Effect of Molecular Characteristics on Cellular Uptake, Subcellular Localization, and Phototoxicity of Zn(II) N-Alkylpyridylporphyrins
Effect of Molecular Characteristics on Cellular Uptake, Subcellular Localization, and Phototoxicity of Zn(II) N-Alkylpyridylporphyrins
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DOI：
10.1074/jbc.m113.511642
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发表时间：
2013-12-20
影响因子：
4.8
通讯作者：
Benov, Ludmil T.
中科院分区：
文献类型：
--
作者：
Ezzeddine, Rima;Al-Banaw, Anwar;Benov, Ludmil T.
背景：将分子递送到选定的细胞区室对于分析和实践目的是重要的。结果：改变烷基取代基的长度和位置导致特定细胞结构优先摄取锌卟啉。结论：卟啉的吸收、分布和光毒性依赖于电荷、亲油性和分子形状。重要性：为了研究光敏剂（PS）的三维结构和亲脂性对细胞摄取、亚细胞分布和光动力学效应的影响，合成了亲脂性递增的四阳离子meso-四（N-烷基吡啶-2（或-3或-4）-基）卟啉锌（ZnPs）。通过将连接到吡啶氮的N-烷基取代基从邻位移动到Meta和帕拉，研究了分子的三维形状的影响。从较短的亲水性（甲基）到较长的两亲性（己基）烷基链的亲脂性的逐步增加增加的ZnP PS的光毒性。当烷基取代基从邻位转移到间位和从Meta位转移到帕拉时，所有衍生物的PS功效也增加。PS的细胞摄取和亚细胞分布受亲脂性和卟啉环周围烷基链的位置的影响。而亲水性ZnPs表现出主要是溶酶体分布，两亲性己基衍生物与线粒体，内质网和质膜。己基异构体的比较显示，细胞摄取和分配到膜遵循帕拉> Meta >邻位的顺序。改变烷基取代基的位置和长度影响（i）阳离子电荷与阴离子生物分子的静电相互作用的暴露和（ii）分子的亲油性。PS的电荷、亲脂性和三维形状是决定PS的细胞摄取、亚细胞分布以及因此的PS的光毒性的主要因素。
Background: Delivering molecules to selected cellular compartments is important for analytical and practical purposes. Results: Varying the length and positions of alkyl substituents results in preferential uptake of zinc porphyrins by particular cellular structures. Conclusion: Uptake, distribution, and phototoxicity of porphyrins depend on charge, lipophilicity, and molecular shape. Significance: Systematic chemical modification provides the basis for rational design of molecules targeting specific cellular compartments.Tetra-cationic Zn(II) meso-tetrakis(N-alkylpyridinium-2 (or -3 or -4)-yl)porphyrins (ZnPs) with progressively increased lipophilicity were synthesized to investigate how the tri-dimensional shape and lipophilicity of the photosensitizer (PS) affect cellular uptake, subcellular distribution, and photodynamic efficacy. The effect of the tri-dimensional shape of the molecule was studied by shifting the N-alkyl substituent attached to the pyridyl nitrogen from ortho to meta and para positions. Progressive increase of lipophilicity from shorter hydrophilic (methyl) to longer amphiphilic (hexyl) alkyl chains increased the phototoxicity of the ZnP PSs. PS efficacy was also increased for all derivatives when the alkyl substituents were shifted from ortho to meta, and from meta to para positions. Both cellular uptake and subcellular distribution of the PSs were affected by the lipophilicity and the position of the alkyl chains on the periphery of the porphyrin ring. Whereas the hydrophilic ZnPs demonstrated mostly lysosomal distribution, the amphiphilic hexyl derivatives were associated with mitochondria, endoplasmic reticulum, and plasma membrane. A comparison of hexyl isomers revealed that cellular uptake and partition into membranes followed the order para > meta > ortho. Varying the position and length of the alkyl substituents affects (i) the exposure of cationic charges for electrostatic interactions with anionic biomolecules and (ii) the lipophilicity of the molecule. The charge, lipophilicity, and the tri-dimensional shape of the PS are the major factors that determine cellular uptake, subcellular distribution, and as a consequence, the phototoxicity of the PSs.