title: Retrograde delivery of photosensitizer (TPPp-O-beta-GluOH)3 selectively potentiates its photodynamic activity.
abstract: Photodynamic therapy involves administration of a photosensitizing drug and its subsequent activation by visible light of the appropriate wavelength. Several approaches to increasing the specificity of photosensitizers for cancerous tissues and, in particular, through their conjugation to ligands that are directed against tumor-associated antigens have been investigated. Here, we have studied the delivery of the photocytotoxic porphyrin compound TPP(p-O-beta-D-GluOH)3 into tumor cells that overexpress the glycosphingolipid Gb3, using the Gb3-binding nontoxic B-subunit of Shiga toxin (STxB) as a vector. To allow for site-directed chemical coupling, an STxB variant carrying a free sulfhydryl moiety at its C-terminal end has been used. Binding affinity, cellular uptake, singlet oxygen quantum yield, and phototoxicity of the conjugate have been examined. Despite some effect of coupling on both the photophysical properties of TPP(p-O-beta-D-GluOH)3 and the affinity of STxB for its receptor, the conjugate exhibited a higher photocytotoxic activity than the photosensitizer alone and was exquisitely selective for Gb3-expressing tumor cells. Furthermore, our data strongly suggest that STxB-mediated retrograde delivery of the photosensitizer to the biosynthetic/secretory pathway is critical for optimal cytotoxic activity. In conclusion, a strong rationale for using retrograde delivery tools such as STxB in combination with photosensitizing agents for the photodynamic therapy of tumors is presented.
authors.affiliation: Institut Curie, Centre de Recherche, 26 rue d'Ulm, F-75248 Paris Cedex 05, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Amessou
authors.forename: Danièle
authors.initials: D
authors.lastname: Carrez
authors.forename: Delphine
authors.initials: D
authors.lastname: Patin
authors.forename: Marianne
authors.initials: M
authors.lastname: Sarr
authors.forename: David S
authors.initials: DS
authors.lastname: Grierson
authors.forename: Alain
authors.initials: A
authors.lastname: Croisy
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Tedesco
authors.forename: Philippe
authors.initials: P
authors.lastname: Maillard
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
mesh_terms: D005455:Fluorescent Antibody Technique; D009682:Magnetic Resonance Spectroscopy; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011789:Quantum Theory; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D017319:Photosensitizing Agents