Design and synthesis of 5-aminolaevulinic acid/3-hydroxypyridinone conjugates for photodynamic therapy: enhancement of protoporphyrin IX production and photo-toxicity in tumor cells
Design and synthesis of 5-aminolaevulinic acid/3-hydroxypyridinone conjugates for photodynamic therapy: enhancement of protoporphyrin IX production and photo-toxicity in tumor cells
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DOI：
10.1039/c6md00040a
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发表时间：
2016-06
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通讯作者：
Tao Zhou;Le-Le Shao-Le;S. Battah;Chun-Feng Zhu;R. Hider;B. Reeder;A. Jabeen;A. MacRobert;Gerui Ren;Xinle Liang
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文献类型：
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作者：
Tao Zhou;Le-Le Shao-Le;S. Battah;Chun-Feng Zhu;R. Hider;B. Reeder;A. Jabeen;A. MacRobert;Gerui Ren;Xinle Liang
5-氨基乙酰丙酸(ALA)及其衍生物作为光敏剂原卟啉IX(PpIX)的前体，在皮肤科和泌尿科被广泛应用于光动力疗法(PDT)。然而，ALA的生物利用度较低，这限制了ALA-PDT的生物利用度，这是因为在生理pH下，ALA的两性离子性质使其很难被细胞吸收。为了提高治疗效果和诱导较高水平的PpIX，通过氨基键将丙氨酸与3-羟基吡啶-4-酮(HPO)铁络合剂偶联，合成了一系列丙氨酸前药。药代动力学研究表明，与ALA单独或ALA和CP94(1，2-二乙基-3-羟基吡啶-4-酮)联合给药相比，一种ALA-HPO结合物显著增加了一系列肿瘤细胞中PpIX的产生。光暴露后细胞内的卟啉荧光水平与细胞的光毒性有很好的相关性，提示ALA-HPO偶联物在光动力治疗中有潜在的应用前景。
5-Aminolaevulinic acid (ALA) and its derivatives have been widely used in photodynamic therapy (PDT) as precursors of the photosensitizer, protoporphyrin IX (PpIX) in dermatology and urology. However, ALA-PDT is limited by the low bioavailability of ALA due to the fact that ALA is poorly absorbed by cells by virtue of its zwitterionic nature at physiological pH. In order to improve the therapeutic effect and induce higher levels of PpIX, a series of ALA prodrugs were synthesized by the conjugation of ALA to 3-hydroxypyridin-4-one (HPO) iron chelator using an amino acid linkage via amide bonds. Pharmacokinetic studies indicated that one ALA–HPO conjugate significantly enhanced PpIX production in a range of tumor cell lines over ALA alone or the co-administration of ALA and CP94 (1,2-diethyl-3-hydroxypyridin-4-one). The intracellular porphyrin fluorescence levels showed good correlation with cellular photo-toxicity following light exposure, suggesting the potential application of the ALA–HPO conjugates in photodynamic therapy.