Doped Titania for Cancer Therapy

用于癌症治疗的掺杂二氧化钛

• 批准号: EP/K502376/1
• 负责人: Ian Thompson
• 金额: $ 27.97万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FK502376%2F1
• 关键词: Doped; Titania; Cancer; Therapy

Rates of cancer mortality have remained virtually unchanged since the 1950's while death rates from heart disease and stroke have dropped significantly. Surgical treatments are often limited by physical access to the tumour, and are usually augmented by other therapies due to the large risk associated with remaining malignant cells after removal of the main tumour. Chemotherapeutic approaches have extremely unpleasant side effects and cancerous cells often become resistantto the drugs and at present the efficacy of radiation therapy is limited by damage to healthy tissue and associated sideeffects. Nanoparticulates provide a better penetration of therapeutic and diagnostic substances within the body, at areduced risk in comparison to conventional therapies.We have designed a system based on the semiconductor, titanium dioxide (titania), which exhibits a high photoactivity which generates Reactive Oxygen Species (ROS) upon excitation of valence band electrons to the conduction band by absorption of photons. As such titania nanoparticles, especially those of the anatase crystallographic phase may be used for ultraviolet light stimulated ROS production for photodynamic therapy (PDT). The penetration depth of light limits this technique to tumours on, or just under, the skin. We have generated nanoparticles which have been designed to optimize the interaction of the titania with X-rays, a more deeply penetrating energy source. The nanoparticles have been doped with elements which have been selected to absorb the maximum energy from a typical medical X-ray with a broad emission spectrum centred around 60keV. This allows the nanoparticle ROS treatment to be extended to deep tissue and large tumours which could not be treated by photodynamic therapy.The doped TiO2 nanoparticles have been coated with silica to improve biocompatibility and have been shown to passively enter cells in monolayer culture. In the absence of irradiation there is no significant decrease in cell viability illustrating thebio-compatibility of the particles. Excitation of the nanoparticles by X-rays has been demonstrated in vitro to generate ROSand exposure of the cells containing nanoparticles to X-ray results in generation of cell-damaging ROS from the titania.Preclinical trials have tested the efficacy of the particles against xenografts of lung non-small cell carcinoma. Tumours which were injected with the nanoparticles prior to irradiation were shown to be half the size of those treated with radiotherapy alone.The aim of the current study is to improve the efficacy of the nanoparticles and to scale-up the synthesis to produce acommercially viable product with a clear supply chain. The particles will be synthesized using flame spray pyrolysis; a technique developed by Johnson Matthey. The nanoparticles made at lab-bench scale are polycrystalline and approximately 65nm. Attempts will be made to produce single crystal nanoparticles which are less likely to suffer losses of energy within the particle and therefore produce ROS with greater efficiency. The distribution of rare earth ions will also be assessed and methods developed to produce a highly uniform distribution of ions. Furthermore, the combination of rare earth dopants will be investigated and the nanoparticulate diameter modified since the production of smaller particles may allow access in to the nucleus with resulting increases in efficacy.The scale-up of the nanoparticles will ensure the reproducible production of a homogeneously doped nanoparticle with auniform biocompatible coating and particulate size control. This will enable translation of the technology to Pharma and reduce the time taken to reach the clinic.

自20世纪50年代以来，癌症死亡率几乎保持不变，而心脏病和中风的死亡率则显著下降。手术治疗通常受到物理接近肿瘤的限制，并且通常通过其他疗法来增强，因为在切除主要肿瘤后与剩余恶性细胞相关的风险很大。化疗方法有非常令人不快的副作用，癌细胞经常对药物产生抗药性，目前放射治疗的疗效受到健康组织损伤和相关副作用的限制。纳米颗粒提供了一个更好的渗透体内的治疗和诊断物质，在降低风险相比，传统therapy.We设计了一个系统的基础上的半导体，二氧化钛（二氧化钛），它表现出高的光活性，产生活性氧物种（ROS）时，激发价带电子的导带吸收光子。因此，二氧化钛纳米颗粒，特别是那些具有结晶相的二氧化钛纳米颗粒可以用于光动力疗法（PDT）的紫外光刺激的ROS产生。光的穿透深度限制了这项技术对皮肤上或皮肤下的肿瘤的应用。我们已经产生了纳米颗粒，这些纳米颗粒被设计用于优化二氧化钛与X射线的相互作用，X射线是一种更深入的能量来源。纳米颗粒掺杂了一些元素，这些元素被选择用来吸收典型的医用X射线的最大能量，其发射光谱以60 keV为中心。这使得纳米颗粒活性氧治疗扩展到深层组织和大肿瘤，不能通过光动力疗法治疗。掺杂的二氧化钛纳米颗粒已被二氧化硅包覆，以提高生物相容性，并已被证明是被动进入单层培养细胞。在没有辐射的情况下，细胞活力没有显著降低，说明颗粒的生物相容性。在体外实验中，X射线对纳米粒子的激发可以产生ROS，而将含有纳米粒子的细胞暴露于X射线中，则会导致二氧化钛产生细胞损伤性ROS。临床前试验已经测试了纳米粒子对肺非小细胞癌异种移植物的疗效。在放疗前注射纳米粒子的肿瘤大小是单纯放疗的一半。目前研究的目的是提高纳米粒子的疗效，并扩大合成规模，以生产具有明确供应链的商业可行产品。这些颗粒将使用火焰喷雾热解合成;这是约翰逊万丰公司开发的一种技术。实验室规模制备的纳米颗粒是多晶的，约65 nm。将尝试生产单晶纳米颗粒，其不太可能遭受颗粒内的能量损失，因此以更高的效率产生ROS。还将评估稀土离子的分布，并开发产生高度均匀的离子分布的方法。此外，将研究稀土掺杂剂的组合，并修改纳米颗粒的直径，因为更小颗粒的产生可以允许进入核，从而增加功效。纳米颗粒的规模将确保可重复地生产具有均匀生物相容性涂层和粒度控制的均匀掺杂的纳米颗粒。这将使该技术能够转化为制药，并减少到达诊所所需的时间。

项目成果

Direct quantification of rare earth doped titania nanoparticles in individual human cells.

• DOI: 10.1088/0957-4484/27/28/285103
• 发表时间: 2016-07-15
• 期刊: Nanotechnology
• 影响因子: 3.5
• 作者: Jeynes JC;Jeynes C;Palitsin V;Townley HE
• 通讯作者: Townley HE