Interest of RGD-containing linear or cyclic peptide targeted tetraphenylchlorin as novel photosensitizers for selective photodynamic activity.
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 cyclic[RGDfK] 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.
Frochot
Céline
C
DCPR, UMR 7630 CNRS-INPL, Groupe ENSIC, Nancy Université, 1 rue Grandville, 54000 Nancy, France.
Di Stasio
Benoît
B
Vanderesse
Régis
R
Belgy
Marie-Josée
MJ
Dodeller
Marc
M
Guillemin
François
F
Viriot
Marie-Laure
ML
Barberi-Heyob
Muriel
M
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis / Q000737:chemistry*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy*; D051379:Mice; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D010778:Photochemotherapy / Q000379:methods; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011166:Porphyrins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C513508:5-(4-carboxyphenyl)-10,15,20-triphenylchlorin; D039302:Integrin alphaVbeta3; D010455:Peptides; D010456:Peptides, Cyclic; D017319:Photosensitizing Agents; D011166:Porphyrins