Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET-Hospital de Clínicas Gral, José de San Martín, Ciudad Autónoma de Buenos Aires, Argentina.
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Buenos Aires, Argentina; Universidad de Buenos Aires, CONICET, Unidad de Microanálisis y Métodos Físicos Aplicados a Química Orgánica (UMYMFOR), Buenos Aires, Argentina.
J Photochem Photobiol B. 2021 Aug;221:112244. doi: 10.1016/j.jphotobiol.2021.112244. Epub 2021 Jun 23.
The delta-amino acid 5-aminolevulinic acid (ALA), is the precursor of the endogenous photosensitiser Protoporphyrin IX (PpIX), and is currently approved for Photodynamic Therapy (PDT) of certain superficial cancers. However, ALA-PDT is not very effective in diseases in which T-cells play a significant role. Cutaneous T-cell lymphomas (CTCL) is a group of non-Hodgkin malignant diseases, which includes mycosis fungoides (MF) and Sézary syndrome (SS). In previous work, we have designed new ALA esters synthesised by three-component Passerini reactions, and some of them showed higher performance as compared to ALA. This work aimed to determine the efficacy as pro-photosensitisers of five new ALA esters of 2-hydroxy-N-arylacetamides (1f, 1 g, 1 h, 1i and 1 k) of higher lipophilicity than ALA in Myla cells of MF and HuT-78 cells of SS. We have also tested its effectiveness against ALA and the already marketed ALA methyl ester (Me-ALA) and ALA hexyl ester (He-ALA). Both cell Myla and SS cells were effectively and equally photoinactivated by ALA-PDT. Besides, the concentration of ALA required to induce half the maximal porphyrin synthesis was 209 μM for Myla and 169 μM for HuT-78 cells. As a criterion of efficacy, we calculated the concentration of the ALA derivatives necessary to induce half the plateau porphyrin values obtained from ALA. These values were achieved at concentrations 4 and 12 times lower compared to ALA, according to the derivative used. For He-ALA, concentrations were 24 to 25 times lower than required for ALA for inducing comparable porphyrin synthesis in both CTCL cells. The light doses for inducing 50% of cell death (LD50) for He-ALA, 1f, 1 g, 1 h and 1i were around 18 and 25 J/cm for Myla and HuT-78 cells respectively, after exposure to 0.05 mM concentrations of the compounds. On the other hand, the LD50s for the compound 1 k were 40 and 57 J/cm for Myla and HuT-78, respectively. In contrast, 0.05 mM of ALA and Me-ALA did not provoke photokilling since the concentration employed was far below the porphyrin saturation point for these compounds. Our results suggest the potential use of ALA derivatives for topical application in PDT treatment of MF and extracorporeal PDT for the depletion of activated T-cells in SS.
δ-氨基-5-氨基酮戊酸（ALA）是内源性光敏剂原卟啉 IX（PpIX）的前体，目前已被批准用于某些浅表癌症的光动力疗法（PDT）。然而，ALA-PDT 在 T 细胞起重要作用的疾病中效果并不显著。皮肤 T 细胞淋巴瘤（CTCL）是一组非霍奇金恶性疾病，包括蕈样真菌病（MF）和塞扎里综合征（SS）。在之前的工作中，我们设计了通过三组分 Passerini 反应合成的新型 ALA 酯，其中一些与 ALA 相比表现出更高的性能。本工作旨在确定五种新型 2-羟基-N-芳基乙酰胺的 ALA 酯（1f、1g、1h、1i 和 1k）作为前光敏剂的功效，其亲脂性高于 MF 的 Myla 细胞和 SS 的 HuT-78 细胞中的 ALA。我们还测试了它们对 ALA 以及已上市的 ALA 甲酯（Me-ALA）和 ALA 己酯（He-ALA）的有效性。ALA-PDT 可有效且同等地光灭活 Myla 细胞和 SS 细胞。此外，ALA 诱导半最大卟啉合成所需的浓度为 Myla 细胞 209 μM，HuT-78 细胞 169 μM。作为功效标准，我们计算了诱导从 ALA 获得的半最大卟啉值所需的 ALA 衍生物浓度。根据所用衍生物，这些值在浓度低 4 到 12 倍的情况下即可达到。对于 He-ALA，在 CTCL 细胞中诱导可比卟啉合成所需的浓度比 ALA 低 24 到 25 倍。在用 0.05 mM 浓度的化合物处理后，He-ALA、1f、1g、1h 和 1i 的诱导 50%细胞死亡的光剂量（LD50）分别为 Myla 和 HuT-78 细胞的约 18 和 25 J/cm。另一方面，化合物 1k 的 LD50 分别为 Myla 和 HuT-78 的 40 和 57 J/cm。相比之下，0.05 mM 的 ALA 和 Me-ALA 不会引发光杀伤，因为所用的浓度远低于这些化合物的卟啉饱和点。我们的结果表明，ALA 衍生物有可能用于 MF 的局部 PDT 治疗和 SS 中激活 T 细胞的体外 PDT 耗竭。
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