Design, synthesis, and biological evaluation of folic acid targeted tetraphenylporphyrin as novel photosensitizers for selective photodynamic therapy.
Photodynamic therapy (PDT) is a cancer treatment involving systemic administration of a tumor-localizing photosensitizer; this, when activated by the appropriate light wavelength, interacts with molecular oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. Targeted PDT offers the opportunity of enhancing photodynamic efficiency by directly targeting diseased cells and tissues. Two new conjugates of three components, folic acid/hexane-1,6-diamine/4-carboxyphenylporphyrine 1 and folic acid/2,2'-(ethylenedioxy)-bis-ethylamine/4-carboxyphenylporphyrine 2 were synthesized. The conjugates were characterized by 1H NMR, MALDI, UV-visible spectroscopy, and fluorescence quantum yield. The targeted delivery of these photoactive compounds to KB nasopharyngeal cell line, which is one of the numerous tumor cell types that overexpress folate receptors was studied. It was found that after 24 h incubation, conjugates 1 and 2 cellular uptake was on average 7-fold higher than tetraphenylporphyrin (TPP) used as reference and that 1 and 2 cellular uptake kinetics increased steadily over the 24 h period, suggesting an active transport via receptor-mediated endocytosis. In corresponding results, conjugates 1 and 2 accumulation displayed a reduction of 70% in the presence of a competitive concentration of folic acid. Survival measurements demonstrated that KB cells were significantly more sensitive to conjugated porphyrins-mediated PDT. Under the same experimental conditions and the same photosensitizer concentration, TPP displayed no photocytotoxicity while conjugates 1 and 2 showed photodynamic activity with light dose values yielding 50% growth inhibition of 22.6 and 6.7 J/cm2, respectively.
Schneider
Raphaël
R
Synthèse Organométallique et Réactivité, UMR 7565 CNRS-UHP, Faculté des Sciences, BP 239, 54506 Vandoeuvre les Nancy, France. m.barberi@nancy.fnlcc.fr
Schmitt
Frédéric
F
Frochot
Céline
C
Fort
Yves
Y
Lourette
Natacha
N
Guillemin
François
F
Müller
Jean-François
JF
Barberi-Heyob
Muriel
M
D001667:Binding, Competitive / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D015195:Drug Design; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D007624:KB Cells; D007700:Kinetics; D008027:Light; D015394:Molecular Structure; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011166:Porphyrins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors
D017319:Photosensitizing Agents; D011166:Porphyrins; C409084:tetraphenylporphyrin; D005492:Folic Acid