Price Research Group Summary
The Price research group is focused on multidisciplinary research, spanning the fields of chemistry, cancer and disease biology, radiochemistry, molecular imaging, nuclear medicine, and clinical translation. The overarching goals of the Price research group are to improve early detection of a variety of cancers and multi-drug resistant bacterial infections using molecular imaging techniques such as near-infrared and positron emission tomography (PET) imaging, and then to treat them using “smart drugs” that harness therapeutic radioactive metals. Once injected, these radioactive “smart drugs” can selectively seek out cancerous cells or bacteria in the body by binding selectively to diseased cells that present specific receptors or biological processes. These radioactive drugs have applications in both human and animal health, and in collaboration with the Royal University Hospital and the Western College of Veterinary Medicine at the U of S, they could have a direct impact on the health of animals and the Canadian population.
Dr. Price’s interdisciplinary research program and CRC in Radiochemistry at the University of Saskatchewan is working to create new chemical reagents as tools for the creation of next-generation diagnostics and treatments of diseases such as cancer. The Price lab is creating a library of modular and versatile chemical tools that are being deployed to improve many aspects of modern and clinically used radiopharmaceutical drugs to solve real-world problems plaguing molecular imaging and radionuclide therapy of diseases. These chemical tools are being painstakingly designed and synthesized to be modular, much like LEGO, to provide maximum value and utility.
Molecular Imaging Background
Positron emission tomography (PET) has emerged as the most powerful molecular imaging technique available because it can non-invasively monitor biochemical reactions inside living people. The body is effectively “transparent” to nuclear imaging techniques. Indeed, PET is a valuable research tool used to evaluate disease promoting biochemical processes, evaluate response to drugs, and diagnose diseases such as cancer, heart-conditions, and Alzheimer’s. The U of S has recently built advanced labs dedicated to the discovery of new compounds as potential PET radiotracers and constructed a state-of-the-art cyclotron facility that produces PET isotopes.
The fields of nuclear medicine and molecular imaging rely upon radioactive drugs for imaging and treating a number of diseases. Molecular imaging drugs contain combinations of “reporting” groups that allow for images to be obtained, including radioactive isotopes (e.g. 18F/89Zr for positron emission tomography, PET, or 99mTc/111In for single photon emission computed tomography, SPECT), fluorescent or near-infrared dyes (e.g. IRdye800 for optical imaging), and magnetic resonance contrast agents (e.g. gadolinium for magnetic resonance imaging, MRI). Radioactive isotopes can be incorporated into various types of molecules, including small-molecule drugs, peptide and antibody proteins, and nanoparticles. Radioactive isotopes are attached to these biologically active molecules (also referred to as targeting vectors, biomolecules, targeting drugs), which act as in vivo delivery devices of the attached dyes/radioactive isotopes to provide the biological activity and targeted delivery (e.g., selectively to cancer cells, bacteria, brain receptors) (Figure 1).
Many new radiopharmaceuticals are based on proteins, usually in the form of antibodies, peptides, or protein domains (nanoparticles can possess similar chemistry and properties as well). To create these, one must assemble several key components which each serve specific functions, and each can be swapped/optimized through synthetic organic and bioconjugation chemistry. These components include 1) a chelator to quickly bind and stably hold radioactive metal ions to enable PET imaging or radionuclide therapy, 2) a linker to provide physical space and/or other chemical structures between the chelator and the bioconjugation reagent, typically to give the targeting vector ample space to engage with its receptor “dock” or to improve water solubility, or with the Price lab linkers to even provide new functions, 3) the bioconjugation reagent/moiety to quickly and selectively provide a strong chemical linkage between the chelator-linker (or dye/drug-linker) and the protein, and 4) the targeting vector such as a peptide or antibody to provide selective receptor-based targeting to many different diseases and biological markers.
Core projects in the Price lab have been designed to solve or improve many of the practical issues and deficiencies of modern radiopharmaceuticals via the first three of these four key components: the chelators, functional linkers, and the bioconjugation reagents. These deficiencies have been identified by Dr. Price over his career through the evaluation of academic and clinical data on modern molecular imaging and radionuclide therapy agents. From observing and studying the problems with current radiopharmaceuticals, Dr. Price is trying to identify the chemical origins of these problems and utilize his expertise in the USask Chemistry department to solve them. Dr. Price’s lab is creating new chemical tools which are modular and are designed with unique structural properties which have been hypothesized to improve properties of radiopharmaceuticals in the key areas outlined above.
To produce a PET image, a tiny amount of a PET radiotracer (a molecular probe labeled with a radioactive isotope) is injected into the patient who is then placed into a PET camera. Radioactive isotopes attached to drugs allow researchers and clinicians to quantitatively “trace” their location (hence being called “tracers” or “radiotracers”) throughout their time in the body. Molecular imaging allows for the non-invasive imaging and quantification of cellular and metabolic events anywhere in the body (including all tumors, metastasis, cancer cells) in real time, by quantifying how much radioactive isotope accumulates in different tissues and cells using special cameras (e.g. PET, SPECT) (Figure 2). This is in contrast to traditional diagnostic techniques (radiographs, computed tomography(CT)) which provide basic anatomical features, or assays (e.g. blood tests, biopsy) that provide a static and limited sampling of biological activity in a small cross section of tissue (e.g. small core of a tumor).
Several pressing issues in this field revolve around the challenging chemistry required to make suitable chelators and linkers that can be attached to drug vectors (e.g. peptides, antibodies) without negatively altering their properties (e.g. reduced water solubility, increased “sticking” in excretory organs). Chelators must tightly hold radiometals against all competition for binding in vivo (e.g., abundant blood proteins such as transferrin and albumin).2,3 The radiometal is effectively chemically tethered to a drug using a chelator, and if it is released from the grasp of the chelator in vivo, the “free” radiometal will be partially excreted (e.g., urine, feces) and partly taken up by other tissues, such as the bones, liver, and kidneys, causing damage to the patient (Figure 3).1-3 The major hurdles in the study of new chelators is their challenging synthesis, protection chemistry (abundance of polar and charged functional groups), and purification. Another challenge is their solubility, as the addition of linker groups (spacers between the chelator and drug) and dyes can drastically change the polarity of the radiopharmaceutical, which subsequently changes the biological distribution.
Project Descriptions: New Chelators and Modular Linkers for Enhancing PET Imaging and Therapy of Cancer and Bacterial Infections – Inverting Traditional Radiopharmaceutical Design: The Price Group is perusing a diverse set of research projects and goals in the fields of Chemistry, Radiochemistry, and Molecular Imaging. Instead of creating new targeting vectors for disease (e.g. new peptides, antibodies, drugs), the Price group is focused on creating new chemical technologies that can modulate the properties of existing agents. These projects include but are not limited to the synthesis and study of new chelators for binding radioactive metals, new modular linker groups to improve solubility and minimize background uptake of peptide-based radiopharmaceuticals, linkers to improve uptake and retention of radiopharmaceuticals in tumors, radiopharmaceuticals for imaging and treating multi-drug resistant bacterial infections, and radioactive antibodies for imaging and treating cancer. A few of these projects will be described briefly.
1. New Chelators and Modular Linkers for Improved Harnessing of Radiometals: The method that radiometals are incorporated into radiopharmaceuticals is by utilizing selective chelators (molecules that have a number of binding groups that essentially “grab” the metal and hold it tightly) that each have a preference for what type of metal ion they will grab. The currently used 89Zr chelator “DFO” is insufficient, as substantial uptake of 89Zr is observed in bone.4 The Price lab is creating new radiometal chelators that can be broadly applied to any targeting vector, which means a large potential impact on the field of molecular imaging. In addition to new chelators, new modular linker groups will be synthesized to help improve solubility of chelators and chelator-bioconjugates, and will allow for a variety of conjugation chemistry to be utilized (Figure 4). Once synthesized, testing of these new chelators will include radiolabeling, in vitro radioactive assays (e.g., blood serum, hydroxyapatite), and in vivo biodistribution and PET imaging studies in mice. This field of study links in with antibody imaging, as chelators and radiometals such as 89Zr are commonly used for PET imaging with antibodies. The Price Group has established a collaboration with Quest PharmaTech in Alberta to obtain a clinically used antibody for treating ovarian and lung cancer. The Price Group will utilize their new and improved bifunctional chelators for 89Zr to transform Quest PharmaTech’s antibody into a dual-modal optical-PET imaging agent, with the goal of improving patient selection for therapy and overall clinical outcomes.
2. Improving Peptide-based Imaging and Therapy: Peptides are a very popular class of targeting vectors used for molecular imaging, as high affinity peptides can be produced for many targets present in vivo. Most molecular imaging probes, such as peptides, have a large amount of non-specific binding and retention in non-target tissues (e.g. muscle, fat, skin, excretory organs) in vivo. Modular linker groups with a variety of charges, functional groups, and spacers will be investigated for a simple and efficient way to change the polarity and biodistribution of any small drug/peptide based radiometal conjugate. An additional class of novel linker groups will contain functional groups with the goal of improving tumor retention. This work will involve both cancer and bacteria targeting peptides.
3. Selective Targeting of Bacterial Infections: Radiopharmaceutical agents have been used for imaging infection in humans, including 111In-oxinate- or 99mTc-HMPAO-labeled leukocytes (white blood cells), 67Ga-citrate, 99mTc-ciprofloxacin, and 18F-FDG; however, these methods cannot differentiate between infection and inflammation.5-8 In general, few PET imaging agents have been studied for imaging bacterial infection, as most agents to date have utilized SPECT. Non-glucose sugar derivatives have, however, shown improved selectivity for bacterial infections when compared to FDG.9 Antimicrobial peptides offer a more selective method for targeting bacteria, as they are positively charged (e.g., polylysine) and interact preferentially with negatively charged bacterial membranes (prokaryotic).10 Using in vitro binding assays and in vivo PET imaging, various peptide derivatives will be tested and the most promising compounds with the highest accumulation in sites of bacterial infection will be selected as a PET imaging agents.
Impact of the Price Group’s Research on Canada, and Future Goals: Molecular imaging is revolutionizing our understanding of normal and pathological processes in plants, animals and humans by providing tools for visualizing and quantifying physiological and biochemical events in real-time without invasive procedures. Given our aging population in North America and increasing global population, the burden that diseases such as cancer, Parkinson’s, and drug-resistant bacterial infections have on individual families, world economies, and the national healthcare systems is rapidly increasing. In addition, the alarmingly swift emergence of multi-drug resistant bacteria is now a global health risk that requires immediate action. Creating new radiopharmaceuticals and molecular imaging probes will assist in answering important questions related to human and animal health as well as both treating and diagnosing important diseases.
It is important to highlight the availability of a human PET/CT scanner at Royal University Hospital (at the U of S) run by Dr. Paul Babyn, which provides an avenue for large animal (dogs, sheep and pigs) as well as human trials for molecular imaging/ treatment as a long-term goal of the Price Group. As radiopharmaceutical agents are delivered in micro-doses (nano-mole to pico-mole quantities), they are often classified as being “sub-pharmacological” and therefore have relaxed testing guidelines from regulatory bodies (e.g., Exploratory Investigational New Drugs (eIND) program and “Abbreviated New Drug Submission to Health Canada). This accelerates the progression of new radiopharmaceuticals through the development pipeline from the bench to the clinic (e.g. fewer animal studies and toxicology studies required), when compared to traditional pharmaceuticals. Commercialization and technology transfer of new radioactive drugs will be investigated with assistance from the Industrial Liaison Office at the U of S.
Translation of new molecular imaging probes into the human or veterinary clinics and into Saskatchewan and Canadian industry is an ideal opportunity to impact both human and animal patient care and in generating spin-off companies, which would create revenue for Saskatchewan and Canada while also disseminating new knowledge to the scientific community. New intellectual property obtained from these activities could lead to economic gains for Saskatchewan universities and Canada in the form of licensing income, attraction of new investment, and job creation.
Local collaborations at the U of S include the Canadian Light Source synchrotron (CLS) to study metal-chelate binding properties with collaborators Drs. Graham George and Ingrid Pickering. A recently awarded SHRF Collaborative Innovation Development grant with Drs. George, Pickering, Price, and Dmitriev will provide seed money to start a collaboration looking at the role of copper and zinc in Alzheimer’s disease. Dr. Price is also collaborating closely with Drs. Chris Phenix and Ron Geyer, where they are attempting to improve delivery and selectivity of highly toxic chemotherapeutic drugs by using the cellular machinery of cancer (enzymes) against itself. Dr. Price has also been recently awarded a CIHR Project Grant with Drs. Andrew Freywald and Franco Vizeacoumar to generate cutting-edge personalized medicine for triple negative breast cancer by combining genotype-directed cancer therapy with radioactive antibodies. Drs. Price and Phenix have also recently been awarded a SHRF Collaborative Innovation Development grant with collaborator Dr. Mike Moser, a Surgeon at the Royal University Hospital and NanoKnife cancer treatment specialist, to create a new type of prodrug to be used with NanoKnife treatment to improve efficacy in pancreatic cancer.
Funding sources for Dr. Price’s research are crucial and greatly appreciated, include the Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Research Chairs (CRC), Canada Foundation for Innovation (CFI), Saskatchewan Health Research Foundation (SHRF), Canadian Institutes of Health Research (CIHR), the Fedoruk Centre, and startup funds from the University of Saskatchewan.
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(8) Signore, A.; Annovazzi, A.; Corsetti, F.; Capriotti, G.; et al. BioDrugs 2002, 16, 241.
(9) Weinstein, E. A.; Ordonez, A. A.; DeMarco, V. P.; Murawski, A. M.; et al. Sci. Transl. Med. 2014, 6, 259ra146.
(10) Yeaman, M. R.; Yount, N. Y. Pharmacological Reviews 2003, 55, 27.