Molecular Cancer Therapeutics Activated By Cerenkov Radiation

背景与目的光动力疗法(PDT)是一种利用光选择性地破坏癌细胞的癌症治疗方法。一种光敏化合物，光敏剂(PS)，通过暴露在特定波长的光中而被给予和激活。这会引发化学反应，产生细胞毒性活性氧物种(ROS)，导致癌细胞死亡。目前，光动力疗法仅限于浅表性癌症或可通过内窥镜检查的癌症，因为它需要外光源。一种内部光源可以克服这些限制，并允许靶向更深的肿瘤。一种可能的内部光源是切伦科夫辐射(CR)；当粒子在组织中的传播速度快于光速时，某些放射性同位素产生的光。其中一些放射性同位素已经用于核医学，并可以通过实施纳米材料来调整，以通过它们产生的CR激活PSS。这项研究的目标是开发和批判性地评价切伦科夫辐射激活的新型分子癌症疗法，目的是扩大光动力疗法的范围。这不仅有可能促进各种癌症的治疗，而且还将为核医学和纳米材料领域提供新颖和有洞察力的信息。该项目的总体目标将分为以下目标：1)新型可光激活化合物和放射性标记癌症靶向载体的合成和表征2)放射性标记靶向载体和可光激活化合物的组合以量化和分类ROS产生3)研究与合成化合物在临床前细胞研究中成功治疗应用相关的参数。可光激活和放射性同位素之间的紧密空间接近将确保CR和随后的ROS产生将被限制在癌细胞中。此外，还将检查与成功应用这些新型光可激活物质和癌症靶向载体相关的参数，例如治疗剂量、所需的放射性水平以及放射性对化合物半衰期和β粒子发射的影响。方法1)新型可光激活化合物和放射性标记抗癌载体的合成和表征o将纳米材料与PSS连接以合成新的光活性物质。利用标准生化技术对抗癌载体进行放射性标记化合物的表征2)结合放射性标记抗癌载体和可光激活化合物来量化和分类ROS的产生o开发和优化一种分析方法，以确定产生最大ROS的最佳条件。o将实施对照组，以验证所产生的ROS是共孵育的结果，而不是单独的试剂。o ROS生产的量化和分类3)与合成的化合物在治疗中的成功应用相关的参数的研究临床前细胞研究o将可光激活和放射性标记的癌症靶向载体应用于人类癌细胞，以确定疗效。o将化合物应用于几种癌细胞系，以确定观察到的治疗效果的选择性。o将对化合物进行优化，以确定治疗剂量。也有机会研究这种新颖的光动力疗法对更广泛种类的癌细胞株的影响。

BACKGROUND & AIMSPhotodynamic therapy (PDT) is a cancer therapy which utilises light to selectively destroy cancer cells. A light sensitive compound, photosensitiser (PS), is administered and activated through exposure to light of a specific wavelength. This triggers a chemical reaction which produces cytotoxic reactive oxygen species (ROS) and leads to cancer cell death. At present PDT is limited to superficial cancers or cancers accessible by endoscope, as it requires an external light source. An internal source of light could overcome these limitations and allow deeper tumours to be targeted. One possible internal light source is Cerenkov radiation (CR); light generated from certain radioisotopes when particles travel faster than the speed of light in tissue. Several of these radioisotopes are already used in nuclear medicine and could be adapted through the implementation of nanomaterials to activate PSs through the CR they produce. The goal of this research project is to develop and critically evaluate novel molecular cancer therapeutics that are activated by Cerenkov radiation, with the aim of expanding the scope of PDT. Not only does this have the potential to contribute to advancing the treatment of various cancers, but will also provide novel and insightful information to the fields of nuclear medicine and nanomaterials. The overarching aim of the project will be split into the following objectives:1) Synthesis and characterisation of novel photoactivatable compounds and radiolabelled cancer-targeting vectors2) Combination of radiolabelled targeting vectors and photoactivatable compounds to quantify and classify ROS production3) Investigation of the parameters associated with the successful therapeutic application of the synthesised compounds in preclinical cell studies.The close spatial proximity between photoactivatable and radioisotope will ensure that the CR and subsequent ROS production will be confined to cancer cells. Furthermore, the parameters associated with the successful application of these novel photoactivatables and cancer-targeting vectors, e.g. therapeutic dosing, required level of radioactivity and impact of radioactivity on compound half-life and beta particle emission will be examined. METHODOLOGY1) Synthesis and characterisation of novel photoactivatable compounds and radiolabelled cancer-targeting vectorso Conjugation of nanomaterials to PSs to synthesise novel photoactivatables o Radiolabelling of cancer-targeting vectorso Characterisation of compounds using standard biochemical techniques2) Combination of radiolabelled cancer-targeting vectors and photoactivatable compounds to quantify and classify ROS production o Development and optimisation of an assay to determine optimal conditions for greatest ROS production.o Control groups will be implemented to verify that resulting ROS is produced as a result of co-incubation rather than a reagent alone.o Quantification and classification of ROS produced3) Investigation of the parameters associated with the successful therapeutic application of the synthesised compounds in preclinical cell studies.o Application of photoactivatable and radiolabelled cancer-targeting vector to human cancer cells to determine efficacy.o Application of compounds in several cancer cell lines to determine selectivity of the observed therapeutic effect.o Optimisation of compounds will be carried out to determine therapeutic dosing. There is also scope to investigate the impact of this novel PDT approach across a wider variety of cancer cell lines.