Photoactivation strategies for delivery of platinum prodrugs; oxygen independent photodynamic therapy (PDT)

癌症患者通常接受手术、放射治疗或化疗。目前世界上使用最广泛的化疗药物是以铂为基础的；一个主要的例子是顺铂，一种含有铂的化合物，带有2+电荷。人们普遍认为，顺铂和其他密切相关的铂化合物的抗癌活性来自于它们能够破坏癌细胞中的DNA，导致细胞死亡。现有的铂药物对人体内的健康细胞和癌细胞都有很高的毒性。因此，治疗的严重副作用是化疗中经常遇到的严重问题。这些副作用可能非常严重，以至于不得不停止治疗，导致治疗失败，最终导致患者死亡。在某些情况下，患者体内的癌细胞在反复服用药物后会产生抗药性；然后这些细胞不会被药物杀死，癌症也无法治愈。该研究项目旨在开发新的铂类抗癌药物，其作用方式与顺铂不同。如果铂类药物在进入癌细胞之前是无害的，然后只在肿瘤组织中被激活，这将极大地减少不必要的副作用，允许治疗对顺铂耐药的肿瘤，也可能允许治疗更广泛的癌症。我们提出的战略是一种新战略。我们将使用含铂的化合物和4+电荷。这些化合物不会对细胞产生反应，必须在杀死细胞之前转化为铂2+化合物。我们将使用定向的细小光束在癌细胞中激活它们，而不是在其他正常细胞中激活它们。为了给癌细胞带来更大的选择性，我们将用癌细胞比正常细胞(多肽、抗体)有选择地识别和吸收的标记来标记化合物。我们的战略将引入杀死癌细胞的新机制，这正是规避当前铂类药物耐药性所需的。我们令人鼓舞的初步数据表明，我们可以制造比顺铂本身更有效的化合物。令人兴奋的是，使用新的光学设备来激活我们的化合物的前景。这些光子晶体光纤可以在远距离传输非常精确的颜色的激光。这将导致更可控的激活，并可能到达人体内部目前无法照射的部位。这项研究项目旨在设计(在计算机预测的帮助下)、合成和表征新的可光激活的铂配合物。这些络合物的合成预计将是具有挑战性的，因为它们必须在不直接暴露于光的情况下制成。将对它们进行稳定性、溶解性和细胞摄取等特性测试，并确定它们的光活性。将对这些新配合物的光谱性质进行广泛的研究，并将大量利用核磁共振技术来了解这些配合物在光活化后发生化学变化的机制。我们还将使用标准化学技术，如质谱学、紫外可见光谱和X射线结晶学来全面表征我们的新化合物。还将研究铂络合物在细胞内的分布、DNA和蛋白质的选择性铂化以及络合物对不同类型癌细胞的活性。由于较长波长的光(例如红光)比较短波长的光(例如蓝光)更深入地穿透组织；因此，设计通过照射这些较长波长的光来激活的化合物将是一个挑战。这可能是通过使用能够同时吸收两个光子的化合物，或者通过仔细设计络合物上的配体来实现的。

People suffering from cancer are typically treated with either surgery, radiotherapy or chemotherapy. Currently the world's most widely used chemotherapeutic drugs are platinum-based; a leading example is cisplatin, a compound containing platinum with a 2+ charge. It is generally accepted that the anticancer activity of cisplatin and other closely related platinum compounds arises from their ability to damage DNA in cancer cells leading to cell death.The existing platinum drugs are highly toxic to both healthy and cancerous cells in the body. As a result, serious side-effects of treatment are a frequent and serious problem in chemotherapy. These side-effects can be so severe that treatment has to be stopped, leading to treatment failure and ultimately to the death of the patient. In some cases the cancerous cells in the bodies of patients become resistant after repeated doses of the drugs; then the cells are not killed by the drug and the cancer is not cured. This research project aims to develop new platinum anticancer drugs which work in a different way to cisplatin. If the platinum drug could be made harmless until it enters the cancer cells and then be activated only in the tumour tissue, this would greatly reduce unwanted side-effects, allow treatment of cisplatin-resistant tumours, and may also allow treatment of a wider range of cancers. Our proposed strategy is a new one. We will use compounds containing platinum with a 4+ charge. These will not be reactive towards cells and must be converted to platinum 2+ compounds before they kill cells. We will activate them specifically in cancer and not in other normal cells using a directed fine beam of light. To introduce even greater selectivity for cancer cells, we will tag the compounds with labels that are selectively recognised and taken up by cancer cells in preference to normal cells (peptides, antibodies). Our strategy will introduce new mechanisms for killing cancer cells, just what is needed to circumvent resistance to current platinum drugs. Our encouraging preliminary data suggest that we can make compounds that are more effective than cisplatin itself.Exciting is the prospect of using new optical devices to activate our compounds. These photonic crystal fibres can deliver laser light of a very precise colour over long distances. This should lead to more controllable activation and perhaps the prospect of reaching internal sites of the human body which are currently inaccessible to irradiation.This research project aims to design (with the help of computer predictions), synthesise and characterise new photoactivatable platinum complexes. The synthesis of these complexes is anticipated to be challenging since they must be made without direct exposure to light. They will be tested for features such as stability, solubility and cell uptake, and their photoactive properties determined. Extensive investigation into the spectroscopic properties of these new complexes will be carried out and much use will be made of nuclear magnetic resonance techniques to understand the mechanisms through which these complexes change chemically following activation by light. We will also use standard chemical techniques such as mass spectrometry, UV-Vis spectroscopy, and X-ray crystallography to fully characterise our new compounds. The distribution of the platinum complexes within cells and the selective platination of DNA and proteins and activity of the complexes towards different types of cancer cells will also be investigated.Since longer wavelengths of light (e.g. red light) penetrate tissue more deeply than shorter (e.g. blue light); a challenge will be to design compounds which are activated by irradiation of light with these longer wavelengths. This may be possible through using compounds which are able to absorb two photons at once, or by careful design of the ligands on the complexes.