Development of a laboratory XANES system for the analysis of metals in tissue for cancer research and chemotherapy drug development

Project Summary/Abstract Due to recent major advances in understanding platinum chemotherapy drugs, which are used to treat an estimated 50-70% of cancer patients, a new frontier of metal-based anti-cancer drugs is emerging. Many promising novel metal-based drugs (e.g. Ru, Co, Au, Sn, etc.) and several new formulations of platinum prodrugs are now being investigated as replacements for conventional platinum therapies. These alternatives hold significant potential for overcoming the well-known disadvantages of current Pt-based chemotherapy, including the development of patient resistance and toxicity to non-tumorous tissue, including hair fall-out and damage to vital organs such as the kidney and brain. X-ray absorption near edge spectroscopy (XANES) is a powerful chemical analysis technique used to investigate the local atomic structure of these drugs. The electron structure of these new metal-based chemotherapy drugs is critical to their performance, including: intracellular activation in tumorous cells, transportation to the tumor, activity, and lifetime of the drug. However, these drugs exist in low concentrations in biological tissue and currently, XANES analysis requires researchers to travel to synchrotron light sources, which generate intense beams of x-rays but of which there are just a handful, as they cost $1B to build and ~$100M/year to operate. Synchrotron XANES systems are often extremely oversubscribed, with up to a 6-9-month application process and some beamlines limiting groups to a single run per year, all of which significantly limit access and the rate of research progress. We propose to develop a laboratory XANES system that utilizes a combination of breakthrough innovations to bring access to the capabilities of synchrotron-based XANES to laboratories worldwide. The system is expected to critically enable research in novel metal-based anti-cancer drugs, in addition to emerging research on the role of trace metal chemistry in pathologies including cancer. The proposed Phase I 6-month project is a proof-of-principle demonstration of the advantages stemming from the x-ray optic and geometry in a breadboard prototype. The proposed Phase II 24-month project is to develop a complete prototype.Project Narrative This project proposes to develop a laboratory x-ray absorption near edge spectroscopy (XANES) system optimized to address major questions in novel anti-cancer metal-based chemotherapy. XANES enables understanding of the local atomic state of elements, a capability that is not easily accessible to the broader research community because it currently requires travel to one of the handful of synchrotron facilities located around the world that, due to oversubscription, provide only limited access. Bringing XANES to laboratories would not only have an immense impact on significantly accelerating metal-based anti-cancer drug development, but is also expected play a major role in emerging research on the role of metals in critical biological functions and in pathologies such as neurodegenerative diseases and cancer.