Porter Research Group
Professor Chris Porter
Professor and Director, Monash Institute of Pharmaceutical Sciences
Tel: 9903 9649
Chris Porter’s research is focused in the area of drug absorption and drug delivery. His major interests are in understanding, quantifying and predicting the mechanisms of absorption of drug molecules and drug delivery systems after oral and parenteral delivery. His group has contributed substantially to the drug delivery literature (>220 peer reviewed papers and book chapters; >16,000 citations; h-index 70, Google Scholar). Porter’s group has published widely on the mechanisms of absorption and disposition of small molecular weight drugs and high molecular weight proteins and nanoparticulate carriers such as nanoparticles and dendrimers. His group has a specific interest in using endogenous lipid transport pathways to promote the delivery of poorly water soluble drugs. This includes the use of lipids to enhance oral drug absorption, the use of lipid-mimetic prodrugs to target the lymphatic system and the potential role of intracellular lipid transport systems to promote drug transport to intracellular target sites. Porter’s group has also made significant contributions to understanding the potential for PEGylation of dendritic nanostructures to improve therapeutic utility. His work has led to the filing of >15 patent families and major licencing/assignment deals with Starpharma, PureTech Health and Lonza. Porter has delivered >100 invited presentations including presentations at major meetings including the annual meetings of the American Association of Pharmaceutical Scientists (AAPS) and the Controlled Release Society (CRS), the British Pharmaceutical Conference and the FIP World Congress of Pharmaceutical Science. He is an elected Fellow of the American Association of Pharmaceutical Scientists and the Royal Australian Chemical Institute, sits on the editorial board of Molecular Pharmaceutics, Pharm Res, J Pharm Sci and J Pharm Pharmacol and was an elected member of the Scientific Advisory Board of CRS. He was named as a Clarivate analytics Highly Cited Researcher in 2015, 2016 and 2018 and was awarded the Australasian Pharmaceutical Sciences Association (APSA) Medal in 2017.
My group is focused on the design and development of novel drug delivery systems. We aim to use drug delivery technologies: 1) to overcome limitations to drug absorption resulting from low drug solubility; 2) to target drugs to the lymphatics (a site rich in immune cells and tissues and therefore a site of action for many immunotherapeutics); 3) to better understand the mechanisms by which drugs are trafficked specifically to critical organelles within the cell; and finally 4) to design nanomaterials to better target drug delivery to a range of diseases, including cancer
The first three of these research areas are tied together by a common theme and that is the realization that poorly water soluble drugs share many characteristics with dietary lipids. Unlike most poorly water soluble drugs, lipids are very well absorbed and distributed around the body. This reflects millennia of evolution that have resulted in the development of highly sophisticated transport processes to absorb, distribute and utilize lipids. Much of our work is focused on better understanding these transport processes and harnessing them for drug absorption – in essence ‘piggybacking’ drug absorption and transport onto natural lipid transport pathways.
- Trevaskis, N.L., Kaminskas, L.M., Porter, C.J.H. From sewer to saviour - targeting the lymphatic system to promote drug exposure and activity. Nat. Rev. Drug Discov. (2015), 14, 781-803.
- 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.
- 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.
- Feeney, O.M., Crum, M.F., McEvoy, C.L., Trevaskis, N.L., Williams, H.D., Pouton, C.W., Charman, W.N., Bergström, C.A.S. and Porter, C.J.H. 50 years of oral lipid-based formulations: provenance, progress and future perspectives Adv. Drug Deliv. Rev (2016) 101, 167-194.
- 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.
- Bergström, C.A.S., Charman, W.N., Porter, C.J.H. Computational prediction of formulation strategies for beyond-rule-of-5 compounds. Adv. Drug Deliv. Rev. (2016) 101, 6-21.
- Kaminskas, L.M., Boyd, B.J., Porter, C.J.H. Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties. Nanomedicine (2011) 6, 1063-1084.
- 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.
Using lipid based formulations to enhance absorption
Lipid based formulations are unlike many typical formulations in that they stimulate physiological changes in the GI environment (stimulation of biliary and pancreatic secretions) and these changes change the nature of the formulation. As such this is a highly interactive environment and understanding and predicting how a formulation will respond to these stimuli and what the net effects on drug absorption are, is complex. We are particularly interested in the role of lipid digestion on formulation processing and my colleague Prof. Colin Pouton and I have been heavily involved in the development of in vitro models of lipid digestion to predict drug absorption. In recent years, we have become increasingly interested in the potential benefits that lipid based formulations can provide in continually increasing supersaturation (and therefore absorption) as formulations are digested, processed and the lipids containing within them are absorbed. Most recently, in collaboration with Prof. Peter Scammells, I have become interested in the conversion of drugs to ionic liquids to enhance drug solubility in, and the utility of, lipid based formulations. The IP that we generated in this area was acquired by our long term collaborator Capsugel (now Lonza) and forms the basis of an ongoing research collaboration.
- Suys, E.J.A., Chalmers, D.K., Pouton, C.W., Porter, C.J.H. Polymeric precipitation inhibitors promote fenofibrate supersaturation and enhance drug absorption from a Type IV lipid-based formulation. Mol. Pharmaceut. (2018) 15, 2355-2371.
- Williams, H.D., Ford, L., Lim, S., Han, S., Baumann, J., Sullivan, H., Vodak, D., Igonin, A, Benameur, H., Pouton, C.W., Scammells, P.J., Porter, C.J.H. Transformation of BCS class I and III drugs into ionic liquids and lipophilic salts for enhanced developability using lipid formulations. J Pharm Sci (2018) 107, 203-216.
- McEvoy, C.L., Trevaskis, N.L., Feeney, O.M., Edwards, G.A. Perlman, M.E., Ambler, C.M., Porter, C.J.H. Correlating in vitro solubilisation and supersaturation profiles of the CETP inhibitor CP-532,623 with in vivo exposure for long and medium chain lipid based formulations. Mol. Pharmaceut. (2017) 14, 4525-4538.
- Crum, M.F., Trevaskis, N.L., Pouton, C.W., Porter, C.J.H. Transient supersaturation supports drug absorption from lipid-based formulations when absorptive flux is rapid, but ongoing solubilisation is required when the time required for absorption lengthens. Mol Pharmaceut (2017) 14, 394–405.
- Crum, M.F., Trevaskis, N.L., Williams, H.D., Pouton, C.W., Porter, C.J.H., A new in vitro lipid digestion – in vivo absorption model to evaluate the mechanisms of drug absorption from lipid-based formulations. Pharm Res (2016) 33, 970–982.
- Sahbaz, Y., Williams, H.D., Nguyen, T-H., Saunders, J., Ford, L., Charman, S.A., Scammells, P.J., Porter, C.J.H. Transformation of poorly water-soluble drugs into lipophilic ionic liquids enhances drug exposure from lipid based formulations. Mol Pharmaceut. (2015) 12, 1980-1991.
- Feeney, O., Williams, H. D., Pouton, C.W., Porter, C.J.H., Stealth Lipid Based Formulations: Poly(ethylene glycol) Mediated Digestion Inhibition Improves Oral Bioavailability of a Model Poorly Water Soluble Drug. J. Control. Release. (2014) 192, 219-222.
- Williams, H.D., Sahbaz, Y., Ford, L., Nguyen, T-H., Scammells, P.J., Porter, C.J.H. Ionic liquids provide unique opportunites for oral drug delivery: structure optimisation and in vivo evidence of utility. Chem Comm. (2014) 50, 1688-1690.
- Anby, M.U., Williams, H.D., McIntosh, M.P, Benameur, H., Edwards, G.A., Pouton, C.W., Porter, C.J.H., Lipid digestion as a trigger for supersaturation: evaluation of the impact of supersaturation stabilisation on the in vitro and in vivo performance of self-emulsifying drug delivery systems. Mol. Pharmaceut (2012) 9, 2063-2079.
- Williams, H.D., Sassene, P., Kleberg, K., Bakala-N’Goma, J-C., Caderone, M., Jannin, V., Igonin, A., Partheil, A., Marchaud, D., Jule, E., Vertommen, J., Maio, M., Blundell, R., Benameur, H., Carrière, F., Müllertz, A., Porter, C.J.H., Pouton, C.W.,Towards the establishment of standardized in vitro tests for lipid-based formulations: 1) Initial method parameterisation and comparison of in vitro digestion profiles across a range of representative formulations J. Pharm. Sci. (2012) 101, 3360-3380
Intestinal lymphatic transport
After oral administration, most drugs are absorbed across the GI tract into the portal blood and from there via the liver to the systemic (general) circulation. Dietary lipids, however, are absorbed, assembled into lipoproteins in the enterocyte and transported back to the systemic circulation via the lymphatics. Importantly the lymphatic system funnels lipoproteins through at least one and usually many lymph nodes before emptying into the blood via the major veins in the neck. Drug absorption and transport via the lymph (rather than the blood) therefore provides benefits in targeted delivery to lymphatic tissues and, since lymph avoids first pass metabolic events in the liver, increases in bioavailability. Together with my colleague Natalie Trevaskis I have a particular interest in better understanding how drugs access the lymph, and how we might be able to promote that by the design and synthesis of lymph-targeted prodrugs. Out initial studies have explored the potential for lymph directed prodrugs to improve oral bioavailability and the activity of immunosuppressants targeted to the lymphocytes within the lymphatics. Ongoing studies are focused on the possible benefits in modulating immune-metabolic disease. IP generated in this area was licensed to PureTech Health and forms the basis of an ongoing collaboration to develop the technology further. A major collaboration between PureTech and Boehringer Ingelheim was recently announced to apply the prodrug platform in the area of immune-oncology.
- Cao, E., Lindgren, A., Martinsson, S., Hu, L., Lindfors, L., Sigfridsson, K., Skantze, U., Michaëlsson, E., Trevaskis, N.L., Porter, C.J.H. Promoting intestinal lymphatic transport targets a liver-X receptor (LXR) agonist (WAY-252,623) to lymphocytes and enhances immunomodulation. J Control. Rel. (2019) 296, 29-39.
- Han, S., Hu, L., Gracia, Quach, T., Simpson, J.S., Edwards, G.A., Trevaskis, N.L., Porter, C.J.H. Lymphatic transport and lymphocyte targeting of a triglyceride mimetic prodrug is enhanced in a large animal model: Studies in greyhound dogs. Mol Pharmaceut, (2016) 13, 3351-3361.
- Hu, L., Quach, T., Han, S., Lim, S.F., Senyschyn, D., Trevaskis, N.L., Simpson, J.S., Porter, C.J.H. Self immolative glyceride mimetic prodrugs promote lymphatic transport, avoid first pass metabolism and enhance bioavailability. Angew. Chem. Ind. Ed. (2016) 55, 13700-13705.
- 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.
- 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.
- 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.
- 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.
- White, K.L., Nguyen, G., Charman, W.N., Edward, G.A., Faassen, W.A., Porter, C.J.H. Lymphatic transport of methylnortestosterone undecanoate (MU) and the bioavailability of methylnortestosterone are highly sensitive to the mass of co-administered lipid following oral administration of MU. J. Pharmacol. Exp. Therap. (2009) 331, 700-709.
Lipid transport pathways as intracellular targeting routes
The physicochemical properties of lipids and lipophilic drugs are somewhat similar – both have very low water solubility and in general prefer lipidic environments to aqueous environments. Myriad lipid transport pathways have evolved within the cell to allow highly specific patterns of distribution of different lipids to different organelles – membranes, endosomes, the nucleus etc. In light of this a recent focus of the lab has been to understand whether we can highjack these intracellular transport pathways to promote drug targeting to intracellular drug targets. Our initial interests have been in harnessing lipid binding proteins to promote transport to nuclear receptors and in forming lipid conjugated drugs that bind strongly to membranes and concentrate within endosomes. In these areas we have strong collaborations with structural (Prof. Martin Scanlon) and cell (Prof. Nigel Bunnett) biologists to allow an integrated picture of the relationship between structure, location and function as drugs traffic through the cell.
- Jensen, D.D., Lieu, T.M., Halls, M.L., Veldhuis, N.A., Imlach, W.L., Mai, Q.N., Poole, D.P., Quach, T., Aurelio, L., Conner, J., Klein Herenbrink, C., Barlow, N., Simpson, J.S., Scanlon, M.J., Graham, B., McCluskey, A., Robinson, P.J., Escriou, V., Nassini, R., Materazzi, S., Geppetti, P., Christie, M.J., Porter, C.J.H., Canals, M., Bunnett, N.W. Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. Sci Trans Med (2017) 9, eaal3447.
- To, E.E., Vlahos, R., Luong, R., Halls, M.L., Reading, P., King, P., Chan, C., Drummond, G.R., Sobey, C.G., Broughton, B.R.S., Starkey, M., van der Sluis, R., Lewin, S.R., Bozinovski, S., Quach, T., Porter, C.J.H., Brooks, D.A., O’Leary, J., Selemidis, S. Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy. Nat. Commun. (2017) 8, 69.
- Yarwood, R.E., Imlach, W.L., Lieu, T., Veldhuis, N.A., Jensen, D.D., Klein Herenbrink, C., Aurelio, L., Cai, Z., Christie, M.J., Poole, D.P., Porter, C.J.H., McLean, P., Hicks, G.A., Geppetti, P., Halls, M.L., Canals, M., Bunnett, N.W. Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission Proc. Natl. Acad. Sci. (USA) (2017) 114, 12309-12314.
- Hughes, M.L.R., Liu, B., Halls, M.L., Wagstaff, K.M., Patil, R., Velkov, T., Jans, D.A. Bunnett, N.W., Scanlon, M.J., Porter, C.J.H. Fatty Acid Binding Proteins 1 and 2 Differentially Modulate the Activation of Peroxisome Proliferator-Activated Receptor α in a Ligand-Selective Manner. J. Biol. Chem. (2015) 290, 13895-13906.
- Patil, R., Laguerre, A., Wielens, J., Headey, S., Williams, M., Hughes, M., Mohanty, B., Porter, C.J.H., Scanlon, M.J. Characterization of a second drug-binding site in human intestinal fatty acid binding protein. ACS Chem. Biol. (2014) 9, 2526-2534.
- Trevaskis, N.L., Nguyen, G., Scanlon, M.J., Porter, C.J.H. Fatty acid binding proteins: potential chaperones of cytosolic drug transport in the enterocyte? Pharm Res. (2011) 63, 890-900.
- Chuang, S., Velkov, T; Horne, J., Wielens, J., Chalmers, D., Porter, C.J.H, Scanlon, M.J., Probing the Fibrate Binding Specificity of Rat Liver Fatty Acid Binding Protein. J. Med. Chem. (2009) 52, 5344–5355.
- Chuang, S., Horne, J., Velkov, T., Porter, C.J.H., Scanlon, M.J. Characterisation of the drug binding specificity of rat L-FABP. J Med Chem (2008) 51, 3755-3764.
- Velkov, T., Horne, J., Laguerre, A., Jones, E., Scanlon, M.J., Porter, C.J.H. Examination of the role of fatty acid binding protein in drug absorption using a parallel artificially membrane permeability assay. Chem Biol (2007) 14, 453-465.
- Velkov, T., Chuang, S., Wielens, J., Sakellaris, H., Charman, W.N., Porter, C.J.H., Scanlon, M.J. The interaction of lipophilic drugs with intestinal fatty acid binding protein. J Biol Chem. (2005) 280, 17769-17776.
Nanomedicine approaches to targeted drug delivery
Nanomaterials stand poised to revolutionise drug delivery. Our focus in this fascinating new field has been to better understand the relationship between nanomaterial structure and their in vivo disposition and activity. The majority of my work in this area had been conducted in collaboration with Dr Lisa Kaminskas (now at UQ) and Prof Ben Boyd here at MIPS and with the Melbourne based biotech company Starpharma (http://www.starpharma.com/) This work has sought to explore PEGylated poly-lysine dendrimers as an improved drug delivery system after intravenous, subcutaneous and pulmonary delivery. The first dendrimer based drug candidate to come out of this collaboration is currently in Phase 2 clinical trial. Our group is also a key part of the activities of the ARC Centre of Excellence in Bio-Nano Science and Technology that is headquartered at MIPS and we now collaborate with scientists across the country to better understand how improvements in nanomaterial design can drive benefits in drug delivery.
- Yong, K., Yuen, D., Chen, M.Z., Porter, C.J.H., Johnston, A.P.R. Pointing in the right direction: Controlling the orientation of proteins on nanoparticles improves targeting efficiency. Nano Lett. (2019) 19, 1827-1831.
- Ryan, G.M., McLeod, V.M., Mehta, D., Kelly, B.D., Stanislawski, P.C., Owen, D.J., Kaminskas, L.M., Porter, C.J.H. Lymphatic transport and lymph node targeting of methotrexate-conjugated PEGylated dendrimers is enhanced by reducing the length of the drug linker or masking interactions with the injection site. Nanomed-Nanotechnol. (2017) 13, 2485-2494.
- Song, D., Cui, J., Sun, H., Nguyen, T.H., Alcantara, S., De Rose, R., Kent, S.J., Porter, C.J.H., Caruso, F., Templated polymer replica nanoparticles to facilitate assessment of material-dependent pharmacokinetics and biodistribution. ACS Appl Mater Inter (2017) 9, 33683-33694.
- Müllner, M., Mehtha, D., Nowell, C.J., Porter, C.J.H. Passive tumour targeting and extravasation of cylindrical polymer brushes in mouse xenografts. Chem. Commun. (2016) 52, 9121-9124.
- Müllner, M., Dodds, S.J., Nguyen, T-H., Senyschyn, D., Porter, C.J.H., Boyd, B.J., Caruso, F. Size and Rigidity of Cylindrical Polymer Brushes Dictates Long Circulating Properties in vivo. ACS Nano (2015) 9, 1294-1304.
- Kaminskas, L.M., McLeod, V.M., Ascher, D.B., Ryan, G.M., Jones, S., Haynes, J., Trevaskis, N.L., Chan, L.J., Sloan, E.K., Finnin, B., Williamson, M., Velkov, T., Williams, E.D., Owen, D.J., Porter, C.J.H. Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumour-burdened lymph nodes after intravenous and subcutaneous administration in rats. Mol. Pharmaceut (2015) 12, 432-443.
- Ryan, G.M., Kaminskas, L.M., Bulitta, J.B., McIntosh, M.P., Owen, D.J., Porter, C.J.H. PEGylated polylysine dendrimers increase lymphatic exposure to doxorubicin when compared to PEGylated liposomal and solution formulations of doxorubicin. J. Control. Release (2013) 172, 128-136.
- Kaminskas, L.M., McLeod, V.M., Ryan, G.M., Haynes, J. Kelly, B.D., Williamson, M., Owen, D.J., Porter, C.J.H. Pulmonary administration of a doxorubicin-conjugated dendrimer enhances exposure of lung metastases to drug and improves cancer therapy. J Control. Release (2014) 183, 18-26.
- Kaminskas, L.M., Ascher, D.B., McLeod, V.M., Herold, M.J., Le, C.P., Sloan, E.K., Porter, C.J.H., PEGylation of interferon α2 improves lymphatic exposure after subcutaneous and intravenous administration and improves antitumour efficacy against lymphatic breast cancer metastases. J. Control. Release. (2013) 168, 200-208.
- Kaminskas, L.M., McLeod, V.M., Kelly, B.D., Sberna, G., Boyd, B.J., Williamson, M., Owen, D.J., Porter, C.J.H. A comparison of changes to doxorubicin pharmacokinetics, antitumour activity and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems. Nanomed-Nanotechnol. (2012) 8, 103-111.
- Kaminskas, L.M., Kelly, B.D., McLeod, V.M., Sberna, G., Owen, D.J., Boyd, B.J., Porter, C.J.H., Characterisation and tumour targeting of PEGylated polylysine dendrimers bearing doxorubicin via a pH labile linker J. Control. Release (2011) 152, 241-248.
Major Collaborating Laboratories: Professor Colin Pouton, Professor Nigel Bunnett, Professor Tom Davis, Professor Ben Boyd, Professor Martin Scanlon, Professor Peter Scammells, Dr Natalie Trevaskis, Dr Lisa Kaminskas, Dr Michelle Halls, Dr Meri Canals, Dr Angus Johnston.
Major Industrial Collaborators: Capsugel/Lonza (Strasbourg, France; Bend, Oregon), PureTech Health (Boston, USA), Starpharma (Melbourne, Aust), Halozyme (San Diego, CA), Servier (Paris, France).
Post Docs: Sifei Han, Tim Quach, Orlagh Feeney, Luojuan Hu, Fern Lim, Leigh Ford, Olga Ilyichova, Garima Sharma, Nathania Leong, Tri Nguyen, Katie Ardipradja, Stepjhanie Rietwyk, Indu Chandrashekaran, Leo Noi, Daniel Yuen
Research Assistants: Bonan Liu, Danielle Senyschyn
PhD Students: Enyuan Cao, Anthony Lai, Gordon Lee, Ruby Kochappan, Given Lee, Gracia, Erin Tay, Ian Styles, Estelle Suys, Quynh Mai, Xiaotong Zhou, Daniel Brundel
Current Major Funding
Science and Industry Endowment Fund (SIEF): Protein engineering approaches to next generation targeting agents (2017-2019)
NHMRC Development Grant (APP1117470): A safe orally administered agent for dengue (2017-2020)
NHMRC Project Grant (APP1124161): Anti-metastasis therapy via nanoparticle mediated drug delivery (2017-2020)
NHMRC Project Grant (APP1122506): Targeting endosomal NOX2 oxidase in viral disease (2017-2019)
NHMRC Project Grant (APP11000360: Drug targeting to sites of lymph-adipose interaction to transform the treatment of disease (2016-2018)
ARC Discovery Grant (DP150102587): Promoting tissue specific patterns of nuclear targeting and nuclear receptor activation (2015-2019)
ARC Centre of Excellence (CE140100036): Convergent Bio-Nano Science and Technology (2014-2020)
NHMRC Project Grant (1083054): The Importance of Receptor Trafficking for Signalling of Pain and Inflammation (2015-2019)
ARC Linkage Grant (LP140100377): Perturbation of the extracellular architecture to promote the absorption and lymphatic transport of biological macromolecules (2014-2017)