Stallivieri Aurélie, Colombeau Ludovic, Devy Jérôme, Etique Nicolas, Chaintreuil Carine, Myrzakhmetov Bauyrzhan, Achard Mathilde, Baros Francis, Arnoux Philippe, Vanderesse Régis, Frochot Céline
Laboratoire Réactions et Génie des Procédés (LRGP), UMR 7274, Université de Lorraine, CNRS, Nancy, France.
Laboratoire Réactions et Génie des Procédés (LRGP), UMR 7274, Université de Lorraine, CNRS, Nancy, France; Laboratoire de Chimie Physique Macromoléculaire (LCPM), UMR 7375, Université de Lorraine, CNRS, Nancy, France.
Bioorg Med Chem. 2018 Feb 1;26(3):688-702. doi: 10.1016/j.bmc.2017.12.034. Epub 2017 Dec 24.
Further improvements in Photodynamic therapy (PDT) necessitate that the dye targets more selectively tumour tissues or neovascularization than healthy cells. Different enzymes such as matrix metalloproteinases (MMPs) are overexpressed in tumour areas. Among these MMPs, gelatinases (MMP-2 and MMP-9) and its activator MMP-14 are known to play a key role in tumour angiogenesis and the growth of many cancers such as glioblastoma multiforme (GBM), an aggressive malignant tumour of the brain. These last years, the concept of photodynamic molecular beacons (PMB) became interesting for controlling the photosensitizer's ability to generate singlet oxygen (O) close to target biomolecules as MMPs. We report herein novel PMBs triggered by MMP-2 and/or MMP-9 and/or MMP-14, comprising a photosensitizer and a singlet oxygen quencher linked by MMP cleavable peptide linker (H-GRIGFLRTAKGG-OH). First of all, we focused on the synthesis and the photophysical study of different derivatives photosensitizer-peptide. This preliminary work concluded on an influence of the nature and the distance from the peptide, but not of the position of the photosensitizer in these derivatives on the proteolytic enzymatic action. The nature of the quencher used (a blackberry quencher (BBQ-650) or a black hole quencher (BHQ3)) does not influence the enzymatic action. We also studied the influence of an additional PEG spacer. Finally, the synthesis, the singlet oxygen quenching efficiency and the enzymatic activation of these new MMP- cleavable-PMBs were compared.
光动力疗法（PDT）的进一步改进要求染料比健康细胞更具选择性地靶向肿瘤组织或新血管形成。不同的酶，如基质金属蛋白酶（MMPs），在肿瘤区域过度表达。在这些MMPs中，明胶酶（MMP - 2和MMP - 9）及其激活剂MMP - 14在肿瘤血管生成和许多癌症（如多形性胶质母细胞瘤（GBM），一种侵袭性脑恶性肿瘤）的生长中起关键作用。近年来，光动力分子信标（PMB）的概念对于控制光敏剂在靠近如MMPs等靶标生物分子处产生单线态氧（O）的能力变得很有意义。我们在此报告由MMP - 2和/或MMP - 9和/或MMP - 14触发的新型PMB，其包含通过MMP可裂解肽接头（H - GRIGFLRTAKGG - OH）连接的光敏剂和单线态氧猝灭剂。首先，我们专注于不同衍生物光敏剂 - 肽的合成和光物理研究。这项初步工作得出结论，肽的性质和与肽的距离有影响，但光敏剂在这些衍生物中的位置对蛋白水解酶作用没有影响。所用猝灭剂的性质（黑莓猝灭剂（BBQ - 650）或黑洞猝灭剂（BHQ3））不影响酶促作用。我们还研究了额外的聚乙二醇间隔基的影响。最后，比较了这些新型MMP可裂解PMB的合成、单线态氧猝灭效率和酶促激活。
