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

这个项目的主要目的是设计光动力疗法(PDT)的新药，光动力疗法是一种可以用来摧毁癌症和杀灭感染性细菌的疗法。光动力疗法的主要特点是它使用了一种被称为“光敏剂”的光激活药物。当光激活药物时，这会对肿瘤细胞或细菌产生毒性作用，导致肿瘤的破坏或细菌感染的愈合。实际上，光只在暴露在光线下的区域“打开”药物。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，但通常水平很低。然而，如果细胞或细菌暴露在高浓度的丙氨酸中，就会产生一种光敏剂(一种卟啉)，它可以在从红色到蓝色的广泛范围内吸收光线，因此可以用于光动力疗法。例如，皮肤肿瘤可以通过首先用含有ALA的洗剂覆盖肿瘤来治疗，然后放置几个小时。在ALA渗入肿瘤后，光线照射几分钟以杀死肿瘤细胞。或者，ALA溶液可以注射或口服治疗体内肿瘤，在这种情况下，可以使用内窥镜将光线引导到肿瘤上。然而，使用ALA的一个主要问题是，它不会很快被细胞吸收。我们计划改变其化学结构，以便细胞或细菌能够更容易地吸收它，特别是通过将氨基酸连接到ALA来帮助细胞吸收它。进入细胞后，药物会分解释放ALA。如果修改后的ALA药物更容易进入细胞，那么原则上它对肿瘤治疗应该更有效，而且由于氨基酸是组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使用光动力疗法治疗。光动力疗法治疗细菌的一个优点是，对抗生素有抗药性的细菌可以治疗。例如，烧伤创面通常会受到感染，在这种情况下，可以将PDT药物涂在伤口上，然后在药物渗透到感染区域后进行照射。如果新型ALA药物能够更有效地被细菌吸收，那么PDT治疗应该会更有效。我们还希望设计修改的ALA药物，通过附加氨基酸来特定地被细菌分解，而不是被健康的细胞分解，其结构与正常情况下自然发现的氨基酸相似。

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.