Neuropilin-1 targeting photosensitization-induced early stages of thrombosis via tissue factor release.
OBJECTIVE
This article characterizes the vascular effects following vascular-targeted photodynamic therapy with a photosensitizer which actively targets endothelial cells.


METHODS
This strategy was considered by coupling a chlorin to a heptapeptide targeting neuropilin-1 in human malignant glioma-bearing nude mice. A laser Doppler microvascular perfusion monitor was used to monitor microvascular blood perfusion in tumor tissue. Endothelial cells' ultra structural integrity was observed by transmission electron microscopy. The consequences of photosensitization on tumor vessels, tissue factor expression, fibrinogen consumption, and thrombogenic effects were studied by immunohistochemical staining.


RESULTS
Treatment of glioma-bearing mice with the conjugate showed a statistically significant tumor growth delay. Vascular effect was characterized by a decrease in tumor tissue blood flow at about 50% baseline during treatment not related to variations in temperature. This vascular shutdown was mediated by tumor blood vessels' congestion. A pro-thrombotic behavior of targeted endothelial cells in the absence of ultra structural changes led to the induction of tissue factor expression from the earliest times post-treatment. Expression of tissue factor-initiated thrombi formation was also related to an increase in fibrinogen consumption.


CONCLUSIONS
Using a peptide-conjugated photosensitizer targeting neuropilin-1, induction of tissue factor expression immediately post-treatment, led to the establishment of thrombogenic effects within the vessel lumen.
Bechet
Denise
D
Centre de Recherche en Automatique de Nancy (CRAN), Nancy-University, CNRS, Centre Alexis Vautrin, Avenue de Bourgogne, Brabois, 54511, Vandoeuvre-lès-Nancy, France.
Tirand
Loraine
L
Faivre
Béatrice
B
Plénat
François
F
Bonnet
Corinne
C
Bastogne
Thierry
T
Frochot
Céline
C
Guillemin
François
F
Barberi-Heyob
Muriel
M
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D039942:Neuropilin-1 / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013925:Thromboplastin / Q000378:metabolism*; D013927:Thrombosis / Q000139:chemically induced*
D009842:Oligopeptides; D017319:Photosensitizing Agents; D011166:Porphyrins; D039942:Neuropilin-1; C006969:chlorin; D013925:Thromboplastin