Interest of RGD-containing linear or cyclic peptide targeted tetraphenylchlorin as novel photosensitizers for selective photodynamic activity |
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Authors: | Frochot Céline Di Stasio Benoît Vanderesse Régis Belgy Marie-Josée Dodeller Marc Guillemin François Viriot Marie-Laure Barberi-Heyob Muriel |
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Institution: | DCPR, UMR 7630 CNRS-INPL, Groupe ENSIC, Nancy Université, 1 rue Grandville, 54000 Nancy, France. |
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Abstract: | Destruction of the neovasculature is essential for tumor eradication by photodynamic therapy. Since the over-expression of integrins is correlated with tumor angiogenesis, we conjugated a photosensitizer (5-(4-carboxyphenyl)-10,15,20-triphenylchlorin or porphyrin) to the alpha(v)beta(3) integrin specific peptide RGD (H-Arg-Gly-Asp-OH) motif as a common sequence. We reported an efficient solid-phase synthesis of a new family of peptidic photosensitizers with linear or cyclicRGDfK] RGD motif and compared conjugates in vitro selectivity and photodynamic activity. The conjugates were characterized by (1)H NMR, MALDI, UV-visible spectroscopy and singlet oxygen formation was performed. Chlorins containing linear and constrained RGD motif were incorporated up to 98- and 80-fold more, respectively, than the unconjugated photosensitizer over a 24-h exposure in human umbilical vein endothelial cells (HUVEC) over-expressing alpha(v)beta(3) integrin. Peptidic moiety also led to a non-specific increased cellular uptake by murine mammary carcinoma cells (EMT-6), lacking RGD binding receptors. Survival measurements demonstrated that HUVEC were greatly sensitive to conjugates-mediated photodynamic therapy. |
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Keywords: | Chlorin Porphyrin RGD Solid-phase synthesis Singlet oxygen quantum yield HUVEC EMT-6 αvβ3 integrin |
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