Trevaskis Lab

Dr Natalie Trevaskis

Dr Natalie Trevaskis
Lecturer
Tel: 9903 9708
Email: Natalie.Trevaskis@monash.edu
Linkedin

Biosketch
Natalie Trevaskis is a Lecturer in Drug Delivery, Disposition and Dynamics at the Monash Institute of Pharmaceutical Sciences and Faculty of Pharmacy and Pharmaceutical Sciences at Monash University, Melbourne. She completed her BPharm and PhD studies at Monash University receiving the Gold Medal (2001) and Mollie Holman Doctoral Medal (2006), respectively, as top ranked student. This was followed by industry (Pfizer, Novartis) and NHMRC funded post-doctoral fellowships before commencing as a lecturer in 2014. Natalie's research program focusses on understanding and quantifying drug absorption, disposition and dynamics. A major focus has been in lymphatic drug delivery, disposition and dynamics and more recently, the potential to enhance the treatment of obesity related diseases by targeting drug delivery to the lymphatics and associated immune-metabolic cells. Natalie's program has been funded by NHMRC, Monash University, Multiple Sclerosis Research Australia and the Collier Foundation, and resulted in 32+ peer reviewed papers. Natalie has supervised over 10 research students. So far 2 PhD, 1 masters and 3 honours students have graduated with her supervision. 


Research Areas
Natalie's group is focussed on the design and development of novel drug delivery solutions for the treatment of obesity related diseases. Recent advances have established that obesity induces change in lymphatic and immune-metabolic function, promoting chronic disease such as inflammatory diseases, cardiometabolic diseases and cancer. These diseases reduce life quality and length. Current treatments only modestly improve symptoms and life expectancy. Paradoxically, current treatments cause life-limiting side effects and toxicities. Better treatments are therefore needed. Natalie's team thus aims to design such treatments by i) developing novel delivery strategies to target drugs to sites of action in the lymphatics and immune-metabolic cells, ii) elucidating the mechanisms by which these strategies facilitate drug delivery to the lymphatics and immune-metabolic cells and importantly, iii) establishing whether the delivery strategies provide improved treatment of obesity related diseases.

Lymphatics in obesity related diseases
Obesity induces changes in immune and metabolic function that are increasingly being linked to the development of chronic diseases. The lymphatics form an essential immune-metabolic network that disseminates immune cells and lipids, is surrounded by adipose and is also the primary site to which tumours metastasise. Lymphatic function has thus been directly linked to obesity related diseases such as inflammatory diseases, obesity, atherosclerosis and cancer.

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The lymphatic system
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Lymphatic vessel function is assessed using 2-photon microscopy
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Fat cells exposed to lymph (right) are expanded and contain more lipid than control fat cells (left)

Our lab is studying the role of changes in lymphatic function in the development of obesity induced insulin resistance. We have found that lymphatics are ‘leaky’ in obesity and that increased access of lymph to fat promotes fat cell expansion and changes in fat cell function consistent with the potential to promote insulin resistance. Together with my colleagues Chris Porter and Matthew Watt, I am interested in identifying the mechanisms by which changes in lymph content and/or access to fat cells stimulate changes to fat cell function, and the potential to treat insulin resistance by modulating lymph content or access to fat.


Intestinal lymphatic drug transport
After oral or parenteral administration, most small molecule drugs are absorbed into blood capillaries and transported to the systemic circulation. From here they distribute non-specifically to target tissues. In contrast, dietary lipids are absorbed, assembled into lipoproteins in enterocytes and transported to the systemic circulation via the lymphatics. Lipophilic drugs or prodrugs can also be assembled into lipoproteins and transported via the lymphatics when administered with a lipid source (formulation or food derived) that promotes lipoprotein formation. Drug absorption and transport via the lymph (rather than the blood) provides benefits in targeted delivery to lymphatic tissues and since lymph avoids first pass metabolic events in the liver, increases in bioavailability.

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Our lab is studying the mechanisms by which drugs access the intestinal lymph. Lipophilic drugs associate with lipoproteins in the endoplasmic reticulum and Golgiapparatus and these lipoprotein-drug complexes enter the lymph. Together with Chris Porter and Jamie Simpson, our group is designing lipid prodrugs that integrate into lipoprotein assembly pathways to promote lymph access. With Bernard Flynn we are exploring drug structural modifications to enhance lymphatic access.

Lymphatic access from the systemic circulation

Lymph targeting strategies have traditionally been based on the enhanced permeability of lymph when compared to blood capillaries and have centred on i) interstitial (e.g. subcutaneous or intramuscular) injection of macromolecular therapeutics or delivery systems that are transported via the lymph capillaries that drain the injection site or ii) oral administration of drugs that associate with lipoproteins that are transported via the intestinal lymphatic system. Recently substantial transfer of endogenous lipoproteins and macromolecular therapeutics from the blood circulation to the lymphatics has been described. This brings the opportunity to target and treat diseases in areas of the lymphatic system that cannot be reached via interstitial injection or oral administration, such as in the liver.

Nanoparticles transfer from blood to lymph vessels in the liver
Nanoparticles (green) transfer from blood to lymph vessels in the liver
nanoparticle delivery systems
Our nanoparticle delivery systems

Our lab is studying the mechanisms that direct blood to lymph transfer of lipoproteins and macromolecular delivery systems (e.g.nanoparticles). Together with Angus Johnston, Lisa Kaminskas, David Shackleford and Chris Porter, we are investigating the impact of delivery system properties and disease states on the efficiency and site of lymphatic access. Ultimately we are interested in developing delivery systems to better treat diseases associated with lymphatics at specific sites such as liver diseases and cancer.


Targeted delivery to immune-metabolic cells
After delivery to the lymphatic system, lipoprotein-drug complexes and macromolecular delivery systems funnel through at least one and usually many lymph nodes before emptying into the blood via the major veins in the neck. This enhances access to immune cells within the lymph fluid and lymph node. Additionally, the lymphatics are surrounded by fat tissue providing the opportunity for direct access to fat cells. After emptying into the systemic circulation lymph lipoprotein-drug complexes are taken up into various metabolic cells, such as fat cells, via specific receptors and enzymes.

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Lymphocytes that have taken up a fluorescent drug-lipoprotein complexes
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MS image of lipid prodrug targeted to lymph node via assembly into lymph lipoproteins
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Transport in lymph lipoproteins alters drug and prodrug delivery to metabolic tissues such as fat

Our lab is studying the mechanisms by which drug-lipoprotein complexes facilitate drug delivery to immune-metabolic cells. Drugs that are absorbed via the blood are transported relatively non-specifically to target tissues. In contrast, we have found that transport within lymph lipoproteins facilitates drug and prodrug delivery to lymph and lymph node lymphocytes, and immune-metabolic tissues such as fat, skeletal muscle and liver. Together with my colleagues Chris Porter, Suzanne Caliph and Jamie Simpson I am interested in identifying the biological processes, receptors and enzymes that promote drug/prodrug delivery to immune-metabolic cells and the potential to harness these processes by optimising drug structure and formulation.

Therapeutic advantage of delivery to lymphatics and immune-metabolic cells

Immune-metabolic and lymphatic function influence a far more diverse range of diseases than once thought including cancer and metastases, inflammatory conditions, metabolic disease (obesity, hypertension, atherosclerosis), liver disease, and acute and critical illness. These findings have driven the recognition that targeted delivery to the lymph and immune-metabolic cells has the potential to transform disease treatment.

Our lab is establishing whether delivery strategies that promote access to the lymphatics and immune-metabolic cells provide improved treatment of obesity related diseases. We have found that drug delivery strategies that promote access to the lymph enhance the potency of drugs with lymphocyte associated targets. Together with a number of collaborators we are now studying whether lymph, lymphocyte and adipose targeting strategies enhance the treatment of autoimmune diseases, insulin resistance, atherosclerosis, and acute and critical illness.

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Lipids promote the assembly of drug-lipoprotein (LP) complexes (2) that are exocytosed into the lamina propria (3) and also stimulate lymphocyte recruitment (4). Drug-LP complexes increase drug access to lymphocytes in the lamina propria (5) and lymph (6).
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Co-administration with lipids (white triangle) increases the access and impact of a lipophilic immune-modulator on lymph lymphocyte function relative to control formulations.

Major Reviews

  1. Trevaskis, N.L., Charman, W.N., Porter, C.J.H. Lipid based delivery systems and intestinal lymphatic drug transport: a mechanistic update. Adv. Drug Deliv. Rev. (2008) 60, 702-716.
  2. Trevaskis, N.L., Kaminaskas, L, Porter, C, From sewer to saviour - targeting the lymphatic system to promote drug exposure and activity. Nature Rev Drug Discovery (2015) 14, 781–803
  3. Porter, C.J.H, Trevaskis, N.L., Charman, W.N. Lipids and lipid-based formulations: optimising the oral delivery of lipophilic drugs. Nat. Rev. Drug Discov (2007) 6, 231-248.
  4. Williams, H.D., Trevaskis, N.L., Charman, S.A., Shanker, R.M., Charman, W.N., Pouton, C.W., Porter, C.J.H. Strategies to address the challenge of low drug solubility in discovery and development Pharmacol. Rev. (2013) 65, 315-499.
  5. Williams, H.D., Trevaskis, N.L., Yeap, Y.Y., Anby, M.U., Pouton, C.W., Porter, C.J.H Lipid-based formulations and drug supersaturation: Harnessing the unique benefits of the lipid digestion/absorption pathway. Pharm Res (2013) 30, 2976–2992

Key Publications

  1. Trevaskis, N.L., Hu, L.J., Caliph, S.M., Han, S.F. & Porter, C.J.H. The Mesenteric Lymph Duct Cannulated Rat Model: Application to the Assessment of Intestinal Lymphatic Drug Transport. Journal of Visualized Experiments (2014) In press.
  2. Han, S., Quach, T., Hu, L., Wahab, A., Charman, W.N., Stella, V.J., Trevaskis, N.L., Simpson, J.S., Porter, C.J.H. Targeted delivery of a model immunomodulator to the lymphatic system: Comparison of alkyl ester versus triglyceride mimetic lipid prodrug strategies J Control. Release (2014) 177, 1-10.
  3. Yeap, Y.Y., Trevaskis, N.L., Porter, C.J.H., Lipid Absorption Triggers Drug Supersaturation at the Intestinal Unstirred Water Layer and Promotes Drug Absorption from Mixed Micelles, Pharm Res (2013) 30, 3045-58
  4. Trevaskis, N.L., Caliph, S.M., Nguyen, G., Tso, P., Charman, W.N., Porter, C.J.H. A mouse model to evaluate the impact of species, sex and lipid load on lymphatic drug transport. Pharm. Res. (2013) 30, 3254–3270.
  5. Caliph, S.C., Cao, E., Hu, L., Han, S., Porter, C.J.H., Trevaskis, N.L. The impact of lymphatic transport on the systemic disposition of lipophilic drugs, J Pharm Sci (2013) 102 (7): 2395-408
  6. Caliph, S.C., Trevaskis, N.L., Charman, W.N., Porter, C.J.H. Intravenous Dosing Conditions May Affect Systemic Clearance for Highly Lipophilic Drugs: Implications for Lymphatic Transport and Absolute Bioavailability Studies J Pharm Sci (2012) 101(9), 3540-3546. Printed in a theme issue dedicated to Prof Val Stella.
  7. Trevaskis, N.L., Charman, W.N., Porter, C.J.H. Acute hypertriglyceridemia promotes intestinal lymphatic lipid and drug transport: a positive feedback mechanism in lipid and drug absorption Mol Pharmaceut.(2011) 8, 1132–1139
  8. Trevaskis, N.L., Charman, W.N., Porter, C.J.H. Targeted drug delivery to lymphocytes: a route to site-specific immunomodulation Mol Pharmaceutics (2010) 7, 2297-2309.
  9. Trevaskis, N.L., Shanker, R.M., Charman, W.N., Porter, C.J.H. The mechanism of lymphatic access of two cholesteryl ester transfer protein inhibitors (CP524,515 and CP532,623) and evaluation of their impact on lymph lipoprotein profiles. Pharm. Res. (2010) 27, 1949-1964.
  10. Trevaskis, N.L., Shackleford, D.M., Charman, W.N., Edwards, G.A., Gardin, A., Appel-Dingemanse, S., Kretz, O., Galli, B., Porter, C.J.H. Intestinal lymphatic transport enhances the post prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first pass metabolism. Pharm. Res. (2009) 26, 1486-1495.

Group Members

Major Collaborating Laboratories: Prof Chris Porter, Dr Jamie Simpson, Prof Matthew Watt, Dr Angus Johnston, Dr Lisa Kaminskas, Dr David Shackleford, Dr Suzanne Caliph, Dr Bernard Flynn, Prof Frank Alderuccio, Prof John Windsor, Dr Anthony Phillips

Post Docs: Hannah Chu, Sifei Han, Luojuan Hu

Research Assistants: Preeti Yadav

PhD Students: Enyuan Cao, Gracia, Given Lee, Matthew Crum, Ruby Kochappan