tetraphenylporphine and Retinoblastoma

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.

Topics: Blood Proteins; Drug Carriers; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Lipoproteins; Photochemotherapy; Photosensitizing Agents; Porphyrins; Protein Binding; Retinoblastoma; Serum Albumin; Tissue Distribution

Porphyrins are photosensitizers usable in photodynamic therapy. Although these molecules are clinically effective, their low water solubility and their lack of specificity are major drawbacks to their development. Our study was aimed at analysing the interfacial behaviour of glycoconjugated tetraphenylporphyrins newly synthesized at the Curie Institute, and their interaction with model membranes bearing a specific lectin mimicking a mannose membrane receptor in retinoblastoma.. The interfacial behaviour of the porphyrins was analysed by surface pressure measurements, and their specific interaction with the lectin, by dynamic light scattering (liposomes) and the quartz crystal microbalance technique (supported bilayers).. All porphyrin derivatives were able to organize at the air/liquid interface. The dendrimeric compounds formed more stable monolayers than the others, and generally showed good mixing properties with the phospholipid used for liposome preparation. In the presence of concanavalin A, the porphyrin bearing-liposomes behaved differently depending on the nature (mannosylated or not) of the porphyrins.. The interfacial behaviour of the tetraphenylporphyrins is directly related to the orientation of the tetrapyrrolic macrocycle controlled by the grafted groups. Incorporated into a liposome bilayer, glycodendrimeric porphyrins expose their sugar moieties at the vesicle surface. The spacer length plays a crucial role by increasing sugars freedom and enhancing glycosylated liposomes interaction with the lectin.. Compared to the other studied compounds, the glycodendrimeric porphyrins seem very promising compounds and are now evaluated on cell cultures.

Topics: Biomimetics; Cell Line, Tumor; Cell Membrane; Concanavalin A; Dendrimers; Glycoconjugates; Humans; Lectins; Membranes, Artificial; Phospholipids; Photochemotherapy; Photosensitizing Agents; Porphyrins; Retinal Neoplasms; Retinoblastoma; Surface Properties