Molecular Cancer Therapeutics Activated By Cerenkov Radiation

点击翻译按钮获取中文摘要

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.