, such as significant reduction of the dark cytotoxicity, improved water-solubility, greater cellular uptake, and sugar-dependent photocytotoxicity [34][35][36][37][38].…”

Chemical Synthesis and Medicinal Applications of Glycoporphyrins

“…No significant difference in Log P was observed, but chlorins 540a and 540c were only slightly more hydrophilic than 540b,d [271] . Similar methods were used by Hirohara et al to study a range of O-glycosylated tetraarylporphyrins and -chlorins, which showed several advantages including reduced dark cytotoxicity, improved water-solubility, better cellular uptake, and sugar-dependent photocytotoxicity [165,261,262,272,273] . The O-glycosylated chlorins had promising photocytotoxicity in HeLa cells but were difficult to purify.…”

“…cellular uptake and ROS) and structural diversity of the sugar unit [273] . The photocytotoxicity profiles poorly related to the amount of cellular uptake of the PSs.…”

“…Looking at the light-absorbing moiety the phototoxicity increased in the order of zinc porphyrin < porphyrin < chlorin. For example, taking EC 50 values 514a (0.7 μM) < 30 (4.0 μM) < 45 (5.0 μM) this showed the chlorin to be almost 6 times more phototoxic than the porphyrins [273] . On the other hand, no difference in the quantum yields of the porphyrin and chlorin derivatives were identified.…”

Current Developments in Using MESO-(TETRA) Substituted Porphyrins for PDT

“…78 The O-glycosylated chlorins had promising photocytotoxicity in HeLa cells but were difficult to purify. 79,80 Photosensitizers 80a, 82, 83, 85, 87 and 88 showed no significant photocytotoxicity at a concentration of 0.5 μM (24 h, 16 J.cm -2 ), while the deprotected photosensitizers 74, 75, 84 and 86 were photocytotoxic (Fig. 17).…”