Doped Titania for Cancer Therapy

自20世纪50年代以来，癌症死亡率几乎没有变化，而心脏病和中风的死亡率则大幅下降。手术治疗通常受到肿瘤的物理接触的限制，并且由于切除主要肿瘤后残留的恶性细胞的风险很大，因此通常通过其他治疗来增强手术治疗。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耐药性，目前放射治疗的疗效受到对健康组织的损害和相关副作用的限制。纳米颗粒提供了治疗和诊断物质在体内更好的渗透，与传统疗法相比风险更低。我们设计了一种基于半导体二氧化钛（二氧化钛）的系统，二氧化钛具有高的光活性，通过吸收光子将价带电子激发到导带，产生活性氧（ROS）。因此，二氧化钛纳米颗粒，特别是锐钛矿晶体相的纳米颗粒可用于紫外光刺激下的ROS生产光动力治疗（PDT）。光线的穿透深度限制了这种技术只能用于皮肤上或皮肤下的肿瘤。我们已经制造了纳米粒子，这些纳米粒子的设计是为了优化二氧化钛与x射线的相互作用，x射线是一种更深入的能量源。纳米粒子被掺杂了一些元素，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60keV为中心。这使得纳米粒子ROS治疗可以扩展到深层组织和大肿瘤，而这些是光动力疗法无法治疗的。掺杂的TiO2纳米颗粒被二氧化硅包覆以提高生物相容性，并已被证明在单层培养中被动进入细胞。在没有照射的情况下，细胞活力没有显著下降，说明颗粒的生物相容性。在体外实验中，已证明x射线激发纳米颗粒可产生活性氧，将含有纳米颗粒的细胞暴露于x射线下可导致二氧化钛产生破坏细胞的活性氧。临床前试验已经测试了颗粒对肺非小细胞癌异种移植物的疗效。在放射治疗前注射纳米粒子的肿瘤大小是单独放射治疗的肿瘤大小的一半。目前这项研究的目的是提高纳米颗粒的功效，并扩大合成规模，以生产具有明确供应链的商业上可行的产品。采用火焰喷雾热解法合成颗粒；这是Johnson Matthey开发的一种技术。在实验室-实验台上制造的纳米颗粒是多晶的，大约65纳米。将尝试生产单晶纳米粒子，这种纳米粒子不太可能遭受粒子内部的能量损失，从而以更高的效率产生活性氧。还将评估稀土离子的分布，并开发使离子分布高度均匀的方法。此外，将研究稀土掺杂剂的组合，并修改纳米颗粒直径，因为生产更小的颗粒可能允许进入原子核，从而提高效率。纳米颗粒的放大将确保具有均匀生物相容性涂层和颗粒尺寸控制的均匀掺杂纳米颗粒的可重复性生产。这将使技术转化为制药，并减少到达诊所所需的时间。

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.