A peptide competing with VEGF165 binding on neuropilin-1 mediates targeting of a chlorin-type photosensitizer and potentiates its photodynamic activity in human endothelial cells.
Destruction of the neovasculature is essential for efficient tumor eradication by photodynamic therapy (PDT). Since the over-expression of receptors for vascular endothelial growth factor (VEGF) is correlated with tumor angiogenesis and subsequent growth, we conjugated a photosensitizer (5-(4-carboxyphenyl)-10,15,20-triphenyl-chlorin, TPC), via a spacer (6-aminohexanoic acid, Ahx), to a VEGF receptor-specific heptapeptide ... (ATWLPPR). ATWLPPR and TPC-Ahx-ATWLPPR bound exclusively to neuropilin-1 (NRP-1) recombinant chimeric protein (IC50=19 and 171 microM, respectively) but were devoid of affinity for VEGF receptor type 2 (VEGFR-2, KDR), to which ATWLPPR was initially thought to bind. TPC-Ahx-ATWLPPR was incorporated up to 25-fold more in human umbilical vein endothelial cells (HUVEC) than TPC over a 24-h period, and the addition of 8 mM ATWLPPR induced a significant decrease of this uptake (P<0.05), corroborating a receptor-mediated incorporation. Slightly less cytotoxic in the dark, TPC-Ahx-ATWLPPR exhibited enhanced in vitro photodynamic activity (10.4-fold), compared to TPC. Pharmacokinetic analysis in nude mice xenografted with U87 human malignant glioma cells revealed relevant tumor levels as soon as 1 h after intravenous injection of TPC-Ahx-ATWLPPR, and a rapid elimination from the blood compartment. Moreover, TPC-Ahx-ATWLPPR was not degraded in vivo up to 2 h after intravenous injection. Taken together, our results demonstrate that TPC-Ahx-ATWLPPR is a much more potent photosensitizer in vitro than TPC, in NRP-1-expressing cells. Thus, it may efficiently potentiate the vascular effect of PDT in vivo.
Mesh Terms:
Animals, Blotting, Western, Cell Line, Cell Line, Tumor, Cell Survival, Drug Delivery Systems, Drug Synergism, Endothelial Cells, Female, Glioblastoma, Humans, Light, Mice, Mice, Nude, Neuropilin-1, Oligopeptides, Photochemotherapy, Photosensitizing Agents, Porphyrins, Protein Binding, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A, Xenograft Model Antitumor Assays
Animals, Blotting, Western, Cell Line, Cell Line, Tumor, Cell Survival, Drug Delivery Systems, Drug Synergism, Endothelial Cells, Female, Glioblastoma, Humans, Light, Mice, Mice, Nude, Neuropilin-1, Oligopeptides, Photochemotherapy, Photosensitizing Agents, Porphyrins, Protein Binding, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A, Xenograft Model Antitumor Assays
J Control Release
Date: Mar. 10, 2006
PubMed ID: 16423422
View in: Pubmed Google Scholar
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