Chris Orvig

Contact InformationChris Orvig
#D316, 2036 Main Mall, Vancouver, BC, Canada V6T 1Z1
Tel 1-604-822-4449
orvig@chem.ubc.ca

Current Positions

  • Professor of Chemistry and Pharmaceutical Sciences
  • Director, Medicinal Inorganic Chemistry Group

Research Interests

Research projects in our labs study the roles of metal ions in the etiology, diagnosis, and therapy of disease. These projects encompass a variety of metal ions as well as numerous ligand systems and a wide panoply of techniques and collaborations. Synthesis of organic ligands and inorganic complexes as well as physical (potentiometric and spectrophotometric titrations, various spectroscopies, electrochemistry etc.) and biological studies (in cells, at UBC Bioservices and/or in collaboration) are undertaken in the research programme.

Glycosylated Pro-drugs for Metal Passivation in Neurodegenerative Diseases

The amyloid hypothesis seeks to explain the aetiology of Alzheimer’s disease (AD) by linking irregularities present in the affected brain, insoluble aggregates of β-amyloid (Aβ) protein and elevated levels of redox active metal ions, with the observed symptoms of oxidative stress and brain tissue damage.  β-amyloid is a ubiquitous, normal brain protein that, in the case of AD, becomes pathogenic through an unknown mechanism.  While currently available therapeutic strategies such as the administration of cholinesterase inhibitors focus on relief of symptoms of AD (in this example, reduced neuronal activity), we have developed a strategy which seeks to target together two brain pathologies described in the amyloid hypothesis: elevated levels of metal ions and oxidative stress.

Our strategy seeks to obtain synergistic benefits from multifunctional drugs that bind and passivate redox active metal ions, particularly Cu(II), while also being potent inhibitors of the free radical oxidative processes that can lead to neurological tissue destruction.  In addition, glucose substituents are incorporated into the compounds to promote prodrug uptake by the brain.  Every compound is designed to include: 1) carbohydrate substituent(s) for improved central nervous system (CNS) access; 2) antioxidant functionality for reduction of oxidative stress conditions; 3) metal chelation capabilities to sequester excess CNS metal ions; and amyloid targeting substutents.

Two prototype compound families have been synthesized, characterized, studied and patented in order to compare multiple variations of the two classes of designed multi-functional compounds through cell cytotoxicity and pharmacokinetic profiling, to identify lead compounds that can be used in further in vitro and in vivo studies.

This novel strategy has potential synergistic benefits for both prevention and treatment of neurological disorders, including Alzheimer’s and Parkinson’s diseases, and goes well beyond currently proposed therapies that either target reactive oxygen species (ROS), or non-specifically bind excess metal ions in the tissues of neurodegenerative disease patients.

Lanthanide Compounds for Bone Resorption Disorders

Bone density disorders, including osteoporosis, affect 1 in 4 women and 1 in 8 men over age 50 in North America; as the population ages, these diseases are incurring substantial annual health care costs escalating into billions of dollars.  Osteoporosis is characterized by low bone mineral density that leads to enhanced bone fragility and a consequent risk of low-impact bone fractures.  The low bone mineral density is a result of an imbalance between bone resorption and bone formation.  Normally, building and absorption of bone is a tightly regulated cycle wherein the bone matrix is manufactured by osteoblast cells and removed by osteoclast cells.  Either increased activity of osteoclasts or decreased bone formation by osteoblasts leads to microarchitectural deterioration of bone tissue.  Many contributing factors are known to influence the pathogenesis of the disease with the most prominent being inadequate calcium uptake.

Few therapeutic agents exist currently, either for prevention or for amelioration of these serious diseases, and patient compliance with the existing treatments is low due to adverse gastrointestinal side effects and/or high costs.  A new class of osteoporosis drugs, including oral strontium ranelate, stimulate osteoblast proliferation and inhibit osteoclast activity; however, uncertainty regarding the potential toxicity of chronic strontium accumulation in bone may limit the utility of this product.  Lanthanides Ln(III) are known for their therapeutic and diagnostic applications as agents for magnetic resonance imaging, cancer and radiotherapy.  Low doses of Ln have been shown to act similarly to strontium ranelate.  In vivo, Ln(III), a functional mimic of Ca(II), has been found to exchange with Ca(II) in bone to modify the bone remodeling cycle by stimulating osteoblast proliferation and impeding bone resorption by inhibiting osteoclast differentiation.  Based on this evidence, lanthanum carbonate (La2(CO3)3) has been proposed as a potential preventative measure for post-menopausal osteoporosis; however, gastrointestinal upset is a known negative side effect of this treatment.  La2(CO3)3 is currently being used to treat hyperphosphatemia under the trade name of Fosrenol™.  Unfortunately, due to its extremely low bioavailability (<0.0007%), high doses of elemental La(III) are administered for this application, leading to adverse gastrointestinal (GI) tract side effects.

Adjustments to the ligand structure around the Ln(III) ions have the potential to increase the oral bioavailability of Ln(III) for the treatment of bone density disorders while decreasing unwanted side effects.  In collaboration with Prof. K. Wasan of UBC’s Faculty of Pharmaceutical Sciences and Prof. Rizhi Wang of UBC’s Biomaterials Group, we are investigating neutral Ln(III) tris(bidentate ligand) complexes as bone agents.  La(III), Gd(III), and Yb(III) ions were investigated, with selection of specific lanthanides based on their known medicinal applications and for size comparison and the potential of these compounds as therapeutic agents for the treatment of bone resorption disorders is being assessed in cytotoxicity studies, in comparative bifunctional transport in human colon carcinoma cells with intestinal cell like properties (Caco-2 cells), in hydroxyapatite binding and in a variety of other in vitro tests preparing for the 2012 in vivo studies of our two lead candidates.

Ferrocenyl-chloroquine/mefloquine-carbohydrate Conjugates in Malaria

Malaria is a widespread parasitic disease that affects a large population.  Four species of the human infecting parasite are known, plasmodium falciparum being the most lethal of these.  It is estimated that 2 billion people have been exposed to the parasite. It is estimated that yearly 300-500 million new cases are reported, and between 1 and 2.7 million people die from the infection. Historically, malaria is found in tropical areas, including the poorest countries.  Although the majority of cases originate in Africa, Southeast Asia, India, and parts of South America, the disease is now threatening to spread into more temperate zones of the world and global warming would certainly facilitate this reach. Currently, no commercially available vaccine for malaria exists, and drug resistance is becoming rampant.

The need for different categories of anti-malarials, active against the resistant strains, has risen.  Unfortunately, scant funding for a poor person’s disease has led to insufficient research for novel drugs and treatments for malaria and to our work with UBC’s Neglected Global Diseases Initiative – NGDI.  Some alternative drugs are being investigated, but are either costly or have adverse side effects, such as toxicity.

An attractive area of research for new malarial treatment is directed metal conjugates, particularly those of known anti-malarial drugs.  Ferrocene has several properties that have facilitated its investigation for potential biological applications.  Typically, organometallic compounds are sensitive to moisture and air, but ferrocene belongs to a unique group thereof whose members are stable under both aqueous and aerobic conditions.  The small size, relative lipophilicity, easy chemical modification, and accessible one electron oxidation potential of ferrocene make it an attractive reporter moiety and an intriguing pharmaceutical vector.  Ferrocenoyl carbohydrate conjugates have potential as metalloantimalarials.  Combining the ferrocene moiety with a glucose derivative and with known antimalarial drugs is a novel approach for developing targeted therapy.  The ferrocene moiety has proven to be a successful addition to known malaria therapeutics, increasing efficacy towards chloroquine resistant strains of the parasite.  As well, glucose uptake and metabolism in infected erythrocytes is elevated at all stages of the parasite’s life cycle and glucose consumption has been a target in anti-malarial research.  The hypothesis of this work is that ferrocenyl-chloroquine/mefloquine-carbohydrate conjugates have the potential to retain activity in chloroquine resistant parasite strains, and to have increased efficacy by targeting infected cells.  This work studies the cytotoxicity and anti-plasmodial activity of several ferrocene conjugates, and includes the synthesis and characterization of numerous new conjugates.

With Dr. M. J. Adam of TRIUMF, we have published some preliminary studies showing that ferrocenyl carbohydrate conjugates exhibit some selective anti-malarial activity – glucose uptake and metabolism in infected erythrocytes is elevated at all stages of the parasite’s life cycle.  The main goal of the project is to synthesize new ferrocenyl-chloroquine/mefloquine-carbohydrate conjugates that are inexpensive to produce, have activity in chloroquine-resistant parasites strains and that will have increased efficacy by targeting infected cells.

Coordination Chemistry of Metallic Isotopes in Nuclear Medicine

Our group works together with Dr. M. J. Adam, Head of PET Chemistry at TRIUMF, and with the Canadian isotope supplier Nordion to add value to their growing line of nuclear medicine radiometals. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are two imaging modalities that our aging population will depend upon for the early detection of disease, particularly in the area of oncology. PET has become a “gold standard” in the early detection of cancer, relying currently on the use of 18-fluoro-deoxy-glucose (18-FDG).

New promising radiopharmaceuticals, more specific for disease processes, are being developed for both PET and SPECT. In order to achieve this goal, new radiolabelling methods and chemistry are being discovered. Much of this advancement is made possible by the synthetic production of biomolecules (e.g. peptides, lipids, oligosaccharides, oligonucleotides and antibodies) with specific and high affinity for cancer biomarkers. The development of these ligands into viable imaging agents is being realized through the discovery of new robust, reproducible, high-yielding and rapid methods for introducing the radioisotope of choice into these biomolecules to give chemically stable entities, with a particular focus on conjugating Ga-68, In-111, and other lanthanide radionuclides into biological molecules such as peptides, proteins, oligonucleotides, carbohydrates and fatty acids and to evaluate their biological properties as potential imaging or therapy agents.

Publications

  1. Bailey GA, Price EW, Zeglis BM, Ferreira CL, Boros E, Lacasse MJ, Patrick BO, Lewis JS, Adam MJ, Orvig C. H(2)azapa: a Versatile Acyclic Multifunctional Chelator for (67)Ga, (64)Cu, (111)In, and (177)Lu. Inorg Chem. 2012 Oct 29.
  2. Telpoukhovskaia MA, Orvig C. Werner coordination chemistry and neurodegeneration. Chem Soc Rev. 2012 Sep 5.
  3. Boros E, Cawthray JF, Ferreira CL, Patrick BO, Adam MJ, Orvig C. Evaluation of the H2)dedpa scaffold and its cRGDyK conjugates for labeling with 64Cu. Inorg Chem. 2012 Jun 4;51(11):6279-84.
  4. Price EW, Cawthray JF, Bailey GA, Ferreira CL, Boros E, Adam MJ, Orvig C. H4octapa: an acyclic chelator for 111In radiopharmaceuticals. J Am Chem Soc. 2012 May 23;134(20):8670-83.
  5. Boros E, Ferreira CL, Yapp DT, Gill RK, Price EW, Adam MJ, Orvig C. RGD conjugates of the H2dedpa scaffold: synthesis, labeling and imaging with 68Ga. Nucl Med Biol. 2012 Aug;39(6):785-94.
  6. Herrmann C, Salas PF, Patrick BO, de Kock C, Smith PJ, Adam MJ, Orvig C. 1,2-disubstituted ferrocenyl carbohydrate chloroquine conjugates as potential antimalarial agents. Dalton Trans. 2012 Jun 7;41(21):6431-42.
  7. Boros E, Ferreira CL, Patrick BO, Adam MJ, Orvig C. New Ga derivatives of the H2dedpa scaffold with improved clearance and persistent heart uptake. Nucl Med Biol. 2011 Nov;38(8):1165-74.
  8. Boros E, Lin YH, Ferreira CL, Patrick BO, Häfeli UO, Adam MJ, Orvig C. One to chelate them all: investigation of a versatile, bifunctional chelator for (64)Cu, (99m)Tc, Re and Co. Dalton Trans. 2011 Jun 21;40(23):6253-9
  9. Boros E, Ferreira CL, Cawthray JF, Price EW, Patrick BO, Wester DW, Adam MJ, Orvig C. Acyclic chelate with ideal properties for (68)Ga PET imaging agent elaboration. J Am Chem Soc. 2010 Nov 10;132(44):15726-33.
  10. Ferreira CL, Marques FL, Okamoto MR, Otake AH, Sugai Y, Mikata Y, Storr T, Bowen M, Yano S, Adam MJ, Chammas R, Orvig C. Cationic technetium and rhenium complexes with pendant carbohydrates. Appl Radiat Isot. 2010 Jun;68(6):1087-93.
  11. Green DE, Bowen ML, Scott LE, Storr T, Merkel M, Böhmerle K, Thompson KH, Patrick BO, Schugar HJ, Orvig C. In vitro studies of 3-hydroxy-4-pyridinones and their glycosylated derivatives as potential agents for Alzheimer’s disease. Dalton Trans. 2010 Feb 14;39(6):1604-15.

Education

  • Postdoc, McMaster University, 1983-1984
  • NSERC Postdoctoral Fellow, University of California, Berkeley, 1981-83
  • NSERC PGS Ph.D. M.I.T., 1981
  • B.Sc. McGill University, 1976

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