Peptide-conjugated chlorin-type photosensitizer binds neuropilin-1 in vitro and in vivo.
The strategy developed aims to favor the vascular effect of photodynamic therapy (PDT) by targeting tumor vasculature. This approach is considered by coupling a photosensitizer (PS) to an heptapeptide targeting neuropilin-1 (NRP-1). We previously demonstrated that this new conjugated PS, which binds to recombinant NRP-1 protein, was a much more potent PS compared to the non-conjugated PS in human umbilical vein endothelial cells (HUVEC) expressing NRP-1, due to the coupling of the peptide moiety. To argue the involvement of NRP-1 in the conjugated PS cellular uptake, MDA-MB-231 breast cancer cells were used, strongly over-expressing NRP-1 receptor, and we evidenced a significant decrease of the conjugated PS uptake after RNA interference-mediated silencing of NRP-1. In mice xenografted ectopically with U87 human malignant glioma cells, we demonstrated that only the conjugated PS allowed a selective accumulation in endothelial cells lining tumor vessels. Vascular endothelial growth factor (VEGF) plasma and tumor levels could not prevent the recognition of the conjugate by NRP-1. The vascular effect induced by the conjugated PS, was characterized by a reduction in tumor blood flow around 50% during PDT. In vivo, the photodynamic efficiency with the conjugated PS induced a statistically significant tumor growth delay compared to the non-coupled PS. The peptide-conjugated chlorin-type PS uptake involves NRP-1 and this targeting strategy favors the vascular effect of PDT in vivo.
Thomas
Noémie
N
Centre de Recherche en Automatique de Nancy (CRAN), Nancy-University, CNRS, Centre Alexis Vautrin, Vandoeuvre-lès-Nancy, France.
Bechet
Denise
D
Becuwe
Philippe
P
Tirand
Loraine
L
Vanderesse
Régis
R
Frochot
Céline
C
Guillemin
François
F
Barberi-Heyob
Muriel
M
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D011166:Porphyrins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D010455:Peptides; D017319:Photosensitizing Agents; D011166:Porphyrins; D011994:Recombinant Proteins; D039942:Neuropilin-1; C006969:chlorin