title: Plasma distribution of tetraphenylporphyrin derivatives relevant for Photodynamic Therapy: importance and limits of hydrophobicity.
abstract: In the course of a Photodynamic Therapy (PDT) protocol, disaggregation of the sensitizer upon binding to plasma proteins and lipoproteins is one of the first steps following intravenous administration. This step governs its subsequent biodistribution and has even been evoked as possibly orientating mechanism of tumor destruction. It is currently admitted as being mainly dependent on sensitizer's hydrophobicity. In this context, as far as glycoconjugation of meso-tetraphenylporphyrin (TPP) macrocycle, a promising strategy to improve targeting of retinoblastoma cells confers to the sensitizer an amphiphilic character, we have studied the effect of this strategy on binding to plasma proteins and lipoproteins. With the exception of the majoritary protein binding (more than 80%) of more hydrophilic para-tetraglycoconjugated derivatives, high density lipoproteins (HDL) appear as main plasma carriers of the other amphiphilic glycoconjugated photosensitizers. This HDL-binding is a combined result of binding affinities (logKa ranging from 4.90 to 8.77 depending on the carrier and the TPP derivative considered) and relative plasma concentrations of the different carriers. Evaluation of binding affinities shows that if hydrophobicity can account for LDL- and HDL-affinities, it is not the case for albumin-affinity. Molecular docking simulations show that, if interactions are mainly of hydrophobic nature, polar interactions such as hydrogen bonds are also involved. This combination of interaction modalities should account for the absence of clear relationship between albumin-affinity and hydrophobicity. Taken together, our findings clarify the importance, but also the limits, of hydrophobicity's role in structure-plasma distribution relationship.
authors.affiliation: Faculté de Pharmacie, Univ. Paris-Sud, EA 4041, IFR 141, Châtenay-Malabry, France; Institut Curie, UMR 176 CNRS, Centre Universitaire, Univ. Paris-Sud, Orsay, France. Electronic address: benoit.chauvin@u-psud.fr.
authors.forename: Benoît
authors.initials: B
authors.lastname: Chauvin
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif-sur-Yvette, Gif-sur-Yvette, France. Electronic address: bogdan.iorga@icsn.cnrs-gif.fr.
authors.forename: Bogdan I
authors.initials: BI
authors.lastname: Iorga
authors.affiliation: Faculté de Pharmacie, Univ. Paris-Sud, EA 4041, IFR 141, Châtenay-Malabry, France. Electronic address: pierre.chaminade@u-psud.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Chaminade
authors.affiliation: Service de Biochimie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Laboratoire de Biochimie appliquée, EA 4529, Univ. Paris-Sud, Châtenay-Malabry, France. Electronic address: jean-louis.paul@u-psud.fr.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Paul
authors.affiliation: Institut Curie, UMR 176 CNRS, Centre Universitaire, Univ. Paris-Sud, Orsay, France. Electronic address: philippe.maillard@curie.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Maillard
authors.affiliation: Faculté de Pharmacie, Univ. Paris-Sud, EA 4041, IFR 141, Châtenay-Malabry, France. Electronic address: patrice.prognon@u-psud.fr.
authors.forename: Patrice
authors.initials: P
authors.lastname: Prognon
authors.affiliation: Faculté de Pharmacie, Univ. Paris-Sud, EA 4041, IFR 141, Châtenay-Malabry, France. Electronic address: athena.kasselouri@u-psud.fr.
authors.forename: Athena
authors.initials: A
authors.lastname: Kasselouri
mesh_terms: D001798:Blood Proteins / Q000378:metabolism*; D004337:Drug Carriers / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008074:Lipoproteins / Q000378:metabolism; D010778:Photochemotherapy / Q000379:methods; D017319:Photosensitizing Agents / Q000378:metabolism; D011166:Porphyrins / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D012175:Retinoblastoma; D012709:Serum Albumin / Q000378:metabolism; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D001798:Blood Proteins; D004337:Drug Carriers; D008074:Lipoproteins; D017319:Photosensitizing Agents; D011166:Porphyrins; D012709:Serum Albumin; C409084:tetraphenylporphyrin
keywords: Albumin; Hydrophobicity; Lipoprotein; Meso-tetraphenylporphyrin; Photodynamic Therapy; Plasma