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

癌症患者通常通过手术、放疗或化疗进行治疗。目前世界上应用最广泛的化疗药物是以铂为基础的；一个典型的例子是顺铂，一种含2+电荷铂的化合物。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源于它们破坏癌细胞DNA导致细胞死亡的能力。现有的铂类药物对人体内的健康细胞和癌细胞都有很高的毒性。因此，严重的治疗副作用是化疗中一个常见而严重的问题。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；然后细胞不会被药物杀死，癌症也不会被治愈。该研究项目旨在开发新的铂抗癌药物，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，这将大大减少不必要的副作用，允许治疗顺铂耐药的肿瘤，也可能允许治疗更广泛的癌症。我们提出的策略是新的。我们将使用含4+电荷铂的化合物。它们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。我们将在癌症中激活它们，而不是在其他正常细胞中使用定向细光束。为了给癌细胞引入更大的选择性，我们将给化合物贴上标签，这些标签被癌细胞选择性地识别并优先于正常细胞（肽、抗体）。我们的策略将引入杀死癌细胞的新机制，这正是克服当前铂类药物耐药性所需要的。我们令人鼓舞的初步数据表明，我们可以制造出比顺铂本身更有效的化合物。使用新的光学设备来激活我们的化合物的前景令人兴奋。这些光子晶体光纤可以长距离传输颜色非常精确的激光。这将导致更可控的激活，并可能达到目前无法照射的人体内部部位。该研究项目旨在设计（借助计算机预测）、合成和表征新的光活化铂配合物。这些配合物的合成预计是具有挑战性的，因为它们必须在没有直接暴露于光的情况下制造。将测试它们的稳定性、溶解度和细胞摄取等特性，并确定它们的光活性。将对这些新配合物的光谱特性进行广泛的研究，并将大量使用核磁共振技术来了解这些配合物在光激活后发生化学变化的机制。我们还将使用标准的化学技术，如质谱法、紫外可见光谱法和x射线晶体学来全面表征我们的新化合物。铂配合物在细胞内的分布、DNA和蛋白质的选择性铂化以及复合物对不同类型癌细胞的活性也将被研究。因为波长较长的光（如红光）比波长较短的光（如蓝光）更能穿透组织；一个挑战将是设计出能被这些波长较长的光照射激活的化合物。这可以通过使用能够同时吸收两个光子的化合物，或者通过仔细设计复合物上的配体来实现。

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.