Retrograde delivery of photosensitizer (TPPp-O-beta-GluOH)3 selectively potentiates its photodynamic activity.
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.
Amessou
Mohamed
M
Institut Curie, Centre de Recherche, 26 rue d'Ulm, F-75248 Paris Cedex 05, France.
Carrez
Danièle
D
Patin
Delphine
D
Sarr
Marianne
M
Grierson
David S
DS
Croisy
Alain
A
Tedesco
Antonio C
AC
Maillard
Philippe
P
Johannes
Ludger
L
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
D017319:Photosensitizing Agents