Synthesis, cellular internalization and photodynamic activity of glucoconjugated derivatives of tri and tetra(meta-hydroxyphenyl)chlorins.
Glucoconjugated tri and tetra(meta-hydroxyphenyl)chlorins have been synthesized in order to explore how glucoconjugation of the macrocycle affects the photoactivity of the molecule. Internalization processes, photosensitizing efficacy of TPC(m-O-GluOH)(3) and TPC(m-O-GluOH)(4), in HT29 human adenocarcinoma cells have been compared to those of tetra(meta-hydroxyphenyl) chlorin (m-THPC, Foscan). The tetra glucoconjugated chlorin, TPC(m-O-GluOH)(4), was found to be poorly internalized and weakly photoactive. In contrast, the asymmetric and more amphiphilic compound TPC(m-O-GluOH)(3), exhibited superior phototoxicity compared to m-THPC. Drug concentration, temperature and sodium azide effects indicated that TPC(m-O-GluOH)(3) internalization partly proceeds via an active receptor-mediated endocytosis mechanism. Cellular uptake appeared as a saturable process and remained 30% lower than for mTHPC. However, a maximum phototoxicity in HT29 cells (survival fraction of 2+/-0.6%) were observed for concentration as low as 2 microM. A 4-fold higher concentration of m-THPC was necessary to observe the same level of photoactivity. This higher phototoxicity has been correlated to a greater mitochondrial affinity. On the basis of these results, work is in progress to further evaluate the potential of glycosylated chlorins in photodynamic therapy (PDT).
Laville
I
I
LPBC, UMR CNRS 7033 and Université Pierre et Marie Curie, 4 Place Jussieu, case 138, 75252 Paris Cedex 05, France.
Figueiredo
T
T
Loock
B
B
Pigaglio
S
S
Maillard
Ph
P
Grierson
D S
DS
Carrez
D
D
Croisy
A
A
Blais
J
J
D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D006001:Glycoconjugates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D008652:Mesoporphyrins / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011166:Porphyrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D006001:Glycoconjugates; D008652:Mesoporphyrins; D017319:Photosensitizing Agents; D011166:Porphyrins; C006969:chlorin; C072269:temoporfin