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DYNAMIQUE D'INTERACTION DE TETRAPYRROLES AVEC DES MEMBRANES ET DES LIPOPROTEINES :
CONSEQUENCES SUR LA LOCALISATION CELLULAIRE

Abstract : Thanks to their preferential retention in proliferating tissues, some photosensitizers are therapeutically used such as in photodynamic therapy (PDT). In most cases, they are based on the porphyrin structure, but other compounds, of which far-red-light absorption properties are most compatibles with biological tissues irradiation, have been developed. In this work, the focus is given on two amphiphilic tetrapyrroles: deuteroporphyrin (DP) that bears two carboxylic groups on one side of the macrocycle and disulfonated aluminum-phthalocyanine (AlPcS2a) that bears two sulfonated groups on one side. Indeed, the selectivity of photosenzitizers for cells in proliferation, as well as their intracellular localization, depends on their structure, in particular on their hydrophobicity and the symmetry of distribution of their polar chains around the macrocycle. Two major processes are involved. On one hand, lipophilic or amphiphilic photosensitizers possess a high affinity for low-density lipoproteins (LDL). The increased cholesterol catabolism of proliferating tissues results in over-expression of LDL receptors. Hence, LDL could act as natural carriers of photosensitizers and insure their targeting to tumor cells. On the other hand, the relative acid pH of extracellular medium could play an important role by governing the physico-chemical properties of photosensitizers and consequently their ability to cross membranes. In fine, the photosensitizers behavior seems to involve both the physicochemical and biological properties of the microenvironment.
In order to elucidate the implied mechanisms, we studied the interactions of photosensitizers with LDL and with liposomes (SUV, used as membranes-models) with a special interest on dynamics of these processes. A particular attention has been paid to the effects of pH. The data obtained on these simple systems then allowed us to interpret the sub-cellular localization of the photosensitizers on a human line of fibroblasts, and to evaluate the influence of LDL on the intracellular distribution of the compounds. This last point is of major importance because the localization of such photosensitizers (in particular AlPcS2a) in endocytic vesicles and their subsequent ability to induce a release of the contents of these vesicles - including externally added macromolecules - into the cytosol is the basis for a recent method for macromolecule activation, named photochemical internalization (PCI).
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Contributor : Stéphanie Bonneau <>
Submitted on : Friday, November 30, 2007 - 4:02:15 PM
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  • HAL Id : tel-00193125, version 1

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Stéphanie Bonneau. DYNAMIQUE D'INTERACTION DE TETRAPYRROLES AVEC DES MEMBRANES ET DES LIPOPROTEINES :
CONSEQUENCES SUR LA LOCALISATION CELLULAIRE. Biophysique [physics.bio-ph]. Université Pierre et Marie Curie - Paris VI, 2003. Français. ⟨tel-00193125⟩

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