Hu Zhang, Sim Ying, Kon Oi Lian, Ng Wai Har, Ribeiro António J M, Ramos Maria J, Fernandes Pedro A, Ganguly Rakesh, Xing Bengang, García Felipe, Yeow Edwin K L
School of Physical and Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University , 21 Nanyang Link, 637371 Singapore.
Division of Medical Sciences, Laboratory of Applied Human Genetics, Humphrey Oei Institute of Cancer Research, National Cancer Centre , 169610 Singapore.
Bioconjug Chem. 2017 Feb 15;28(2):590-599. doi: 10.1021/acs.bioconjchem.6b00682. Epub 2017 Jan 18.
In this study, unique methyl-functionalized derivatives (TPP) of the drug carrier triphenylphosphonium (TPP) that exhibit significant enhancement of the accumulation of both the cation and its conjugated cargo in cell mitochondria are designed. We show that the presence of methyl group(s) at key positions within the phenyl ring results in an increase in the hydrophobicity and solvent accessible surface area of TPP. In particular, when the para position of the phenyl ring in TPP is functionalized with a methyl group, the cation is most exposed to the surrounding environment, leading to a large decrease in water entropy and an increase in the level of van der Waals interaction with and partition into a nonpolar solvent. Therefore, stronger binding between the hydrophobic TPP and mitochondrial membrane occurs. This is exemplified in a (hexachloro-fluorescein)-TPP conjugate system, where an ∼12 times increase in the rate of mitochondrial uptake and a 2 times increase in photodynamic therapy (PDT) efficacy against HeLa and FU97 cancer cells are achieved when TPP is replaced with TPP. Importantly, nearly all the FU97 cells treated with the (hexachloro-fluorescein)-TPP conjugate are killed as compared to only half the population of cells in the case of the (hexachloro-fluorescein)-TPP conjugate at a similar PDT light dosage. This study thus forms a platform for the healthcare community to explore alternative TPP derivatives that can act as optimal drug transporters for enhanced mitochondrially targeted therapies.
在本研究中，设计了药物载体三苯基膦（TPP）的独特甲基官能化衍生物（TPP），其在细胞线粒体中阳离子及其共轭货物的积累均显著增强。我们表明，苯环内关键位置甲基的存在导致TPP的疏水性和溶剂可及表面积增加。特别是，当TPP中苯环的对位用甲基官能化时，阳离子最暴露于周围环境，导致水熵大幅降低，与非极性溶剂的范德华相互作用水平和分配增加。因此，疏水性TPP与线粒体膜之间发生更强的结合。这在（六氯荧光素）-TPP共轭体系中得到例证，当用TPP取代TPP时，对HeLa和FU97癌细胞的线粒体摄取速率提高约12倍，光动力疗法（PDT）疗效提高2倍。重要的是，在相似的PDT光剂量下，用（六氯荧光素）-TPP共轭物处理的几乎所有FU97细胞都被杀死，而（六氯荧光素）-TPP共轭物处理的细胞只有一半被杀死。因此，本研究为医疗保健界探索可作为增强线粒体靶向治疗的最佳药物转运体的替代TPP衍生物形成了一个平台。
