Improvement of meta-tetra(hydroxyphenyl)chlorin-like photosensitizer selectivity with folate-based targeted delivery. synthesis and in vivo delivery studies.
The cell membrane folate receptor (FR) is a molecular target for tumor-selective drug delivery, including delivery of photosensitizers for anticancer photodynamic therapy (PDT). Tumor selectivity of meta-tetra(hydroxyphenyl)chlorin ( m-THPC), a photosensitizer used in PDT clinical trials, demonstrates a low tumor-to-normal epithelial uptake ratio. We report on the synthesis and on the photophysical properties of a m-THPC-like photosensitizer 1 conjugated to folic acid (compound 8). A comparative study of the accumulation of photosensitizers 1 and 8 is described. Nude mice were xenografted with FR-alpha-positive KB or HT-29 cells lacking FR-alpha as a negative control. Using optical fiber fluorimetry, we demonstrated that conjugate 8 exhibited enhanced accumulation in KB tumors compared to 1 4 h after injection. No significant difference between KB and HT-29 tumors was observed in case of compound 1. Tumor-to-normal tissue ratio exhibited a very interesting selectivity for conjugate 8 (5:1) in KB tumors 4 h postinjection.
Gravier
Julien
J
SRSMC, Structure et Réactivité des Systèmes Moléculaires Complexes, Nancy University, BP 239, F-54506 Vandoeuvre-lès-Nancy, France.
Schneider
Raphaël
R
Frochot
Céline
C
Bastogne
Thierry
T
Schmitt
Frédéric
F
Didelon
Jacques
J
Guillemin
François
F
Barberi-Heyob
Muriel
M
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008652:Mesoporphyrins / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013053:Spectrophotometry; D023041:Xenograft Model Antitumor Assays
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D008652:Mesoporphyrins; D017319:Photosensitizing Agents; D011956:Receptors, Cell Surface; D005492:Folic Acid; C072269:temoporfin