Mannose distribution in glycoconjugated tetraphenylporphyrins governs their uptake mechanism and phototoxicity

Abstract

Tetraphenylporphyrins (TPPs) have been proposed for the treatment of retinoblastoma by photodynamic therapy. Glycoconjugated compounds were synthesized for improving TPP solubility and amphipathy, and to specifically target mannose receptors overexpressed at the surface of cells. The efficiency of four TPP derivatives with different chemical structures was compared by phototoxicity tests and flow cytometry experiments. Interestingly, the absence/presence and distribution of saccharide moieties in the various compounds affected differently their mechanism of interaction with cancer cells and their phototoxic efficiency. For glycodendrimeric TPP-1 and TPP-2 incubated with retinoblastoma cells, a fast two-step uptake-equilibrium process was observed, whereas for a dendrimeric TPP without saccharide moieties (TPP-1c) and a glycoconjugated compound with no dendrimeric structure (TPP(DegMan)[Formula: see text] uptake was very slow. The difference in uptake profiles and kinetics between TPP-1c on the one hand and TPP-1 and TPP-2 on the other hand would account for the interaction of the two glycodendrimeric compounds with a mannose receptor. These TPPs encapsulated in endosomes would induce less damage to cells upon illumination. TPP(DegMan)[Formula: see text] showed the highest phototoxicity, but its efficiency was unaffected by pretreatment of cells by mannan. The penetration of this glycoconjugated compound in cells and its phototoxic effect appeared independent of its interaction with a mannose receptor. Thus, if glycoconjugation influenced TPPs behavior in solution and interaction with serum proteins, phototoxicity was not necessarily related to upfront molecular recognition.