Molecular Cancer Therapeutics Activated By Cerenkov Radiation

切伦科夫辐射激活的分子癌症治疗

• 批准号: 2440410
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2440410
• 关键词: Molecular; Cancer; Therapeutics; Activated; Cerenkov

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.

背景与目的光动力疗法（photodynamic therapy，PDT）是一种利用光选择性地破坏癌细胞的癌症治疗方法.光敏化合物光敏剂（PS）通过暴露于特定波长的光来施用和激活。这会引发化学反应，产生细胞毒性活性氧（ROS）并导致癌细胞死亡。目前，PDT仅限于浅表癌或内窥镜可触及的癌，因为它需要外部光源。内部光源可以克服这些限制，并允许更深的肿瘤被靶向。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超过光速时，某些放射性同位素产生的光。这些放射性同位素中的一些已经用于核医学，并且可以通过实施纳米材料来进行调整，以通过它们产生的CR激活PS。该研究项目的目标是开发和严格评估由切伦科夫辐射激活的新型分子癌症疗法，旨在扩大PDT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见地的信息。该项目的总体目标将分为以下目标：1）新型光活化化合物和放射性标记的癌症靶向载体的合成和表征2）放射性标记的靶向载体和光活化化合物的组合，以定量和分类ROS的产生3）与合成化合物在临床前细胞研究中的成功治疗应用相关的参数的调查。光活化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产生将局限于癌细胞。此外，将检查与这些新型光活化剂和癌症靶向载体的成功应用相关的参数，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）新型光活化化合物和放射性标记的癌症靶向载体的合成和表征将纳米材料与PS缀合以合成新型光活化物靶向载体和光活化化合物，以定量和分类ROS产生。o将实施对照组以验证所产生的ROS是作为共孵育而不是单独试剂的结果产生的。o所产生的ROS的定量和分类3）在临床前细胞研究中与合成化合物的成功治疗应用相关的参数的研究。o将化合物应用于几种癌细胞系中以确定观察到的治疗效果的选择性。o将进行化合物的优化以确定治疗剂量。还有研究这种新型PDT方法在更广泛的癌细胞系中的影响的范围。