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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.

SUBMITTER: Chen X

PROVIDER: S-EPMC6180334 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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Efficient synthesis and photodynamic activity of porphyrin-saccharide conjugates: targeting and incapacitating cancer cells.

Chen Xin X Hui Li L Foster David A DA Drain Charles Michael CM

Biochemistry 20040801 34

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 ...[more]

PMID: 15323552

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Project description:Photodynamic therapy (PDT) is a potential non-invasive approach for application in oncological diseases, based on the activation of a photosensitizer (PS) by light at a specific wavelength in the presence of molecular oxygen to produce reactive oxygen species (ROS) that trigger the death tumor cells. In this context, porphyrins are interesting PS because they are robust, have high chemical, photo, thermal, and oxidative stability, and can generate singlet oxygen (1O2). However, porphyrins exhibit low solubility and a strong tendency to aggregate in a biological environment which limits their clinical application. To overcome these challenges, we developed hybrid nanostructures to immobilize 5,10,15,20-tetrakis[(4-carboxyphenyl) thio-2,3,5,6-tetrafluorophenyl] (P), a new third-generation PS. The biological effect of this system was evaluated against bladder cancer (BC) cells with or without light exposition. The nanostructure composed of lipid carriers coated by porphyrin-chitosan (P-HNP), presented a size of ca. 130 nm and low polydispersity (ca. 0.25). The presence of the porphyrin-chitosan (P-chitosan) on lipid nanoparticle surfaces increased the nanoparticle size, changed the zeta potential to positive, decreased the recrystallization index, and increased the thermal stability of nanoparticles. Furthermore, P-chitosan incorporation on nanoparticles increased the stability and enhanced the self-organization of the system and the formation of spherical structures, as observed by small-angle X-ray scattering (SAXS) analysis. Furthermore, the immobilization process maintained the P photoactivity and improved the photophysical properties of PS, minimizing its aggregation in the cell culture medium. In the photoinduction assays, the P-HNP displayed high phototoxicity with IC50 3.2-folds lower than free porphyrin. This higher cytotoxic effect can be correlated to the high cellular uptake of porphyrin immobilized, as observed by confocal images. Moreover, the coated nanoparticles showed mucoadhesive properties interesting to its application in vivo. Therefore, the physical and chemical properties of nanoparticles may be relevant to improve the porphyrin photodynamic activity in BC cells.

Dataset Information

Efficient synthesis and photodynamic activity of porphyrin-saccharide conjugates: targeting and incapacitating cancer cells.

Publications

Efficient synthesis and photodynamic activity of porphyrin-saccharide conjugates: targeting and incapacitating cancer cells.

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