On the correlation between hydrophobicity, liposome binding and cellular uptake of porphyrin sensitizers
On the correlation between hydrophobicity, liposome binding and cellular uptake of porphyrin sensitizers
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DOI：
10.1562/2005-09-01-ra-669
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发表时间：
2006-05-01
影响因子：
3.3
通讯作者：
Ehrenberg, Benjamin
中科院分区：
文献类型：
--
作者：
Ben-Dror, Shimshon;Bronshtein, Irena;Ehrenberg, Benjamin
选择用于光动力疗法 (PDT) 的卟啉或类似光敏剂的一个关键因素是其融入细胞的能力。对于被动分配到细胞质膜中的疏水性化合物，有机溶剂和水之间的分配系数 P 是可用于预测分子扩散到生物膜中的能力的因素之一。我们合成了几种用两个、三个或四个内消旋取代基修饰的卟啉，并研究了它们的光谱和光物理性质。计算辛醇-水分配系数 log P 作为疏水性参数。我们发现这些卟啉非常疏水，log P 值在 8.9-11.8 范围内。这些与这些卟啉在脂质体中的结合常数 K-b 以及它们被细胞的摄取相关。估计的 log P 和 Kb 之间的相关性几乎是线性的，但呈负相关，这显然表明，随着疏水性的增加，与脂质体的结合较少。另一方面，所有研究的卟啉均被细胞摄取，但细胞摄取与 log P 或 Kb 之间没有明确的相关性。 Lipinski 的药理学“5 规则”预测，当 log P 大于 5 时，药物进入细胞的渗透性较差。这可能与脂质体的扩散结合有关，其中水聚集会强烈干扰细胞摄取。在这种极端条件下，脂质体结合或其他规则似乎都无法预测卟啉的体外行为。
A crucial factor in choosing a porphyrin or analogous photosensitizer for photodynamic therapy (PDT) is its ability to incorporate into the cells. For hydrophobic compounds that partition passively into the cytoplasmic membrane, a partition coefficient between an organic solvent and water, P, is one factor that could be used to predict the molecule's ability to diffuse into biomembranes. We synthesized several porphyrins, modified with two, three or four meso-substituents and studied their spectroscopic and photophysical properties. The octanol-water partitioning coefficients, log P, were calculated as a parameter for hydrophobicity. We found these porphyrins to be very hydrophobic, with log P values in the range of 8.9-11.8. These were correlated with the binding constants of these porphyrins into liposomes, K-b, as well as to their uptake by cells. The correlation between the estimated log P and Kb is nearly linear but negative, indicating, apparently, that there is lesser binding to liposomes with increased hydrophobicity. On the other hand, all of the studied porphyrins are taken up by cells, but there is no clear correlation between cellular uptake and the log P or Kb. Lipinski's pharmacological "rule of 5" predicts poor permeation of drugs into cells when log P is greater than five. This may be relevant for diffusional binding to liposomes, where aqueous aggregation can interfere strongly with cellular uptake. In such extreme conditions, neither liposome binding nor other rules seem to predict porphyrin behavior in vitro.