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
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
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DOI：
10.1016/j.jconrel.2005.11.017
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发表时间：
2006-03-10
影响因子：
10.8
通讯作者：
Barberi-Heyob, M
中科院分区：
文献类型：
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作者：
Tirand, L;Frochot, C;Barberi-Heyob, M
光动力疗法（PDT）的有效根除肿瘤的关键是破坏新生血管。由于血管内皮生长因子（VEGF）受体的过表达与肿瘤血管生成和随后的生长相关，我们通过间隔物（6-氨基己酸，Ahx）将光敏剂（5-（4-羧基苯基）-10，15，20-三苯基二氢卟酚，TPC）缀合至VEGF受体特异性七肽（ATWLPPR）。ATWLPPR和TPC-Ahx-ATWLPPR仅与神经纤毛蛋白-1（NRP-1）重组嵌合蛋白结合（IC 50分别为19和171 μ M），但对ATWLPPR最初被认为与之结合的VEGF受体2型（VEGFR-2，KDR）缺乏亲和力。TPC-Ahx-ATWLPPR在人脐静脉内皮细胞（HUVEC）中的掺入量在24小时内比TPC高25倍，并且添加8 mM ATWLPPR诱导这种摄取显著降低（P < 0.05），证实受体介导的掺入。与TPC相比，TPC-Ahx-ATWLPPR在黑暗中的细胞毒性略低，表现出增强的体外光动力活性（10.4倍）。在用U87人恶性胶质瘤细胞异种移植的裸鼠中的药代动力学分析揭示了TPC-Ahx-ATWLPPR在静脉内注射后1小时就达到相关的肿瘤水平，并且从血液隔室中快速消除。此外，TPC-Ahx-ATWLPPR在静脉内注射后在体内不降解高达2 μ l。总之，我们的结果表明，TPC-Ahx-ATWLPPR是一个更有效的光敏剂在体外比TPC，在NRP-1表达细胞。因此，它可以有效地增强PDT在体内的血管效应。(c)2005 Elsevier B. V.保留所有权利。
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 mu M, 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 I 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 It 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. (c) 2005 Elsevier B.V. All rights reserved.