Glycodendrimeric phenylporphyrins as new candidates for retinoblastoma PDT: blood carriers and photodynamic activity in cells.
Photodynamic therapy (PDT) has recently been proposed as a possible indication in the conservative treatment of hereditary retinoblastoma. In order to create photosensitizers with enhanced targeting ability toward retinoblastoma cells, meso-tetraphenylporphyrins bearing one glycodendrimeric moiety have been synthesized. The binding properties to plasma proteins and photodynamic activity of two monodendrimeric porphyrins bearing three mannose units via monoethylene glycol (1) or diethylene glycol (2) linkers have been compared to that of the non-dendrimeric tri-substituted derivative [TPP(p-Deg-O-α-ManOH)(3)]. The dendrimeric structure was found to highly increase the binding affinity to plasma proteins and to modify to some extent plasma distribution. HDL and to a lesser extent LDL have been shown to be the main carriers of dendrimeric and non-dendrimeric compounds. The phototoxicity observed for the two glycodendrimers (1) and (2) (LD(50)=0.5 μM) in Y79 cells is of the same order of magnitude that for TPP(p-Deg-O-α-ManOH)(3) (LD(50)=0.7 μM), with a similar cellular uptake level for (1) and a lower for (2). A serum content increase from 2% to 20% (v/v) in the incubation medium was found to inhibit both cellular uptake and photoactivity of dendrimeric derivatives, whereas those of TPP(p-Deg-O-α-ManOH)(3) remained little affected. Specificities of glycodendrimeric porphyrins, combining a lower cellular uptake together with a higher affinity toward plasma proteins, make these derivatives possible candidates for a vascular targeting PDT.
EA 4041, Laboratoire de Chimie Analytique, IFR 141, Univ. Paris-Sud, 5 rue J.-B. Clément, F-92296 Châtenay-Malabry, France.
Ze-Jian
ZJ
Wang
Benoît
B
Chauvin
Philippe
P
Maillard
Fabien
F
Hammerer
Danièle
D
Carez
Alain
A
Croisy
Catherine
C
Sandré
Sylvie
S
Chollet-Martin
Patrice
P
Prognon
Jean-Louis
JL
Paul
Jocelyne
J
Blais
Athena
A
Kasselouri
D001692:Biological Transport; D001798:Blood Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry*; D019855:Ethylene Glycol / Q000737:chemistry; D005026:Ethylene Glycols / Q000737:chemistry; D006801:Humans; D008358:Mannose / Q000737:chemistry*; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011166:Porphyrins / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D012175:Retinoblastoma / Q000188:drug therapy* / Q000473:pathology
D001798:Blood Proteins; D050091:Dendrimers; D005026:Ethylene Glycols; D017319:Photosensitizing Agents; D011166:Porphyrins; C013484:diethylene glycol; D019855:Ethylene Glycol; D008358:Mannose