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

铂前药递送的光激活策略；

• 批准号: EP/G006792/1
• 负责人: Peter Sadler
• 金额: $ 53.27万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FG006792%2F1
• 关键词: Photoactivation; strategies; delivery; platinum; prodrugs

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.

患有癌症的人通常用手术、放疗或化疗来治疗。目前，世界上最广泛使用的化疗药物是铂基的;一个主要的例子是顺铂，一种含有2+电荷的铂的化合物。一般认为顺铂和其他密切相关的铂类化合物的抗癌活性源于它们能够破坏癌细胞中的DNA，导致细胞死亡。现有的铂类药物对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常见且严重的问题。这些副作用可能非常严重，以至于不得不停止治疗，导致治疗失败并最终导致患者死亡。在某些情况下，患者体内的癌细胞在重复剂量的药物后变得有抵抗力;然后细胞不会被药物杀死，癌症不会治愈。该研究项目旨在开发新的铂类抗癌药物，其工作方式与顺铂不同。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，允许治疗顺铂耐药肿瘤，也可能允许治疗更广泛的癌症。我们提出的战略是一个新的战略。我们将使用含铂的化合物，带4+电荷。它们对细胞没有反应性，在杀死细胞之前必须转化为铂2+化合物。我们将使用定向的细光束在癌症中特异性地激活它们，而不是在其他正常细胞中。为了对癌细胞引入更大的选择性，我们将用标记物标记化合物，这些标记物优先于正常细胞（肽，抗体）被癌细胞选择性识别和吸收。我们的策略将引入杀死癌细胞的新机制，这正是避免对当前铂类药物产生耐药性所需的。我们令人鼓舞的初步数据表明，我们可以制造出比顺铂本身更有效的化合物。令人兴奋的是使用新的光学器件来激活我们的化合物的前景。这些光子晶体光纤可以在长距离内提供非常精确颜色的激光。这将导致更可控的活化，并可能导致到达目前无法照射的人体内部部位的前景。本研究项目旨在设计（在计算机预测的帮助下），合成和合成新的可光活化的铂络合物。预计这些复合物的合成将具有挑战性，因为它们必须在不直接暴露于光的情况下制备。它们将被测试的功能，如稳定性，溶解性和细胞吸收，并确定其光活性特性。将对这些新复合物的光谱性质进行广泛的研究，并将大量使用核磁共振技术来了解这些复合物在光活化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，紫外可见光谱和X射线晶体学，以充分验证我们的新化合物。铂配合物在细胞内的分布以及DNA和蛋白质的选择性铂化以及配合物对不同类型癌细胞的活性也将被研究。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;一个挑战将是设计通过这些较长波长的光照射而激活的化合物。这可以通过使用能够同时吸收两个光子的化合物，或者通过仔细设计络合物上的配体来实现。

项目成果

Proton Sponge Phosphanes: Reversibly Chargeable Ligands for ESI-MS Analysis

质子海绵磷烷：用于 ESI-MS 分析的可逆带电配体

• DOI: 10.1002/ejic.201100820
• 发表时间: 2011
• 期刊: European Journal of Inorganic Chemistry
• 影响因子: 2.3
• 作者: Farrer N

Platinum(iv) azido complexes undergo copper-free click reactions with alkynes.

• DOI: 10.1039/c7dt04183g
• 发表时间: 2018-08-07
• 期刊: Dalton transactions (Cambridge, England : 2003)
• 作者: Farrer NJ ;Sharma G ;Sayers R ;Shaili E ;Sadler PJ
• 通讯作者: Sadler PJ

A Potent Trans -Diimine Platinum Anticancer Complex Photoactivated by Visible Light

可见光光激活的有效反式二亚胺铂抗癌复合物

• DOI: 10.1002/ange.201003399
• 发表时间: 2010
• 期刊: Angewandte Chemie
• 作者: Farrer N

Fabrication of crystals from single metal atoms.

• DOI: 10.1038/ncomms4851
• 发表时间: 2014-05-27
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Barry, Nicolas P. E.;Pitto-Barry, Anais;Sanchez, Ana M.;Dove, Andrew P.;Procter, Richard J.;Soldevila-Barreda, Joan J.;Kirby, Nigel;Hands-Portman, Ian;Smith, Corinne J.;O'Reilly, Rachel K.;Beanland, Richard;Sadler, Peter J.
• 通讯作者: Sadler, Peter J.