Undergraduate Opportunities

The Nanoscale Organisation and Dynamics Group (Nano) is a multidisciplinary research team within Western Sydney University, whose ultimate aim is to establish the University as an internationally recognised research group for molecular association, organisation and dynamics with an emphasis on nanobiotechnical and nanomedical applications (e.g., drug binding, nanofluids).
There are a number of interesting topic areas and projects available within the Nano group either for Postgraduate study or the Masters program. If you are interested in any of the following projects please contact the primary supervisor for further information and discussion.


Decode nature's way of detoxification – NMR studies on dissolved organic matter in Australian aquatic systems

Primary Supervisor Contact: Dr Gang Zheng, g.zheng@westernsydney.edu.au

Co-Supervisors: Prof. William S. Price

Would suit students interested in: Biology/Chemistry/NMR/Physics

Like ourselves, mother nature has many methods for detoxification. Dissolved organic matter (DOM) plays a major role in natural detoxification in aquatic systems. In fresh water, many harmful versions of heavy metals (e.g., methyl-mercury) latch onto DOM then are more likely broken down into harmless compounds by sunlight. In sea water, however, these nasty metal complexes tend to latch onto salt (i.e., sodium chloride) instead of DOM and therefore are far more likely accumulated through the food chain, according to studies by a US researcher. In this study, the key chemical components of the various DOM in Australian aquatic systems will be identified, their roles in the natural detoxification will be revealed, and environmental factors (e.g., salt) affecting the detoxification process will be identified.

Key References:

  • G. Zheng and W.S. Price, Direct hydrodynamic radius measurement on dissolved organic matter in natural waters using diffusion NMR. Environ. Sci. Tech., 2012. 46(3): p. 1675-1680.
  • G. Zheng, T. Stait-Gardner, P.G. Anil Kumar, A.M. Torres, and W.S. Price, PGSTE-WATERGATE: An STE-based PGSE NMR sequence with excellent solvent suppression. J. Magn. Reson., 2008. 191: 159-163.
  • G. Zheng and W.S. Price, Solvent signal suppression in NMR. Prog. Nucl. Magn. Reson. Spec., 2010. 56: 267-288.

Designing and synthesising platinum complexes with affinity for QDNA

Primary Supervisor Contact: Prof. Janice R. Aldrich-Wright, j.aldrich-wright@westernsydney.edu.au

Co-Supervisors:

Would suit students interested in: Synthetic Chemistry

DNA can form a large number of conformational structures because it is such a flexible biomolecule. These include: cruciform, intramolecular triplexes, slipped-strand, parallel-stranded and unpaired DNA structures and quadruplex DNA (QDNA), in addition to the double stranded B-DNA. Different conformational structures have been identified as being crucial for several cellular processes including replication, gene expression, growth, recombination and repair.1,2 Bioinformatics studies have identified, more than 360,000 different guanine rich telomeres sequences that can assemble into one, two or four stranded folded QDNA structures from single stranded sequences. An example of a guanine rich telomere sequence is the ~100-200 single stranded nucleotides that extend at the end of chromosomal DNA to protect it during replication, performing an essential task in cellular proliferation and cell death.3 In normal cell replication, some of the ~100-200 single stranded nucleotides of the telomeric overhang is lost with each cycle, leading to the successive shortening. At a critical length cell death is initiated. In various cancer cells, cell death can be circumvented by the overexpression of telomerase which extends the length of the telomeres, effectively making the cell line immortal. Stabilisation of QDNA inhibits telomerase activity, which prevents the replication of cancer cells.3-6 Several platinum(II) complexes that have been synthesised at Western Sydney University bind to and stabilise QDNA as well as exhibit anticancer activity. Based upon these results7-10 this project will design, synthesize and characterize effective G-quadruplex stabilisers that incorporate planar aromatic surfaces to increase the stacking interactions6 such as symmetrical [Pt(1,10-phenanthroline-5,6-dione)2] and [Pt(4,5-diazafluoren-9-one)2] to exhibit strong G-quadruplex affinity as well as cytotoxicity in human cancer cell lines. Asymmetrical and dinuclear structures will also be formed to study their effectiveness as QDNA stabilisers and anticancer agents. The resulting metal complexes will be characterised using NMR, HPLC, MS and UV-Vis. Following characterisation cell line testing will be undertaken. By using these techniques, this project aimed to investigate G-quadruplex platinum complex interactions, leading to the contribution towards the development of the next generation of anticancer complexes.

Key References

  1. Bochman, M. L.; Paeschke, K.; Zakian, V. A., DNA secondary structures: stability and function of G-quadruplex structures. Nat Rev Genet 2012, 13 (11), 770-80.
  2. Balasubramanian, S.; Hurley, L. H.; Neidle, S., Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat Rev Drug Discov 2011, 10 (4), 261-275.
  3. Wu, P.; Ma, D.-L.; Leung, C.-H.; Yan, S.-C.; Zhu, N.; Abagyan, R.; Che, C.-M., Stabilization of G-Quadruplex DNA with Platinum(II) Schiff Base Complexes: Luminescent Probe and Down-Regulation of c-myc Oncogene Expression. Chemistry – A European Journal 2009, 15 (47), 13008-13021.
  4. Cree, S. L.; Kennedy, M. A., Relevance of G-quadruplex structures to pharmacogenetics. Frontiers in Pharmacology 2014, 5, 160.
  5. Monchaud, D. Unlocking the Secrets of Four-Strand DNA https://news.cnrs.fr/articles/unlocking-the-secrets-of-four-strand-dna.
  6. Cao, Q.; Li, Y.; Freisinger, E.; Qin, P. Z.; Sigel, R. K. O.; Mao, Z.-W., G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs. Inorg. Chem. Front. 2017, 4 (1), 10-32.
  7. Harper, B. W. J.; van Holst, M.; Aldrich-Wright, J., Platinum(II) Intercalating Complexes Based on 2,2 ':6 ',2 ''-Terpyridine. In Metallointercalators: Synthesis and Techniques to Probe Their Interactions with Biomolecules, 2011; pp 101-128.
  8. Harper, B. W. J.; Morris, T. T.; Gailer, J.; Aldrich-Wright, J. R., Probing the interaction of bisintercalating (2,2':6',2"-terpyridine)platinum(II) complexes with glutathione and rabbit plasma. Journal of Inorganic Biochemistry 2016, 163, 95-102.
  9. Harper,.B. W. J.; Petruzzella, E.; Sirota, R.; Faccioli, F. F.; Aldrich-Wright, J. R.; Gandin, V.; Gibson, D., Synthesis, characterization and in vitro and in vivo anticancer activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)]. Dalton Transactions 2017, 46 (21), 7005-7019
  10. Ang, D. L.; Harper, B. W. J.; Cubo, L.; Mendoza, O.; Vilar, R.; Aldrich-Wright, J., Quadruplex DNA-Stabilising Dinuclear Platinum(II) Terpyridine Complexes with Flexible Linkers. Chemistry-a European Journal 2016, 22 (7), 2317-2325.

Dual Action Platinum(IV) Prodrugs

Primary Supervisor Contact: Prof. Janice R. Aldrich-Wright, j.aldrich-wright@westernsydney.edu.au

Co-Supervisors:

Would suit students interested in: Synthetic Chemistry

Cancer is a global phenomenon and considered to be one of the leading causes of rising mortality and morbidity rates worldwide.1 In 2015, an estimate of 8.8 million cancer-related deaths was recorded and these numbers are expected to increase by 70% over the next 20 years.2 Unfortunately, a cure for cancer is yet to be developed although platinum(II) anticancer drugs including cisplatin, oxaliplatin, and carboplatin are currently available as therapeutic agents for a variety of tumours by covalently bind to DNA and stopping cancer cell replication.3,4 The most recent addition Lobaplatin, (1,2-diamminomethylcyclobutane-platinum(II) lactate) was introduced in 2005. However, these drugs exhibit disadvantages including toxicity, cross-resistance, and intrinsic and acquired resistance.5 In particular, toxicity is a significant issue because of the resulting side effects which can lead to genomic instability and further complications to cancer patients.3-5 The search for metal complexes that will overcome these limitations has been ongoing since 1979, but with the recent development of platinum(IV) complexes and their demonstrated kinetic stability (in vivo), can be administered orally and added potential for targeting, has intensified.6-12 As the need to develop new complexes that are much less toxic the necessitates the development of new effective and efficient platinum(IV) complexes. This project will employ a strategy that combines platinum(II) complexes with demonstrated in vitro activity such as [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane) platinum(II)] dichloride (56MESS, IC50 = 9.2 nM) which is 100 more cytotoxic than cisplatin in the L1210 murine leukaemia cell line.13-15 This would be converted to platinum(IV) form which undergo activation by a two-electron reduction that produces a simultaneous release of the parent cytotoxic platinum(II) drug as well as releasing the two axial ligands. Recently we reported upon several such compounds, e.g. cct-[Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(PhB)2]2+ at ~15 times that of cisplatin.13 In vivo activity, for C57BL mice bearing Lewis lung carcinoma, treated with the same compounds exhibited a 73% reduction in tumour growth, which is comparable to cisplatin at or 75%.

This project aims to utilise unconventional platinum complex, [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane) platinum(II)] dichloride (56MESS), convert this to cct-[Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane) (OH)2]2+ and subsequently exchange either one or two of the axial hydroxides with bioactive molecules The approach here is to explore the effectiveness of platinum(IV) complexes, c,c,t-[Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(R1)(R2)]2+ where R1 or R2 will be a bioactive inhibitor (as shown in the Figure) such as: Tamoxifen (an orally selective estrogen receptor modulator, has been adopted as a first-line endocrine therapy for patients with all stages of ER-positive breast cancer)15,16 inhibitors such as valproate (VPA) or phenylbutyrate (PhB) which alter gene transcription that effects arrest, differentiation, apoptosis, and inhibition of tumor angiogenesis)18,19 to produce dual action anticancer agents.

Key References

  1. Johnstone, T. C.; Park, G. Y.; Lippard, S. J., Understanding and improving platinum anticancer drugs--phenanthriplatin. Anticancer Res 2014, 34 (1), 471-6.
  2. World Health Organization Cancer. http://www.who.int/mediacentre/factsheets/fs297/en/ (accessed 15/11/2017)
  3. Johnstone, T. C.; Suntharalingam, K.; Lippard, S. J., The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs. Chem Rev 2016, 116 (5), 3436-86.
  4. Galanski, M.; Jakupec, M. A.; Keppler, B. K., Update of the preclinical situation of anticancer platinum complexes: novel design strategies and innovative analytical approaches. Curr Med Chem 2005, 12 (18), 2075-94.
  5. Kelland, L., The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 2007, 7 (8), 573-84.
  6. Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J. F.; Rheinheimer, M. I.; Wyer, S. B.; Bossard, G. E.; Higgins, J. D., Carboxylation of Kinetically Inert Platinum(IV) Hydroxy Complexes. An Entr.acte.ee into Orally Active Platinum(IV) Antitumor Agents. Inorganic Chemistry 1995, 34 (5), 1015-1021.
  7. Hall, M. D.; Hambley, T. W., Platinum(IV) antitumour compounds: their bioinorganic chemistry. Coordination Chemistry Reviews 2002, 232, 49-67.
  8. Basu, U.; Banik, B.; Wen, R.; Pathak, R. K.; Dhar, S., The Platin-X series: activation, targeting, and delivery. Dalton Transactions 2016, 45 (33), 12992-13004.
  9. Gibson, D., Platinum(iv) anticancer prodrugs - hypotheses and facts. Dalton Transactions 2016, 45 (33), 12983-12991.
  10. Ang, W. H.; Khalaila, I.; Allardyce, C. S.; Juillerat-Jeanneret, L.; Dyson, P. J., Rational design of platinum(IV) compounds to overcome glutathione-S-transferase mediated drug resistance. J Am Chem Soc 2005, 127 (5), 1382-3.
  11. Neumann, W.; Crews, B. C.; Sárosi, M. B.; Daniel, C. M.; Ghebreselasie, K.; Scholz, M. S.; Marnett, L. J.; Hey-Hawkins, E., Conjugation of Cisplatin Analogues and Cyclooxygenase Inhibitors to Overcome Cisplatin Resistance. ChemMedChem 2015, 10 (1), 183-192.
  12. Pathak, R. K.; Marrache, S.; Choi, J. H.; Berding, T. B.; Dhar, S., The prodrug platin-A: simultaneous release of cisplatin and aspirin. Angew Chem Int Ed Engl 2014, 53 (7), 1963-7.
  13. Harper, B. W. J.; Petruzzella, E.; Sirota, R.; Faccioli, F. F.; Aldrich-Wright, J. R.; Gandin, V.; Gibson, D., Synthesis, characterization and in vitro and in vivo anticancer activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)]. Dalton Transactions 2017, 46 (21), 7005-7019.
  14. Gibson, D.; Harper, B.; Friedman-Ezra, A.; Sirota, R.; Emanuele Petruzzella, E.; Aldrich-Wright, J. R., Probing the interactions of cytotoxic [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] and its Pt(IV) derivatives with human serum. ChemMedChem 2017, n/a-n/a.
  15. Petruzzella, E.; Braude, J. P.; Aldrich-Wright, J. R.; Gandin, V.; Gibson, D., A Quadruple-Action Platinum(IV) Prodrug with Anticancer Activity Against KRAS Mutated Cancer Cell Lines. Angewandte Chemie International Edition 2017, 56 (38), 11539-11544.
  16. Rose, C.; Thorpe, S. M.; Andersen, K. W.; Pedersen, B. V.; Mouridsen, H. T.; Blichert-Toft, M.; Rasmussen, B. B., Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values. Lancet 1985, 1 (8419), 16-9.
  17. Fritsch, M.; Jordan, V. C., Long-term Tamoxifen Therapy for the Treatment of Breast Cancer. Cancer Control 1994, 1 (4), 356-366.
  18. Raveendran, R.; Braude, J. P.; Wexselblatt, E.; Novohradsky, V.; Stuchlikova, O.; Brabec, V.; Gandin, V.; Gibson, D., Pt(iv) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action. Chemical Science 2016, 7 (3), 2381-2391.
  19. Xue, X.; You, S.; Zhang, Q.; Wu, Y.; Zou, G.-z.; Wang, P. C.; Zhao, Y.-l.; Xu, Y.; Jia, L.; Zhang, X.; Liang, X.-J., Mitaplatin Increases Sensitivity of Tumor Cells to Cisplatin by Inducing Mitochondrial Dysfunction. Molecular Pharmaceutics 2012, 9 (3), 634-644.

Effective dual action anticancer agents

Primary Supervisor Contact: Prof. Janice R. Aldrich-Wright, j.aldrich-wright@westernsydney.edu.au

Co-Supervisors:

Would suit students interested in: Synthetic Chemistry

Cancer accounts for 8 million deaths each year and that number projected to rise by 70% over the next two decades.1 The most well-known conventional platinum anticancer complex is cis-diamminedichloroplatinum (cisplatin) which effectively treats testicular, ovarian, head, neck and small-cell lung cancer.2,3 Vomiting (emetogenesis), hearing loss (ototoxicity), kidney damage (nephrotoxicity) and nervous system (neurotoxicity) damage are often the characteristic side effects of treatment.4-5 Acquired resistance is frequently a consequence of sub-toxic accumulation inside the cell, due in part to reduced drug influx and increased drug efflux.6 Resistance in cancer cells is enhanced by the repair/tolerance to DNA-cisplatin adducts, modulation of the pathways that control regulated cell death, loss of function of upregulated sequence-specific binding factors, such as proteins, and an increased concentration of glutathione and metallothioneins.7-9 The clinical limitations of cisplatin have been the motivation for the creation of thousands of cisplatin analogues, resulting in complexes that employ the same mechanism of action where the platinum coordinately binds to DNA. Many researchers are striving to create effective inorganic complexes that exhibit anticancer activity. The intrinsic challenges of chemotherapy demand that new strategies utilising different mechanisms of action to interrupt the cellular machinery of cancer cells be developed.10 Current anticancer compounds interact with in both cancerous and normal cells however researchers aspire to create more potent platinum complexes with increased cytotoxicity which target cancer cells more effectively and will result in a better prognosis. Our groups strategy is to utilise unconventional platinum complexes different mechanism that induces cytotoxicity in cancerous cells. The complex incorporates coordinated polyromantic ligands (PL) and ancillary ligand (AL) to form [Pt(PL)(AL)]2+. Unlike cisplatin this complex cannot covalently bind to DNA. The mechanism for this interaction is not fully understood, however for [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane) platinum(II)] dichloride (56MESS) it is up to 100 times more active than cisplatin in a variety of cell lines, with an IC50 of 0.009 ± 0.002 μM in the L1210 murine leukaemia cell line.11 Increased cytotoxicity reduces the dosage required, treatment time and the reducing the chance of acquired resistance. Although the in vitro activity of these complexes is exceptional, in vivo activity has been disappointing due to poor pharmacokinetics.

The design strategy being explored here is to form platinum(IV) complexes where the two additional axial ligands can be coordinated to either a targeting molecule or a bioactive ligand. The development of Pt(IV) prodrugs is an increasing attractive field as Pt(IV) complexes have many advantages over Pt(II) in vivo. Platinum(IV) complexes are more kinetically inert than the parent platinum(II) complexes, which can be administered orally.12-13 Once inside cancer cells, platinum(IV) complexes undergo activation by a two-electron reduction that produces a simultaneous release of the parent cytotoxic platinum(II) drug as well as the two axial ligands.14 Recently we reported upon several such compounds with valproate (VPA) and phenylbutyrate (PhB), which alter gene transcription that effects arrest, differentiation, apoptosis, and inhibition of tumor angiogenesis.15,16 The resulting complexes Inhibition was demonstrated for cct-[Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(R1)(R2)]2+ (here R1 and R2 are PhB, shown in Figure) ~15 times that of cisplatin.17 In vivo activity, for C57BL mice bearing Lewis lung carcinoma, treated with the same compounds exhibited a 73% reduction in tumour growth, which is comparable to cisplatin at or 75%. This research project will explore the feasibility of introducing other bioactive to generate effective dual action anticancer agents using cct-[Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(R1)(R2)]2+ where R1 and/or R2 will be bioactive molecules such as inhibitors.

Key References

  1. Stewart, B. W.; Wild, C., World Cancer Report 2014. International Agency for Research on Cancer. World Health Organization 2014, 505.
  2. Lu, Q., Molecular reaction mechanism of combination treatments of low-dose cisplatin with radiotherapy and photodynamic therapy. Journal of Medicinal Chemistry 2007, 50, 2601-2604.
  3. Ishida, S.; Lee, J.; Thiele, D.; Herskowitz, I., Uptake of the anticancer drug cisplatin mediated by copper transporter Ctr1 in yeast and mammals. Proceedings of the National Academy of Sciences 2002, 99, 14298-14302.
  4. Rybak, L.; Whitworth, C.; Mukherjea, D.; Ramkumar, V., Mechanisms of cisplatin-induced ototoxicity and prevention. Hearing Research 2007, 226, 157-167.
  5. Petrovic, D.; Stojimirovic, B.; Petrovic, B.; Bugarcic, Z. M.; Bugarcic, Z. D., Studies of interaction between platinum(II) complexes and some biologically relevant molecules. Bioorganic & Medicinal Chemistry 2007, 15, 4203-4211.
  6. Alfarouk, K. O.; Stock, C.-M.; Taylor, S.; Walsh, M.; Muddathir, A. K.; Verduzco, D.; Bashir, A. H. H.; Mohammed, O. Y.; Elhassan, G. O.; Harguindey, S.; Reshkin, S. J.; Ibrahim, M. E.; Rauch, C., Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell International 2015, 15, 71.
  7. Boulikas, T.; Vougiouka, M., Cisplatin and platinum drugs at the molecular level Oncology Reports 2003, 10, 1663-1682.
  8. Perez, R. P., Cellular and Molecular Determinants of Cisplatin Resistance. European Journal of Cancer 1998, 34, 1535-1542.
  9. Kartalou, M.; Essignmann, J. M., Mechanism of resistance to cisplatin Mutation Research 2001, 478, 23-43.
  10. Johnstone, T. C.; Suntharalingam, K.; Lippard, S. J., The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs. Chemical Reviews 2016, 116 (5), 3436-3486.
  11. Krause-Heuer, A. M.; Grünert, R.; Kühne, S.; Buczkowska, M.; Wheate, N. J.; Le Pevelen, D. D.; Boag, L. R.; Fisher, D. M.; Kasparkova, J.; Malina, J.; Bednarski, P. J.; Brabec, V.; Aldrich-Wright, J. R., Studies of the Mechanism of Action of Platinum(II) Complexes with Potent Cytotoxicity in Human Cancer Cells. Journal of Medicinal Chemistry 2009, 52 (17), 5474-5484.
  12. Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J. F.; Rheinheimer, M. I.; Wyer, S. B.; Bossard, G. E.; Higgins, J. D., Carboxylation of Kinetically Inert Platinum(IV) Hydroxy Complexes. An Entr.acte.ee into Orally Active Platinum(IV) Antitumor Agents. Inorganic Chemistry 1995, 34 (5), 1015-1021.
  13. Hall, M. D.; Hambley, T. W., Platinum(IV) antitumour compounds: their bioinorganic chemistry. Coordination Chemistry Reviews 2002, 232, 49-67.
  14. Wexselblatt, E.; Gibson, D., What do we know about the reduction of Pt(IV) pro-drugs? Journal of Inorganic Biochemistry 2012, 117 (Supplement C), 220-229.
  15. Yang, J.; Sun, X.; Mao, W.; Sui, M.; Tang, J.; Shen, Y., Conjugate of Pt(IV)-histone deacetylase inhibitor as a prodrug for cancer chemotherapy. Mol Pharm 2012, 9 (10), 2793-800.
  16. Raveendran, R.; Braude, J. P.; Wexselblatt, E.; Novohradsky, V.; Stuchlikova, O.; Brabec, V.; Gandin, V.; Gibson, D., Pt(iv) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action. Chemical Science 2016, 7 (3), 2381-2391.
  17. Harper, B. W. J.; Petruzzella, E.; Sirota, R.; Faccioli, F. F.; Aldrich-Wright, J. R.; Gandin, V.; Gibson, D., Synthesis, characterization and in vitro and in vivo anticancer activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)]. Dalton Transactions 2017, 46 (21), 7005-7019.

Expanding the boundaries and applications of diffusion

Primary Supervisor Contact: Prof. William S. Price, w.price@westernsydney.edu.au

Co-Supervisors: Dr Allan Torres

Would suit students interested in: NMR NMR/Physical Chemistry/Physics

Diffusion NMR is routinely used to study various molecular properties, and interactions occurring in solution. This technique is also valuable in MRI as it can be used to probe microscopic structures in biological tissues. Recently, long-lived singlet spin states have been used in NMR diffusion and diffusion-diffraction studies. Unlike regular spin coherences, singlet spin states have significantly longer lifetimes on the order of tens of seconds to a minute making it feasible to study extremely slowly diffusing molecules. In diffusion-diffraction studies, long lived singlet states can potentially be useful for probing structures with larger characteristic distances. In this project, the restricted diffusion of test molecules in glass and flexible silica capillaries will be investigated by utilising singlet spin states and various NMR coherences. The feasibility of performing NMR diffusion experiments in a single capillary with internal diameter of 10-200 micrometres will also be studied.

Imaging Placental Structure and Function in mouse models of preeclampsia

Primary Supervisor Contact: Prof. William S. Price, w.price@westernsydney.edu.au

Co-Supervisors: Prof. A. Hennessey

Would suit students interested in: Biology/Medical Physics/MRI/NMR. This project is a joint project between School of Medicine and School of Science and Health Magnetic

Resonance Imaging (MRI) is a versatile and powerful tool which can yield both structural and functional dynamic information about biological tissue. MRI provides a wide range of methods for the detection of essential physiological parameters such as blood flow, perfusion, oxygenation status and pH, as well as enabling detailed structural information.

The Nanoscale Organisation and Dynamics Group and the School of Medicine have been utilizing MRI to study changes in animal models of disease.

Preeclampsia is a complication of pregnancy and is a leading cause of both foetal and maternal morbidity and mortality. Changes in the placenta are instrumental to the development of this disease which causes hypertension and proteinuria and if left untreated can lead to kidney failure, stroke and convulsions. Analysing both the structural and functional changes to the placenta in experimental models of this disease will not only allow us to gain further insight into preeclampsia, but may yield non-invasive methods for the early detection of this disease.

To date, MRI studies of our mouse model of preeclampsia has shown morphological changes that suggests placental acidosis as well as hypoxia may be features of this disease. Further work modifying and optimizing sequence acquisitions and performing post-acquisition processing in order to obtain multi compartment information (vascular and extravascular) and information on dynamic responses to changes in oxygenation analysis is required. Definitive analysis of changes in tissue pH by MRI and spectroscopic identification of possible metabolic biomarkers of disease are studies that are also earmarked. Additionally, both high resolution (50 µM voxels) MRI of isolated fixed placenta and Diffusion Tensor Imaging (DTI) have the potential for providing details of structural changes in the placenta of the experimental model animals. The anatomical and functional analysis of the placenta by MRI is part of a wider project within the group that aims to link the role of an imbalance in inflammatory cytokines with structural and molecular changes in the placenta and the subsequent secretion of molecules into the maternal circulation that mediate the maternal response. The amelioration of changes in the diseased animals by various treatment procedures is also under investigation.

Investigating biostructures using NMR/MRI

Primary Supervisor Contact: Prof. William S. Price w.price@westernsydney.edu.au

Co-Supervisors: Dr Tim Stait-Gardner

Would suit students interested in: Biology / Mathematics / Medical Physics / MRI / NMR

Biological tissue is not just an amorphous arrangement of cells. Indeed, most tissue has an underlying structure composed of microscopic components as in muscle fibres or, as has more recently been realised, fibre tracts in brain tissue. Although the tracts might ultimately be macroscopic, they are composed of microscopic components. Such structures are not only involved in normal biological function, but also in diseased states, such as multiple sclerosis, epilepsy, and Alzheimer’s disease. Traditional techniques used to visualise such structures are not only limited in their application, but often these methods are invasive and tedious. In this project new NMR/MRI diffusion methods will be used to characterise tissue microstructure on a microscopic scale well below the resolution that is achievable using standard MRI sequences. In addition, the student would participate in the development of new NMR/MRI methods aimed at elucidating sample microstructure.

Investigating restricted diffusion using NMR techniques

Primary Supervisor Contact: Prof. William S. Price, w.price@westernsydney.edu.au

Co-Supervisors: Dr Tim Stait-Gardner

Would suit students interested in: Biology / Chemistry / Mathematics / Medical Physics /MRI / NMR

Modelling self-diffusion in complicated geometries is of fundamental importance in many areas of science including medicine as it will allow more diagnostic information to be extracted from diffusion MRI investigations. Modelling diffusion-controlled reactions - which occur widely in chemical and biochemical systems, and nuclear magnetic resonance diffusion experiments in bounded systems provide many prominent examples of where such modelling is required. Using a simple cellular system as an example, a reacting species diffuses to the enzymatic membrane and then reacts in some way, being either transformed into a product, becoming bound to the surface or transported through the surface. The nature of the interaction at the surface determines the boundary conditions in the modelling. Presently only solutions for some simple geometries are available. This is a serious impediment as most real-world structures that chemical reactions occur in have complicated geometries. Thus, there is a need to develop techniques for modelling diffusive processes near surfaces which are applicable to different geometries and arbitrary boundary conditions.  In this project the student will learn the basics of the underlying theory and develop theoretical and experimental methods for investigating diffusion in restricted systems and their application. It is suitable for mathematically oriented students.

Investigation of diffusive averaging and viscosity effects in bimodal polymer solutions

Primary Supervisor Contact: A/Prof. Gary Dennis, g.dennis@westernsydney.edu.au,

Co-Supervisors: Prof. William S. Price, Dr Gang Zheng, and Dr Scott A. Willis

Would suit students interested in: Physical chemistry / Mathematics / NMR

The most fundamental form of molecular transport is self-diffusion – the random motion of molecules – and measurements of which provide information on the size of the molecule as well as any influences from restrictions/obstructions (e.g., diffusion in a cell or porous rock) or aggregation processes (e.g., drug-binding). A powerful, versatile and non-invasive method for measuring self-diffusion is pulsed gradient spin-echo (PGSE) nuclear magnetic resonance (NMR). However, measurements of self-diffusion in polydisperse systems (e.g., polymer solutions with different molecular weight polymers present or aggregating proteins) is complicated by diffusive averaging effects since the NMR signals are the same or overlapped. Studying diffusive averaging in bimodal polymer solutions is of great significance as synthetic (e.g., polystyrene) and natural (e.g., proteins) polymers are inherently polydisperse. In this project, diffusive averaging will be studied for different bimodal polymer solutions (i.e., two molecular weights or two types of polymers present) of either chemically identical polymers of different molecular weights or mixtures of chemically different polymers of different or similar molecular weights. Several types of polymers could be considered for this study. Measurements of the viscosity of bimodal and monomodal polymer solutions will help to elucidate the diffusive averaging processes.

MRI-based electron density mapping for radiotherapy treatment planning

Primary Supervisor: Prof. William S. Price, w.price@westernsydney.edu.au

Co-Supervisors: Dr Scott A. Willis, Dr Tim Stait-Gardner

Would suit students interested in: Biology / Chemistry / Medical Physics / NMR

Radiation therapy is a recommended treatment for approximately half of cancer cases. Accurate planning of radiation dose requires both a picture of a patient's tissues and a map of the "electron density" of these tissues, currently obtained using CT (or "CAT") scans which use ionising radiation. At present an electron density (ED) map derived from a CT of the patient is the minimum requirement for treatment planning (TP) for external beam radiotherapy. Magnetic resonance imaging (MRI) scans actually provide a clearer tissue image than CT scans (and without using ionising radiation), but traditional medical MRI methods cannot provide a density map – at least not at the present time. Development of a new method which allows MRI to be used to measure tissue composition AND density would eliminate the extra radiation dose of a CT scan and streamline treatment planning.

Multi-action Pt(IV) Prodrugs

Primary Supervisor Contact: Prof. Janice R. Aldrich-Wright, j.aldrich-wright@westernsydney.edu.au

Co-Supervisors:

Would suit students interested in: Synthetic Chemistry

Platinum anticancer compounds are an excellent example of a successful metallodrug which came about through a both serendipity and rational design. After more than three decades they remain in very widespread use for the treatment of solid tumours.1 Three platinum-containing drugs are currently approved worldwide for therapy, cisplatin, carboplatin, and oxaliplatin and despite been introduced almost 40 years ago, they remain among the most widely used anticancer chemotherapeutics. However, the toxicity of the current platinum complexes remains a major limitation to use at doses that would provoke maximum effectiveness. Furthermore, the ability to penetrate solid tumours is limited which contributes to incomplete destruction of the tumour leading to resistance and relapse. Therefore, there is a need to develop new complexes that are as effective in killing cancer cells, less toxic and can permeate all cancer cells particularly those in solid tumours. Some improvements have been made by integrating platinum complexes and other bioactive molecules that an increasing the effectiveness, the range of cancer and reduces the impacts of the toxicity of these complexes.


Developing multi-action Pt(IV) prodrugs dynamic field as Pt(IV) complexes have many advantages over Pt(II) analogues. Platinum(IV) complexes are more kinetically inert compared to the platinum(II) analogues and as a consequence have the potential to be administered orally.2-4 Once they cross the cancer cells membrane, platinum(IV) complexes are reduced by a two-electron reduction that simultaneous releases the cytotoxic platinum(II) drug as well as the two bioactive axial ligands.4 We recently reported the results of several such complexes that incorporate valproate (VPA) and phenylbutyrate (PhB), which alter gene transcription that effects arrest, differentiation, apoptosis, and inhibition of tumor angiogenesis, in the axial positions.5,6 For example, c,c,t-[Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane) (PhB)2]2+ was ~15 more active than cisplatin in vitro and exhibited comparable in vivo reduction in tumour growth in C57BL mice bearing Lewis lung carcinoma, to cisplatin.7 In our aspirations to attain Ehrlich’s a “magic bullet” we wish to continue this research, employing a strategy that brings together our platinum(II) complexes, with exceptional anticancer activity, with bioactive molecules, to deliver multiple cytotoxic payloads to cancer cells.8

This project aims to use our unconventional platinum complex, [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane) platinum(II)] dichloride (56MESS), which unlike cisplatin, cannot covalently bind to DNA but it does exhibit up to 100 times more active than cisplatin in a variety of cell lines.9 Increased potency reduces the dosage required, so creating multi-action complexes we can target different cellular targets in the cancer cell. The approach exploits the coordination of platinum(IV) complexes by adding two bioactive molecules in axial sites to form cct-[Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(R1)(R2)]2+ where R1 and R2 will be inhibitors molecules (such as valproate and phenylbutyrate) to increase the potency of these platinum complexes.

Key References

  1. Kelland, L. R., The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 2007, 7, 573-584.
  2. Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J. F.; Rheinheimer, M. I.; Wyer, S. B.; Bossard, G. E.; Higgins, J. D., Carboxylation of Kinetically Inert Platinum(IV) Hydroxy Complexes. An Entr.acte.ee into Orally Active Platinum(IV) Antitumor Agents. Inorganic Chemistry 1995, 34 (5), 1015-1021.
  3. Hall, M. D.; Hambley, T. W., Platinum(IV) antitumour compounds: their bioinorganic chemistry. Coordination Chemistry Reviews 2002, 232, 49-67.
  4. Wexselblatt, E.; Gibson, D., What do we know about the reduction of Pt(IV) pro-drugs? Journal of Inorganic Biochemistry 2012, 117 (Supplement C), 220-229.
  5. Yang, J.; Sun, X.; Mao, W.; Sui, M.; Tang, J.; Shen, Y., Conjugate of Pt(IV)-histone deacetylase inhibitor as a prodrug for cancer chemotherapy. Mol Pharm 2012, 9 (10), 2793-800
  6. Raveendran, R.; Braude, J. P.; Wexselblatt, E.; Novohradsky, V.; Stuchlikova, O.; Brabec, V.; Gandin, V.; Gibson, D., Pt(iv) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action. Chemical Science 2016, 7 (3), 2381-2391.
  7. Harper, B. W. J.; Petruzzella, E.; Sirota, R.; Faccioli, F. F.; Aldrich-Wright, J. R.; Gandin, V.; Gibson, D., Synthesis, characterization and in vitro and in vivo anticancer activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)]. Dalton Transactions 2017, 46 (21), 7005-7019.
  8. Strebhardt, K.; Ullrich, A., Paul Ehrlich’s Magic Bullet Concept: 100 Years of Progress. Nat. Rev. Cancer 2008, 8, 473.
  9. Krause-Heuer, A. M.; Grünert, R.; Kühne, S.; Buczkowska, M.; Wheate, N. J.; Le Pevelen, D. D.; Boag, L. R.; Fisher, D. M.; Kasparkova, J.; Malina, J.; Bednarski, P. J.; Brabec, V.; Aldrich-Wright, J. R., Studies of the Mechanism of Action of Platinum(II) Complexes with Potent Cytotoxicity in Human Cancer Cells. J. Med. Chem. 2009, 52 (17), 5474-5484

The Next Generation of Platinum Drugs: Targeted Pt(IV) Prodrugs

Primary Supervisor Contact: Prof. Janice R. Aldrich-Wright, j.aldrich-wright@westernsydney.edu.au

Co-Supervisors:

Would suit students interested in: Synthetic Chemistry

Platinum anticancer complexes have been a mainstay of cancer chemotherapy for more than three decades and remain in very widespread use for the treatment of solid tumours.1 Progress has been made in increasing the range of cancers that can be treated by combining platinum complexes with rationally selected molecular targeted agents that decreases the impacts of the toxicity of these complexes. However, the toxicity of the current platinum complexes remains a major impediment to their use at doses that would induce maximum effectiveness and they would achieve the greatest possible benefit from combination with the new molecularly targeted agents. Also, penetration of the platinum complexes into solid tumours, as with nearly all anticancer agents, is sub-optimal which contributes to incomplete destruction of the tumour, leading to relapse and resistance. Therefore, there is a need to develop new complexes that are much less toxic, although are at least as effective in killing cancer cells as the current generation of platinum complexes and can reach all the viable cells in a solid tumour.

In the search to realise Ehrlich’s prediction of a “magic bullet”, we wish to employ a strategy that combines platinum(II) complexes with established anticancer activity targeting molecules to selectively deliver cytotoxic payloads to cancer cells.2 An appropriate targeting vector is overexpressed on the surfaces of cancer cells3 or can be directed to specific organelles at the subcellular level to produce cytotoxicity. This strategy can also be used to direct platinum(II) complexes to cancerous tissue by looking for proteins that are expressed on angiogenic blood vessels or by utilising molecules that are activated by the acidic or hypoxic microenvironment with a cancerous mass.4

The development of Pt(IV) prodrugs is an increasing attractive field as Pt(IV) complexes have many advantages over Pt(II) in vivo. Platinum(IV) complexes are more kinetically inert than the parent platinum(II) complexes which can be administered orally.5-6 Once inside cancer cells, platinum(IV) complexes undergo activation by a two-electron reduction that produces a simultaneous release of the parent cytotoxic platinum(II) drug as well as the two axial ligands.7 Recently we reported upon several such compounds with valproate (VPA) and phenylbutyrate (PhB) which alter gene transcription that effects arrest, differentiation, apoptosis, and inhibition of tumor angiogenesis.8,9 The resulting complexes inhibition was demonstrated for cct-[Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(PhB)2]2+ at ~15 times that of cisplatin.10 In vivo activity, for C57BL mice bearing Lewis lung carcinoma, treated with the same compounds exhibited a 73% reduction in tumour growth, which is comparable to cisplatin at or 75%. This project aims to target cancer cells by utilising unconventional platinum complex, [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane) platinum(II)] dichloride (56MESS). Unlike cisplatin, a clinically used anticancer compound, this complex cannot covalently bind to DNA but it does exhibit up to 100 times more activity than cisplatin in a variety of cell lines with an IC50 of 9.2 ± 2 nM in the L1210 murine leukaemia cell line.11 Increased potency reduces the dosage required, treatment time and the chance of acquired resistance.

The approach here is to explore the feasibility of forming platinum(IV) complexes where the two additional axial ligands can be coordinated to a targeting molecule to produce  effective targeted anticancer agents using cct-[Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(R1)(R2)]2+ where R1 and R2 will be targeting molecules) such as: estrogen (overexpressed on the surface of uterine, breast and ovarian cancer cells)12 and folate receptor proteins (expressed the surface of many cancers, including lung, renal, endometrial, colon, ovarian and breast cancer) to enable preferential uptake by cancer cells via endocytosis.13-15

Key References

  1. Kelland, L. R., The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 2007, 7, 573-584.
  2. Strebhardt, K.; Ullrich, A., Paul Ehrlich’s Magic Bullet Concept: 100 Years of Progress. Nat. Rev. Cancer 2008, 8, 473.
  3. Wang, X.; Guo, Z., Targeting and Delivery of Platinum-Based Anticancer Drugs. Chem. Soc. Rev. 2013, 42, 202.
  4. Tannock, I. F.; Rotin, D., Acid pH in Tumors and Its Potential for Therapeutic Exploitation. Cancer Res. 1989, 49, 4373.
  5. Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J. F.; Rheinheimer, M. I.; Wyer, S. B.; Bossard, G. E.; Higgins, J. D., Carboxylation of Kinetically Inert Platinum(IV) Hydroxy Complexes. An Entr.acte.ee into Orally Active Platinum(IV) Antitumor Agents. Inorganic Chemistry 1995, 34 (5), 1015-1021.
  6. Hall, M. D.; Hambley, T. W., Platinum(IV) antitumour compounds: their bioinorganic chemistry. Coordination Chemistry Reviews 2002, 232, 49-67.
  7. Wexselblatt, E.; Gibson, D., What do we know about the reduction of Pt(IV) pro-drugs? Journal of Inorganic Biochemistry 2012, 117 (Supplement C), 220-229.
  8. Yang, J.; Sun, X.; Mao, W.; Sui, M.; Tang, J.; Shen, Y., Conjugate of Pt(IV)-histone deacetylase inhibitor as a prodrug for cancer chemotherapy. Mol Pharm 2012, 9 (10), 2793-800.
  9. Raveendran, R.; Braude, J. P.; Wexselblatt, E.; Novohradsky, V.; Stuchlikova, O.; Brabec, V.; Gandin, V.; Gibson, D., Pt(iv) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action. Chemical Science 2016, 7 (3), 2381-2391.
  10. Harper, B. W. J.; Petruzzella, E.; Sirota, R.; Faccioli, F. F.; Aldrich-Wright, J. R.; Gandin, V.; Gibson, D., Synthesis, characterization and in vitro and in vivo anticancer activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)]. Dalton Transactions 2017, 46 (21), 7005-7019.
  11. Krause-Heuer, A. M.; Grünert, R.; Kühne, S.; Buczkowska, M.; Wheate, N. J.; Le Pevelen, D. D.; Boag, L. R.; Fisher, D. M.; Kasparkova, J.; Malina, J.; Bednarski, P. J.; Brabec, V.; Aldrich-Wright, J. R., Studies of the Mechanism of Action of Platinum(II) Complexes with Potent Cytotoxicity in Human Cancer Cells. J. Med. Chem. 2009, 52 (17), 5474-5484.
  12. Gagnon, V.; St-Germain, M.-E.; Descôteaux, C.; Provencher-Mandeville, J.; Parent, S.; Mandal, S. K.; Asselin, E.; Bérubé, G., Biological evaluation of novel estrogen-platinum(II) hybrid molecules on uterine and ovarian cancers-molecular modeling studies. Bioorganic and Medicinal Chemistry Letters 2004, 14, 5919-5924.
  13. Krause-Heuer, A.; Grant, M. P.; Orkey, N.; Aldrich-Wright, J. R., Drug delivery devices and targeting agents for platinum(II) anticancer complexes. Australian Journal of Chemistry 2008, 61, 675-681.
  14. Bae, Y.; Jang, W. D.; Nishiyama, N.; Fukushima, S.; Kataoka, K., Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery. Mol. BioSyst 2005, 1, 242-250.
  15. Mueller, C.; Schubiger, P. A.; Schibli, R., In vitro and in vivo targeting of different folate receptor-positive cancer cell lines with a novel 99mTc-radiofolate tracer. Eur. J. Nucl. Med. Mol. Imaging 2006, 33, 1162-1170.

NMR simulation using symbolic algebra

Primary Supervisor Contact: Prof. William S. Price w.price@westernsydney.edu.au

Co-Supervisors: Dr Tim Stait-Gardner

Would suit students interested in: Mathematics / MRI / NMR / Physics

Understanding spin-dynamics is of fundamental importance for NMR students. However, in many instances to understand such complicated theory we must resort to computer simulation, which turns boring memorization into exciting practice. Numerical and symbolic algebra simulation programs can be used for the development of new NMR pulse sequences. In this project students will perform NMR simulations based on a full understanding of spin-dynamics to enhance the development of new NMR methods (e.g., water suppression and diffusion measurements). Exact numerical simulations of NMR experiments are often required for the development of new techniques and for the extraction of structural and dynamic information from the spectra. Designing and synthesising molecules that selectively bind to Quadraplex DNA

Platinum complexes that bind and stabilise Quadruplex-DNA forming sequences

Primary Supervisor Contact: Prof. Janice R. Aldrich-Wright, j.aldrich-wright@westernsydney.edu.au

Co-Supervisors:

Would suit students interested in: Synthetic Chemistry

DNA is a remarkably flexible biomolecule that is found in many conformations such as cruciform, intramolecular triplexes, slipped-strand, parallel-stranded and unpaired DNA structures and quadruplex DNA (QDNA), in addition to the well-known B-DNA. Different structural forms have been reported to be essential in several cellular processes including replication, gene expression, growth, recombination and repair.1,2 More than 360,000 different sequences have been identified, through bioinformatics studies, to have the potential to assemble into one, two or four stranded folded QDNA structures from single stranded guanine rich telomeres sequences. The overhanging telomeres sequences (~100-200 nucleotides) protect chromosomal DNA during replication, and perform an essential task in cellular proliferation and cell death. In normal cell replication, some telomeric overhang is lost with each cycle, leading to the successive shortening.  At a critical length cell death is triggered. In many cancer cells, cell death may be avoided by an overexpression of telomerase which extends the telomeres, effectively rendering the cell line immortal. Stabilisation of QDNA inhibits telomerase activity, which prevents the replication of cancer cells.3-11

Based upon our previous results12-16 this project will characterize the stability of various forms of QDNA by circular dichroism (CD) and thermal melting studies as part of an ongoing investigation that is being performed in association with B. Wallace (Birkbeck College, University of London, UK) and R. Jones (School of Biological and Chemical Sciences Queen Mary University of London, UK). The resulting spectra will be uploaded to a module of Dicroweb, to provide access for all QDNA researchers. Several platinum(II) complexes that have been synthesised at Western Sydney University bind to and stabilise QDNA as well as exhibit anticancer activity. This project plans to synthesize symmetrical, asymmetrical and dinuclear structures such as symmetrical [Pt(5,6-dimethyl-1,10-phenanthroline)2 and [Pt(4,7-dimethyl-1,10-phenanthroline)2] to explore their potential as QDNA stabilizers. Resulting platinum(II) complexes will be characterised using NMR, HPLC, MS and UV-Vis. Following characterisation, CD melting experiments will be undertaken.

Key References

  1. Bochman, M. L.; Paeschke, K.; Zakian, V. A., DNA secondary structures: stability and function of G-quadruplex structures. Nat Rev Genet 2012, 13 (11), 770-80.
  2. Balasubramanian, S.; Hurley, L. H.; Neidle, S., Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat Rev Drug Discov 2011, 10 (4), 261-275.
  3. Wu, P.; Ma, D.-L.; Leung, C.-H.; Yan, S.-C.; Zhu, N.; Abagyan, R.; Che, C.-M., Stabilization of G-Quadruplex DNA with Platinum(II) Schiff Base Complexes: Luminescent Probe and Down-Regulation of c-myc Oncogene Expression. Chemistry – A European Journal 2009, 15 (47), 13008-13021.
  4. Cree, S. L.; Kennedy, M. A., Relevance of G-quadruplex structures to pharmacogenetics. Frontiers in Pharmacology 2014, 5, 160.
  5. Ambrus, A.; Chen, D.; Dai, J.; Jones, R. A.; Yang, D., Solution structure of the biologically relevant G-quadruplex element in the human c-MYC promoter. Implications for G-quadruplex stabilization. Biochemistry 2005, 44 (6), 2048-58.
  6. Crnugelj, M.; Hud, N. V.; Plavec, J., The solution structure of d(G(4)T(4)G(3))(2): a bimolecular G-quadruplex with a novel fold. J Mol Biol 2002, 320 (5), 911-24.
  7. Martino, L.; Virno, A.; Pagano, B.; Virgilio, A.; Di Micco, S.; Galeone, A.; Giancola, C.; Bifulco, G.; Mayol, L.; Randazzo, A., Structural and thermodynamic studies of the interaction of distamycin A with the parallel quadruplex structure [d(TGGGGT)]4. J Am Chem Soc 2007, 129 (51), 16048-56.
  8. Chan, H.-L.; Ma, D.-L.; Yang, M.; Che, C.-M., Bis-intercalative Dinuclear Platinum(II) 6-phenyl-2,2'-bipyridine Complexes Exhibit Enhanced DNA Affinity But Similar Cytotoxicity Compared to the Mononuclear Unit. Inorg. Chem. 2003, 8, 761-769.
  9. Chan, H.-L.; Ma, D.; Yang, M.; Che, C.-M., Synthesis and Biological Activity of a platinum(II) 6-Phenyl-2,2'bipyridine Complex and its Dimeric Analogue. ChemBioChem 2003, 4, 62-68.
  10. Wang, J.; Lu, K.; Xuan, S.; Toh, Z.; Zhang, D.; Shao, F., A Pt(II)-Dip complex stabilizes parallel c-myc G-quadruplex. Chem Commun, 2013, 49 (42), 4758-60.
  11. Cao, Q.; Li, Y.; Freisinger, E.; Qin, P. Z.; Sigel, R. K. O.; Mao, Z. W., G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs. Inorg Chem Front 2017, 4 (1), 10-32.
  12. Harper, B. W. J.; van Holst, M.; Aldrich-Wright, J., Platinum(II) Intercalating Complexes Based on 2,2 ':6 ',2 ''-Terpyridine. In Metallointercalators: Synthesis and Techniques to Probe Their Interactions with Biomolecules, 2011; pp 101-128.
  13. Harper, B. W. J.; Petruzzella, E.; Sirota, R.; Faccioli, F. F.; Aldrich-Wright, J. R.; Gandin, V.; Gibson, D., Synthesis, characterization and in vitro and in vivo anticancer activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)]. Dalton Transactions 2017, 46 (21), 7005-7019.
  14. Harper, B. W. J.; Morris, T. T.; Gailer, J.; Aldrich-Wright, J. R., Probing the interaction of bisintercalating (2,2':6',2"-terpyridine)platinum(II) complexes with glutathione and rabbit plasma. Journal of Inorganic Biochemistry 2016, 163, 95-102.
  15. Harper, B. W. J.; Aldrich-Wright, J. R., The synthesis, characterisation and cytotoxicity of bisintercalating (2,2 ':6 ',2 ''-terpyridine)platinum(II) complexes. Dalton Transactions 2015, 44 (1), 87-96.
  16. Ang, D. L.; Harper, B. W. J.; Cubo, L.; Mendoza, O.; Vilar, R.; Aldrich-Wright, J., Quadruplex DNA-Stabilising Dinuclear Platinum(II) Terpyridine Complexes with Flexible Linkers. Chemistry-a European Journal 2016, 22 (7), 2317-2325.

Probes for G-Quadraplex

Primary Supervisor Contact: Prof. Janice R. Aldrich-Wright, j.aldrich-wright@westernsydney.edu.au

Co-Supervisors:

Would suit students interested in: Synthetic Chemistry

Various structural conformations of DNA other than B-DNA, such as cruciform, intramolecular triplexes, slipped-strand, parallel-stranded and unpaired DNA structures and quadruplex DNA (QDNA), exist and have been shown to be vital in several cellular processes including replication, gene expression, growth, recombination and repair. G-quadruplex motifs have been identified1 in key regulatory regions of the human genome, such as promotors, gene bodies, untranslated regions and more importantly as telomeres located at the ends of chromosomal DNA. Telomeres protect chromosomal DNA during replication and repair processes and play an essential role in cellular proliferation and cell death.1 G-quadruplex motifs can fold into various topologies. In normal cell during replication, non-coding telomeres are removed with each replicative cycle, leading to the successive shortening, at a critical length, cell death is triggered. In cancer cells death is avoided by an overexpression of telomerase which repairs the telomeres so that they are not progressively shortened during replication, effectively rendering the cell line immortal. If G-quadruplex sequences are stabilized, telomerase activity is inhibited, preventing the replication of cancer cells.3-4 Platinum complexes that selectively stabilise and bind strongly to QDNA topologies and also exhibit anticancer activity have been the focus of recent research in the laboratory of Aldrich-Wright at Western Sydney University. Based upon our previous results5-8 this project will design, synthesize and characterize effective G-quadruplex stabilisers that incorporate planar aromatic surfaces to increase the stacking interactions9 such as symmetrical [Pt(1,10-phenanthroline)2] and [Pt(tetramethyl-1,10-phenanthroline)2] to exhibit strong G-quadruplex affinity as well as cytotoxicity in human cancer cell lines. Asymmetrical and dinuclear structures are also to be synthetised to explore their potential as QDNA stabilisers. Each resulting metal complex will be characterised using NMR, HPLC, MS and UV-Vis. Following characterisation, mass spectrometry binding assays and cell line trials will be undertaken. By using these techniques, this project aimed to investigate G-quadruplex platinum complex interactions, leading to the contribution towards the development of the next generation of anticancer complexes.

Key References

  1. Bochman, M. L.; Paeschke, K.; Zakian, V. A., DNA secondary structures: stability and function of G-quadruplex structures. Nat Rev Genet 2012, 13 (11), 770-80.
  2. Balasubramanian, S.; Hurley, L. H.; Neidle, S., Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat Rev Drug Discov 2011, 10 (4), 261-275.
  3. Wu, P.; Ma, D.-L.; Leung, C.-H.; Yan, S.-C.; Zhu, N.; Abagyan, R.; Che, C.-M., Stabilization of G-Quadruplex DNA with Platinum(II) Schiff Base Complexes: Luminescent Probe and Down-Regulation of c-myc Oncogene Expression. Chemistry – A European Journal 2009, 15 (47), 13008-13021.
  4. Cree, S. L.; Kennedy, M. A., Relevance of G-quadruplex structures to pharmacogenetics. Frontiers in Pharmacology 2014, 5, 160.
  5. Harper, B. W. J.; van Holst, M.; Aldrich-Wright, J., Platinum(II) Intercalating Complexes Based on 2,2 ':6 ',2 ''-Terpyridine. In Metallointercalators: Synthesis and Techniques to Probe Their Interactions with Biomolecules, 2011; pp 101-128.
  6. Harper, B. W. J.; Morris, T. T.; Gailer, J.; Aldrich-Wright, J. R., Probing the interaction of bisintercalating (2,2':6',2"-terpyridine)platinum(II) complexes with glutathione and rabbit plasma. Journal of Inorganic Biochemistry 2016, 163, 95-102.
  7. Harper, B. W. J.; Petruzzella, E.; Sirota, R.; Faccioli, F. F.; Aldrich-Wright, J. R.; Gandin, V.; Gibson, D., Synthesis, characterization and in vitro and in vivo anticancer activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)]. Dalton Transactions 2017, 46 (21), 7005-7019.
  8. Ang, D. L.; Harper, B. W. J.; Cubo, L.; Mendoza, O.; Vilar, R.; Aldrich-Wright, J., Quadruplex DNA-Stabilising Dinuclear Platinum(II) Terpyridine Complexes with Flexible Linkers. Chemistry-a European Journal 2016, 22 (7), 2317-2325.
  9. Cao, Q.; Li, Y.; Freisinger, E.; Qin, P. Z.; Sigel, R. K. O.; Mao, Z. W., G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs. Inorg Chem Front 2017, 4 (1), 10-32

Proton exchange between metabolites and water in solutions and tissues studied by NMR/MRI

Primary Supervisor Contact: Dr Gang Zheng g.zheng@westernsydney.edu.au

Co-Supervisors: Dr Tim Stait-Gardner, Dr Nirbhay Yadav (Johns Hopkins), Prof. William S Price

Would suit students interested in: Chemistry / Medical Physicss / NMR / MRI

In general chemistry, we’ve learned that acidic protons are constantly hopping between solute molecules and water molecules. The efficiency of this hopping process is affected by many factors and one of these factors, pH, is directly linked to the disease state of biological tissues (e.g., metastasis of cancer), which means we can achieve medical diagnosis by measuring the micro-environmental acidity in diseased tissues. In this project, the student will study the basics of chemical kinetics, nuclear magnetic resonance (NMR), and experimental magnetic resonance imaging (MRI). From this background, the student will then develop novel chemical exchange saturation transfer (CEST) techniques for the study of proton exchange in solutions and tissues, focusing on the observation and quantification of the CEST peaks close to the water signal of diagnostically important metabolites such as myo-inositol and glucose in the NMR spectrum. If the newly developed techniques afford the distinction between metabolite and water signals in the water-proximate region in the experiments on phantom samples, they will be applied in animal experiments in the School of Medicine, Johns Hopkins University.

Key References:

  • Li, Y., H. Chen, J. Xu, N.N. Yadav, K.W.Y. Chan, L. Luo, M.T. McMahon, B. Vogelstein, P.C.M. van Zijl, S. Zhou, and G. Liu. CEST theranostics: label-free MR imaging of anticancer drugs. Oncotarget, 2016. 7:6369-6378.
  • Yang, X., N.N. Yadav, X. Song, S. Ray Banerjee, H. Edelman, I. Minn, P.C.M. van Zijl, M.G. Pomper, and M.T. McMahon. Tuning Phenols with Intra-Molecular Bond Shifted HYdrogens (IM-SHY) as diaCEST MRI Contrast Agents.Chemistry – A European Journal, 2014. 20:15824-15832.

Studying ice nucleation protein NMR with NMR diffusion measurements

Primary Supervisor Contact: Prof. William S. Price, w.price@westernsydney.edu.au

Co-Supervisors: Dr Scott A. Willis, Dr Allan Torres

Would suit students interested in: Biology / Chemistry / NMR

Freeze tolerance is important for life that exists in low temperature environments. Protection strategies include the use of antifreeze proteins to prevent ice crystal growth or the use of ice nucleation proteins (INPs). INPs initiate ice formation earlier so that the organism has a chance to respond to the freezing for thermal protection or could be used as a means of retrieving nutrients from plants. INPs are thought to bind to water molecules in a way that resembles an ice crystal such that further nucleation is promoted but the mechanism is not fully understood. As such a study of translational diffusion and hydration of these proteins in aqueous solutions at various temperatures is pertinent for understanding this and would be of interest for potential applications of these proteins.

Using Dynamic Light Scattering and Diffusion NMR to measure metal complexes binding to Q-DNA

Primary Supervisor Contact: Prof. Janice R. Aldrich-Wright, j.aldrich-wright@westernsydney.edu.au

Co-Supervisors:

Would suit students interested in: Synthetic Chemistry

More than 360,000 different sequences have been identified, through bioinformatics studies, to have the potential to assemble into one, two or four-stranded quadruplex DNA (Q-DNA) structures. Of particular importance are the telomeres, located on the end (termini) of chromosomes. These are repeat TTAGGG sequences (~100-200+ nucleotides) that ensure complete chromosomal replication during the cell cycle, performing an essential task in cellular proliferation and cell death.1 In a normal cell during replication, these non-coding telomeres are successively shortened with each cycle and once a critical length is achieved cell death is triggered. In many cancer cells, this shortening is mitigated by an overexpression of telomerase which extends the telomeres, effectively rendering the cell line immortal. Stabilisation of QDNA inhibits telomerase activity which prevents the replication of cancer cells.2,3 The guanine of the telomere sequences undergoes self-association at physiological conditions, however the exact topological formation is dependent on the number of guanine bases, their arrangement within the sequence and the hydrogen bonding. The structure is also influenced by the solution conditions, including pH, molecular crowding, dehydration and the presence of specific telomere binding proteins. Consequently, Q-DNA can adopt any number of topologies with varying loop configurations such as – parallel, antiparallel or a combination of both. The Importance of Q-DNA research has increased recently simply because of their connection to cancer. Stabilisation of Q-DNA inhibits the action of telomerase and therefore, is a potential target for anticancer treatment. A number of compounds have been designed to stabilise these structures to halt the progression of cancer. Novel platinum complexes such as [Pt(4,7-diphenyl-1,10-phenanthroline)2], and [Pt(3,4,7,8-tetramethyl-1,10-phenanthroline)2], have been shown in cytotoxicity studies to exhibit modest therapeutic potential with IC50 values in comparison with cisplatin, the clinically used anticancer drug. The interactions have also been assessed in silico using molecular modelling and shown to exhibit good affinity. Based upon our previous results this project will investigate the characterization of various forms of QDNA by Dynamic light scattering (DLS) and Diffusion NMR. DLS is a technique that uses Brownian motion theory to measure particle size suspended within a liquid. Brownian motion refers to the random movement of particles due to solvent molecule bombardment surrounding them. Smaller particles, with less inertia are ‘pushed’ by solvent molecules more rapidly than larger particles; as a result, have a faster Brownian motion. Pulsed gradient spin-echo (PGSE) nuclear magnetic resonance (NMR) is a non-invasive method for the measurement of self-diffusion coefficients in the solution state.4 Together these techniques will be used to assess the binding interactions with metal complexes like [Pt(DIP)2]2+ and [Pt(TMP)2]2+ to explore the potential of this technique to assess Q-DNA binding and stabilizing compounds.

Key References

  1. Ambrus, A.; Chen, D.; Dai, J.; Jones, R. A.; Yang, D., Solution structure of the biologically relevant G-quadruplex element in the human c-MYC promoter. Implications for G-quadruplex stabilization. Biochemistry 2005, 44 (6), 2048-58.
  2. Wu, P.; Ma, D.-L.; Leung, C.-H.; Yan, S.-C.; Zhu, N.; Abagyan, R.; Che, C.-M., Stabilization of G-Quadruplex DNA with Platinum(II) Schiff Base Complexes: Luminescent Probe and Down-Regulation of c-myc Oncogene Expression. Chemistry – A European Journal 2009, 15 (47), 13008-13021.
  3. Cree, S. L.; Kennedy, M. A., Relevance of G-quadruplex structures to pharmacogenetics. Frontiers in Pharmacology 2014, 5, 160.
  4. Price, W. S., NMR studies of translational motion. 1 ed.; Cambridge University Press: Cambridge, 2009.