Improving the delivery of 5-aminolaevulinic acid in photodynamic therapy (PDT): synthesis and biological studies of novel peptide prodrugs

该项目的主要目的是设计用于光动力疗法（PDT）的新药，这是一种可用于摧毁癌症和杀死感染性细菌的治疗方法。PDT的关键特点是它使用一种被称为“光敏剂”的光激活药物。当光线激活这种药物时，就会对肿瘤细胞或细菌产生毒性作用，从而导致肿瘤的破坏或细菌感染的愈合。实际上，光“打开”药物，但只在暴露在光线下的区域。我们建议研究一种基于5-氨基乙酰丙酸（ALA）的新型药物。这是一种天然化合物，存在于许多细胞中，但通常含量很低。然而，如果细胞或细菌暴露在高浓度的ALA中，就会产生光敏剂（卟啉），它吸收从红色到蓝色的广泛范围内的光，因此可以用于PDT治疗。例如，治疗皮肤肿瘤可以先用含有ALA的洗液覆盖肿瘤，然后放置几个小时。当ALA渗入肿瘤后，在其上照射几分钟以杀死肿瘤细胞。另外，可以将ALA溶液注射或口服，用于治疗体内的肿瘤，内窥镜可用于将光线引导到肿瘤上。然而，使用ALA的一个主要问题是它不能很快被细胞吸收。我们计划改变它的化学结构，使细胞或细菌更容易吸收它，特别是通过在ALA上附加氨基酸来帮助细胞吸收它。药物进入细胞后会分解释放ALA。如果经过改良的ALA药物能更容易地进入细胞，那么原则上它对肿瘤治疗应该更有效，而且由于氨基酸是构成蛋白质的天然化合物，这些新药应该可以安全使用。除了治疗癌症，还有几种类型的细菌甚至真菌感染可以用PDT治疗。PDT治疗细菌的一个优点是可以治疗对抗生素有耐药性的细菌。例如，烧伤伤口经常会感染，在这种情况下，PDT药物可以应用于伤口，然后在药物穿透感染区域后照射。如果新的ALA药物能被细菌更有效地吸收，那么PDT治疗应该更有效。我们还希望设计出能被细菌而不是健康细胞特异性分解的改良ALA药物，方法是将氨基酸附加在药物上，使其结构与正常情况下天然存在的氨基酸形成镜像。

The main aim of this project is to design new drugs for photodynamic therapy (PDT) which is a treatment that can be used for destroying cancers and killing infectious bacteria. The key feature feature of PDT is that it uses a light-activated drug known as a 'photosensitiser'. When light activates the drug this results in a toxic effect to tumour cells or bacteria leading to destruction of the tumour or healing of the bacterial infection. In effect, the light 'switches on' the drug but only in areas exposed to light. We propose to look at a new type of drug based on 5-aminolaevulinic acid (ALA). This is a natural compound present in many cells but normally at very low levels. However if cells or bacteria are exposed to high concentrations of ALA then a photosensitiser is produced (a porphyrin) which absorbs light over a wide range from red to blue and can therefore be used for PDT treatment. For example, a skin tumour can be treated by first covering the tumour with a lotion containing the ALA which is then left for a few hours. After ALA has seeped into the tumour, light is shone onto it for a few minutes to kill the tumour cells. Alternatively, a solution of ALA can be injected or given orally for the treatment of tumours inside the body where an endoscope can be used to guide the light onto the tumour. One main problem with using ALA however is that it is not quickly taken up by cells. We plan to change its chemical structure so that cells or bacteria can absorb it more easily, specifically by attaching amino acids to the ALA to help its uptake by cells. After entering the cell the drug would break down to release the ALA. If the modified ALA drug can enter cells more easily then in principle it should be more effective for tumour treatment, and since amino acids are natural compounds which make up proteins these new drugs should be safe to use. As well as treating cancers, there are several types of bacterial or even fungal infection which can be treated using PDT. One advantage of PDT for treating bacteria is that bacteria resistant to antibiotics can be treated. For example, burn wounds often become infected and in this case the PDT drug can be applied to the wounds and then illuminated after the drug has penetrated the infected area. If the new types of ALA drug can be taken up more efficiently by the bacteria then again the PDT treatment should be more effective. We also hope to design modified ALA drugs that are broken down specifically by bacteria and not by healthy cells by attaching amino acids whose structures are the mirror image of those which are normally found naturally.